Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel

Chemotherapy‐induced peripheral neuropathy (CIPN) is a dose‐limiting adverse event associated with treatment with paclitaxel and other chemotherapeutic agents. The prevention and treatment of CIPN are limited by a lack of understanding of the molecular mechanisms underlying this toxicity. In the current study, a human induced pluripotent stem cell–derived sensory neuron (iPSC‐SN) model was developed for the study of chemotherapy‐induced neurotoxicity. The iPSC‐SNs express proteins characteristic of nociceptor, mechanoreceptor, and proprioceptor sensory neurons and show Ca²⁺ influx in response to capsaicin, α,β‐meATP, and glutamate. The iPSC‐SNs are relatively resistant to the cytotoxic effects of paclitaxel, with half‐maximal inhibitory concentration (IC₅₀) values of 38.1 µM (95% confidence interval (CI) 22.9–70.9 µM) for 48‐hour exposure and 9.3 µM (95% CI 5.7–16.5 µM) for 72‐hour treatment. Paclitaxel causes dose‐dependent and time‐dependent changes in neurite network complexity detected by βIII‐tubulin staining and high content imaging. The IC₅₀ for paclitaxel reduction of neurite area was 1.4 µM (95% CI 0.3–16.9 µM) for 48‐hour exposure and 0.6 µM (95% CI 0.09–9.9 µM) for 72‐hour exposure. Decreased mitochondrial membrane potential, slower movement of mitochondria down the neurites, and changes in glutamate‐induced neuronal excitability were also observed with paclitaxel exposure. The iPSC‐SNs were also sensitive to docetaxel, vincristine, and bortezomib. Collectively, these data support the use of iPSC‐SNs for detailed mechanistic investigations of genes and pathways implicated in chemotherapy‐induced neurotoxicity and the identification of novel therapeutic approaches for its prevention and treatment.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Sensory peripheral neuropathy is a common and dose‐limiting adverse event during chemotherapy. The lack of a molecular understanding of this toxicity limits options for its prevention and treatment.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ The current study tested whether sensory neurons differentiated from human induced pluripotent stem cells (iPSC‐SNs) can be used to investigate chemotherapy‐induced neurotoxicity, using paclitaxel as a model neurotoxic chemotherapeutic.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ The iPSC‐SNs are a robust and reproducible model of paclitaxel‐induced neurotoxicity. Treatment of iPSC‐SNs with paclitaxel affects neurite networks, neuron excitability, and mitochondrial function.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ This novel stem cell model of chemotherapy‐induced neurotoxicity will be valuable for identifying genes and pathways critical for this toxicity and could be a useful platform for testing therapeutic approaches for treatment.

Chemotherapy‐induced peripheral neuropathy (CIPN) is a dose‐limiting toxicity associated with a number of drugs used for the treatment of solid tumors and hematological cancers. ¹ , ² , ³ Drugs with diverse mechanisms of action, including microtubule disruptors, proteasome inhibitors, and DNA‐crosslinking agents, all cause significant peripheral neuropathy. CIPN typically presents as burning, tingling, or numbness in the hands and feet that occurs in a glove and stocking distribution. ² , ⁴ In addition to negatively affecting a patient’s quality of life, dose reductions, treatment delays, and discontinuation can impact the therapeutic effectiveness of these drugs. ² Despite years of research, there are no effective therapies to prevent and/or treat CIPN, highlighting the need to define the molecular basis of this toxicity to support the development of novel strategies for treatment.Most mechanistic studies of CIPN have used behavioral testing in rodent models or cell‐based studies using primary rodent dorsal root ganglion (DRG) neurons. Common mechanisms associated with the development of CIPN include axon degeneration, altered Ca²⁺ homeostasis, mitochondrial dysfunction, changes in neuronal excitability, and neuroinflammation, although the relative contribution of these mechanisms varies for individual drugs. ⁵ , ⁶ , ⁷ For example, the microtubule stabilizing effects of paclitaxel inhibit anterograde and retrograde transport of synaptic vesicles down the microtubules, resulting in axon degeneration and membrane remodeling. This phenomenon is thought to be a major contributor to paclitaxel‐induced peripheral neuropathy. ⁸ In contrast, the ability of DNA alkylators, like cisplatin and oxaliplatin, to form adducts with mitochondrial DNA and increase reactive oxygen species contributes significantly to their peripheral neuropathy. ⁵ Although these studies in preclinical models and primary cultures of rodent DRG neurons have enhanced our knowledge of potential mechanisms for CIPN, attempts to translate these findings into humans have been largely unsuccessful. ³ In recent years, human induced pluripotent stem cell (iPSC)‐derived neurons have been used for the study of CIPN. Commercially available iPSC‐derived neurons (e.g., iCell neurons and Peri.4U neurons) have been evaluated as a model of neurotoxicity, ⁹ used to screen for neurotoxic compounds, ¹⁰ , ¹¹ , ¹² , ¹³ and utilized for functional validation of genes identified in human genomewide association studies of CIPN. ⁹ , ¹⁴ , ¹⁵ , ¹⁶ The use of human iPSC‐derived neurons affords an advantage over rodent DRG neurons in their human origin and the potential to differentiate into specific peripheral sensory neuron populations. The iCell neurons are a mixture of postmitotic GABAergic and glutamatergic cortical neurons that are more characteristic of relatively immature forebrain neurons than the sensory neurons found in the DRG. ¹⁷ , ¹⁸ Peri.4U neurons are more peripheral‐like, expressing βIII‐tubulin, peripherin, MAP2, and vGLUT2, but have been minimally characterized with respect to functional properties. ¹⁰ , ¹⁹ Additionally, neurons derived from human fibroblasts, blood, and embryonic stem cells that express more canonical nociceptive markers, like ISL1, BRN3A, P2RX3, the NTRK receptors, and NF200, ²⁰ , ²¹ , ²² , ²³ have also been used to study chemotherapy toxicity. Although these human derived cells resemble the DRG sensory neurons that are targeted by chemotherapeutics, there is significant interindividual variation across donor samples that limits their routine use for mechanistic studies and confounds the evaluation of functional consequences of genetic variation associated with human CIPN. ²⁴ Despite advances made in recent years in the development of human cell‐based models for the study of CIPN, there remains a need for a robust, widely available, and reproducible model for detailed mechanistic studies of this dose‐limiting toxicity. The goal of the studies described below was to develop an iPSC‐derived sensory neuron (iPSC‐SN) model for the study of chemotherapy‐induced neurotoxicity. Paclitaxel was used as a model neurotoxic chemotherapeutic to evaluate morphological, mitochondrial, and functional changes associated with exposure of iPSC‐SNs to neurotoxic compounds.     

Clinical Evaluation of an Investigational 5 mL Wearable Injector in Healthy Human Subjects

An investigational wearable injector (WI), the BD Libertas Wearable Injector (BD Libertas is a trademark of Becton, Dickinson and Company), was evaluated in an early feasibility clinical study for functional performance, tissue effects, subject tolerability, and acceptability of 5 mL, non‐Newtonian ~ 8 cP subcutaneous placebo injections in 52 healthy adult subjects of 2 age groups (18–64 years and ≥ 65 years). Randomized WI subcutaneous injections (n = 208, 4/subject) were delivered to the right and left abdomen and thigh of each subject, 50% (1 thigh and 1 abdomen) with a defined movement sequence during injection. Injector functional performance was documented. Deposition was qualified and quantified with ultrasound. Tissue effects and tolerability (pain) were monitored through 24 hours with corresponding acceptability questionnaires administered through 72 hours. WI (n = 205) automatically inserted the needle, delivered 5 mL ± 5% in 5.42 minutes (SD 0.74) and retracted. Depots were entirely (93.2%) or predominantly (5.4%) localized within the target subcutaneous tissue. Slight to moderate wheals (63.9%) and erythema (75.1%) were observed with ≥ 50% resolution within 30–60 minutes. Subject pain (100 mm Visual Analog Scale) peaked mid‐injection (mean 9.1 mm, SD 13.4) and rapidly resolved within 30 minutes (mean 0.4 mm, SD 2.6). Subjects’ peak pain (≥ 90.2%), injection site appearance (≥ 92.2%) and injector wear, size, and removal (≥ 92.1%) were acceptable (Likert responses) with 100% likely to use the injector if prescribed. Injection site preference was divided between none (46%), abdomen (25%), or thigh (26.9%). The investigational WI successfully delivered 5 mL viscous subcutaneous injections. Tissue effects and pain were transient, well‐tolerated and acceptable. Neither injection site, movement or subject age affected injector functional performance or subject pain and acceptability.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Transitioning chronic disease therapies from intravenous infusion to large volume subcutaneous injection requires reliable and accurate delivery devices that may enable intuitive self or care‐giver administration. Limited options are commercially available.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ An investigational wearable injector’s functionality and tolerability for 5 mL, ~ 8 cP subcutaneous placebo injections to the thigh and abdomen with and without movement in healthy adults of 2 age groups (18–64 years and ≥ 65 years) is described. Depot location, corresponding local tissue effects, and acceptability are documented.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ The investigational injector performed as designed, consistently delivering 5 mL ± 5% to the target subcutaneous tissue in ~ 5.5 minutes with transient, well‐tolerated tissue effects and pain. Neither injection site, movement or subject age affected injector functional performance or subject pain and acceptability.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ The investigational injector demonstrated equivalent functional performance with broad acceptability across subject genders, body mass index categories, and age range with and without movement. Results indicate promising potential of device design and delivery boundaries.

Chronic disease biological therapies are transitioning from traditional intravenous to subcutaneous administration. Adapting intravenous therapies to subcutaneous administration creates delivery challenges, such as larger than traditional volumes and viscosities. ¹ , ² , ³ , ⁴ , ⁵ , ⁶ Intuitive and reliable subcutaneous injection system design will help navigate the complexity of these new delivery challenges while ensuring patient ease of wear and use. Effective subcutaneous injection system design requires a strong understanding of the biomechanical and physiological impact to subcutaneous tissue of delivery at increased volumes and viscosities with corresponding subject tolerability and acceptability. ¹ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ Subcutaneous administration conveys many benefits, such as reduced cost and treatment time and increased patient autonomy, convenience, and tolerance/acceptance. ³ , ²¹ Multiple comparative studies report that both patients and health care providers (HCPs) prefer subcutaneous to intravenous administration, citing improved clinical management, efficiency, and convenience with decreased pain and adverse systemic effects. ¹² , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ Historically, literature has identified multiple thresholds for the subcutaneous bolus limit between 1.5 and 3 mL due to subject pain and tissue feasibility. ¹ , ² , ³ , ⁷ , ¹⁵ , ²⁶ Observation that injection volumes > 2 mL may create site wheals (surface tissue displacement) or induration (hardening of the soft tissue) likely contributed to the anticipated low tolerability of these injections despite the absence of relevant clinical evidence linking wheal formation or induration to pain. ² Multiple studies using pump‐driven injection systems as surrogates for functional subcutaneous injection devices document the feasibility and tolerability of 3 to 20 mL single subcutaneous bolus injections in human clinical subjects. ¹ , ¹⁰ , ¹² , ²⁷ , ²⁸ Subcutaneous administration is both feasible and convenient with the introduction of combination products, such as wearable or on‐body injectors, autoinjectors, and prefilled syringes that use fixed dosing to reduce dosing errors and enable patient choice in injection provider, device type, and setting. ² , ¹² Wearable injectors (WIs) complement and may exceed the volume and viscosity capacities currently available in prefilled syringes or autoinjectors; however, there are currently limited commercial on‐body or WI options available. ³ , ¹⁰ , ²⁹ The current study is a first‐in‐human clinical assessment of an investigational WI for functional performance and corresponding tissue effects, depot location, subject tolerability, and acceptability for 5 mL, ~ 8 cP injections of a viscous non‐Newtonian placebo, hyaluronic acid (HA) diluted in saline. The study included 52 healthy adult subjects of both genders and 2 age groups (18–64 years and ≥ 65 years). Each subject received four injections (2 abdominal and 2 thigh) with and without movement for each location. WI functional performance (injection duration, delivered volume, adherence, and status indicator) was documented from application through removal. Depot location was qualified and quantified via ultrasound. Site tissue effects (wheal and erythema) and subject pain tolerance (100 mm Visual Analog Scale, VAS) were monitored through 24 hours with corresponding acceptability documented via questionnaires through 72 hours postinjection.     

Dose‐Dependent Acute Effects of Everolimus Administration on Immunological,Neuroendocrine and Psychological Parameters in Healthy Men

The rapamycin analogue everolimus (EVR) is a potent inhibitor of the mammalian target of rapamycin (mTOR) and clinically used to prevent allograft rejections as well as tumor growth. The pharmacokinetic and immunosuppressive efficacy of EVR have been extensively reported in patient populations and in vitro studies. However, dose‐dependent ex vivo effects upon acute EVR administration in healthy volunteers are rare. Moreover, immunosuppressive drugs are associated with neuroendocrine changes and psychological disturbances. It is largely unknown so far whether and to what extend EVR affects neuroendocrine functions, mood, and anxiety in healthy individuals. Thus, in the present study, we analyzed the effects of three different clinically applied EVR doses (1.5, 2.25, and 3 mg) orally administered 4 times in a 12‐hour cycle to healthy male volunteers on immunological, neuroendocrine, and psychological parameters. We observed that oral intake of medium (2.25 mg) and high doses (3 mg) of EVR efficiently suppressed T cell proliferation as well as IL‐10 cytokine production in ex vivo mitogen‐stimulated peripheral blood mononuclear cell. Further, acute low (1.5 mg) and medium (2.25 mg) EVR administration increased state anxiety levels accompanied by significantly elevated noradrenaline (NA) concentrations. In contrast, high‐dose EVR significantly reduced plasma and saliva cortisol as well as NA levels and perceived state anxiety. Hence, these data confirm the acute immunosuppressive effects of the mTOR inhibitor EVR and provide evidence for EVR‐induced alterations in neuroendocrine parameters and behavior under physiological conditions in healthy volunteers.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Everolimus (EVR) is a potent inhibitor of mTOR and clinically used to prevent organ rejection and to fight tumor growth. EVR is associated with neurobehavioral and psychological changes in patient studies. However, the effects of EVR under normal physiological conditions are unknown.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ What is the impact of clinically employed doses of EVR on immunological, psychological and neuroendocrine parameters in healthy male individuals?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Our data demonstrate that oral intake of medium and high doses of EVR suppressed T cell proliferation as well as IL‐10 cytokine production in ex vivo mitogen‐stimulated PBMCs. Acute low and medium EVR administration increased state anxiety and noradrenaline concentrations. In contrast, high dose EVR reduced cortisol levels but did not affect state anxiety levels.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ These findings demonstrate a dose dependent impact of EVR on state anxiety and neuroendocrine functions under normal physiological conditons in healthy individuals providing important information for monitoring drug efficacy and unwanted drug side effect for future clinical studies employing immunopharmacotherapy with EVR.

Everolimus (EVR) is a macrolide rapamycin analogue initially developed as an immunosuppressive drug with improved pharmacokinetic properties, including increased solubility, bioavailability, and reduced half‐life in comparison to other rapalogues. ¹ , ² EVR efficiently inhibits the mammalian target of rapamycin (mTOR), a serine/threonine protein kinase and substrate of the PI3K/Akt signaling pathway, crucial for the regulation of cellular homeostasis, including cell growth, proliferation, protein synthesis, cellular stress, and survival. ³ Further, mTOR has been shown to play an essential role in innate and adaptive immune responses either by regulating T cell and B cell proliferation and differentiation as well as inflammatory cytokine and antibody production. ² , ⁴ So far, EVR is the only clinically used mTOR inhibitor approved by the US Food and Drug Administration (FDA) for the oral administration and treatment of malignancies, including breast carcinoma, gastrointestinal tract‐derived neuroendocrine tumors, renal cell carcinoma, and to prevent allograft rejection after heart, kidney, and liver transplantations. ¹ , ² , ⁵ Pharmacokinetic studies with transplant recipients obtaining EVR either with 0.75 mg/dose or 1.5 mg/dose twice a day combined with cyclosporin revealed maximal blood concentration of 11.1 ± 4.6 µg/L and 20.3 ± 8.0 µg/L, respectively, after 1 to 2 hours. ⁶ , ⁷ The elimination half‐life amounts for 18–32 hours and steady‐state is achieved between 4 and 7 days. ⁶ , ⁷ However, in patient studies, EVR intake is frequently accompanied with other immunosuppressive drugs like cyclosporin affecting the pharmacokinetic profile of EVR. ² Pharmacokinetics derived from healthy probands receiving a single 2 mg and 4 mg EVR dose revealed maximal EVR blood concentrations of 17.9 ± 5.9 µg/L and 44.2 ± 13.3 µ/L, respectively, reached after 0.5 to 1 hour with an elimination half‐life of 32 hours ⁸ , ⁹ and that single doses up to 5 mg are well‐tolerated. ¹⁰ Experimental and clinical studies in animal models and patients showed the potent immunosuppressive efficacy of the rapamycin analogue EVR in vitro mediated by blocking lymphocyte proliferation and in vivo by preventing rejections of transplanted organs. ¹¹ , ¹² , ¹³ , ¹⁴ Further, impaired renal function exerted by other medication regimens solely using calcineurin inhibitors in patients improved after acute and chronic treatment with EVR. ¹⁵ , ¹⁶ However, in patient studies, it is difficult to discriminate whether the examined effects solely were induced by EVR because the patients usually obtain a combination therapy consisting of more than one immunosuppressive drug. ¹¹ , ¹⁷ , ¹⁸ Accumulating clinical evidence document that patients receiving immunosuppressive medication, including calcineurin inhibitors like tacrolimus or cyclosporin A, frequently develop affective and cognitive dysfunctions, such as depression or anxiety, and exhibit neurotoxic side effects, including tremor and peripheral neuropathy potentially manifesting in psychoses and seizures. ¹⁹ , ²⁰ , ²¹ , ²² Although a growing body of studies in experimental animal models and clinical trials documented neurobehavioral effects exerted by mTOR inhibitors, the observed findings are controversial. EVR treatment improves neuropsychological deficits and autism in patients with tuberous sclerosis complex ²³ and has beneficial effects on memory and psychiatric symptoms in heart transplant recipients. ¹⁹ However mTOR inhibition also has been linked to depressive and anxiety‐like behavior in rodents and the induction of euphoria followed by melancholy, mimicking biopolar disorder in patients with breast cancer. ²⁴ , ²⁵ , ²⁶ , ²⁷ These observations indicate that mTOR inhibition is associated with neurobehavioral and psychiatric symptoms but the impact of comorbidities on the action of EVR is inconclusive since the findings have been acquired from patient studies. Hence, so far, no data exist documenting whether and to what extent clinically used doses of the mTOR inhibitor EVR affect cellular immunosuppressive responses, central functions on behavioral, neuroendocrine and psychological levels, and, thus, may contribute to central side effects, including anxiety in healthy individuals. Against this background, the present study determined systemic blood levels of EVR after an acute, four‐time oral administration of three different, pharmacological relevant doses of the drug along with its effects on T cell specific cytokine production and proliferation as well as behavioral and neuroendocrine parameters in healthy men.     

Safety and Pharmacokinetics of the Oral TYK2 Inhibitor PF‐06826647: A Phase I,Randomized, Double‐Blind,Placebo‐Controlled,Dose‐Escalation Study

Selective inhibition of tyrosine kinase 2 (TYK2) may offer therapeutic promise in inflammatory conditions, with its role in downstream pro‐inflammatory cytokine signaling. In this first‐in‐human study, we evaluated the safety, tolerability, and pharmacokinetics (PK) of a novel TYK2 inhibitor, PF‐06826647, in healthy participants. This phase I, randomized, double‐blind, placebo‐controlled, parallel‐group study included two treatment periods (single ascending dose (SAD) and multiple ascending dose (MAD)) in healthy participants and a cohort of healthy Japanese participants receiving 400 mg q.d. or placebo in the MAD period ({"type":"clinical-trial","attrs":{"text":"NCT03210961","term_id":"NCT03210961"}}NCT03210961). Participants were randomly assigned to PF‐06826647 or placebo (3:1). Participants received a single oral study drug dose of 3, 10, 30, 100, 200, 400, or 1,600 mg (SAD period), then 30, 100, 400, or 1,200 mg q.d. or 200 mg b.i.d. for 10 days (MAD period). Safety (adverse events (AEs), vital signs, and clinical laboratory parameters), tolerability, and PK were assessed. Overall, 69 participants were randomized to treatment, including six Japanese participants. No deaths, serious AEs, severe AEs, or AEs leading to dose reduction or temporary/permanent discontinuation were observed. All AEs were mild in severity. No clinically relevant laboratory abnormalities or changes in vital signs were detected. PF‐06826647 was rapidly absorbed with a median time to maximum plasma concentration of 2 hours in a fasted state, with modest accumulation (< 1.5‐fold) after multiple dosing and low urinary recovery. PF‐06826647 was well‐tolerated, with an acceptable safety profile for doses up to 1,200 mg q.d. for 10 days, supporting further testing in patients.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Tyrosine kinase 2 (TYK2) inhibitors offer therapeutic promise for the many patients with inflammatory conditions in which IL‐12/23 signaling is implicated, and who have an inadequate response to existing systemic treatment options.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ PF‐06826647 is an oral TYK2 inhibitor with potency against TYK2‐dependent signaling. We aimed to assess the safety, tolerability, and pharmacokinetics of PF‐06826647 in healthy participants.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ PF‐06826647 was well‐tolerated, with an acceptable safety profile at a single dose of up to 1,600 mg, or multiple doses up to 1,200 mg daily.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ PF‐06826647 may offer a future oral treatment option for patients with inflammatory and autoimmune conditions in which IL‐12/23 signaling is implicated.

Tyrosine kinase 2 (TYK2), a member of the Janus kinase (JAK) family, is essential for IL‐12/T‐helper cell 1 and IL‐23/T‐helper cell 17 signaling ¹ , ² and IFN type I/II receptor functioning, ² , ³ and both preclinical and clinical studies have implicated these pathways in the pathogenesis of autoimmune disorders, including psoriasis, inflammatory bowel disease, and systemic lupus erythematosous. ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ In large, human, genome‐wide association studies, single nucleotide polymorphisms of the TYK2 gene have been shown to confer protection against psoriasis, ankylosing spondylitis, Crohn’s disease, multiple sclerosis, and ulcerative colitis. ⁵ Blocking signaling from the pro‐inflammatory cytokines, as well as their downstream pathways, with the TYK2 JH2 domain inhibitor BMS‐986165, ¹⁰ the TYK2/JAK1 inhibitor brepocitinib, ¹¹ or with the monoclonal antibodies ustekinumab (anti‐IL‐12 and IL‐23), ¹² , ¹³ , ¹⁴ risankizumab (anti‐IL‐23), ¹⁴ , ¹⁵ secukinumab (anti‐IL‐17A), ¹⁶ mirikizumab (anti‐IL‐23), ¹⁷ or guselkumab (anti‐IL‐23), ¹⁸ , ¹⁹ has shown efficacy in the treatment of various autoimmune conditions.PF‐06826647 is an oral TYK2 inhibitor with potency against TYK2‐dependent signaling (IFNα/IL‐12/IL‐23), but may have dose‐dependent inhibitory activity against other, TYK2‐independent pathways (IFNγ/erythropoeitin). PF‐06826647 is a compound with a low pKa (< 1.7), low solubility across physiological pH (~ 0.3 μg/mL at pH 6.5), and high cellular permeability (~ 17 × 10^‐6 cm/s). However, based on preclinical exposure data in rats, using a spray‐dried dispersion formulation, it was expected to be moderately‐to‐well absorbed at the predicted clinically effective dose range in the clinic. In addition, preclinical studies demonstrated limited drug clearance via renal and biliary excretion in rats, and the major human clearance pathway for PF‐06826647 was identified to be cytochrome P450 (CYP)‐mediated (via CYP1A2, CYP2D6, and CYP3A) metabolism. ²⁰ PF‐06826647 has shown minimal inhibition of transporter proteins (i.e., MATE1, MRP1, MRP2, MRP3, sodium/Na+ taurocholate co‐transporting polypeptide, OATP1B1, OATP1B3, and OCT2), with the exception of MATE2 inhibition. ²⁰ In a phase I, first‐in‐human study ({"type":"clinical-trial","attrs":{"text":"NCT03210961","term_id":"NCT03210961"}}NCT03210961), we evaluated the safety, tolerability, and pharmacokinetics (PK) of PF‐06826647 in healthy participants. In this report, we present safety, tolerability, and PK data for escalating single and multiple doses of PF‐06826647. We also present the impact of food on PK parameters, and a comparison of PK parameters in plasma and urine between Western participants and a Japanese cohort during the multiple ascending dose (MAD) period at an expected clinically relevant dose of 400 mg q.d. Doses for the single ascending dose (SAD) and MAD study periods were initially selected based on data from in vitro pharmacologic/toxicologic studies. ²⁰ During the dose escalation, the available safety data (adverse events (AEs), vital signs, electrocardiogram (ECG), clinical laboratory, hematology, and urinalysis) from the ongoing cohort were reviewed and the appropriate dose for the next cohort was selected to provide the projected average exposure (based on available PK data from all doses) being ~ ≤ 3‐fold of the exposure and less or equal to the PK stopping limit.     

Pharmacoenhancement of Low Crizotinib Plasma Concentrations in Patients with Anaplastic Lymphoma Kinase‐Positive Non‐Small Cell Lung Cancer using the CYP3A Inhibitor Cobicistat

The inhibitor of anaplastic lymphoma kinase (ALK) crizotinib significantly increases survival in patients with ALK‐positive non‐small cell lung cancer (NSCLC). When evaluating crizotinib pharmacokinetics (PKs) in patients taking the standard flat oral dose of 250 mg b.i.d., interindividual PK variability is substantial and patient survival is lower in the quartile with the lowest steady‐state trough plasma concentrations (C_min,ss), suggesting that concentrations should be monitored and doses individualized. We investigated whether the CYP3A inhibitor cobicistat increases C_min,ss of the CYP3A substrate crizotinib in patients with low exposure. Patients with ALK‐positive NSCLC of our outpatient clinic treated with crizotinib were enrolled in a phase I trial (EudraCT 2016‐002187‐14, DRKS00012360) if crizotinib C_min,ss was below 310 ng/mL and treated with cobicistat for 14 days. Crizotinib plasma concentration profiles were established before and after a 14‐day co‐administration of cobicistat to construct the area under the plasma concentration‐time curve in the dosing interval from zero to 12 hours (AUC_0–12). Patients were also monitored for adverse events by physical examination, laboratory tests, and 12‐lead echocardiogram. Enrolment was prematurely stopped because of the approval of alectinib, a next‐generation ALK‐inhibitor with superior efficacy. In the only patient enrolled, cobicistat increased C_min,ss from 158 ng/mL (before cobicistat) to 308 ng/mL (day 8) and 417 ng/mL (day 14 on cobicistat), concurrently the AUC_0–12 increased by 78% from 2,210 ng/mL*h to 3,925 ng/mL*h. Neither safety signals nor serious adverse events occurred. Pharmacoenhancement with cobicistat as an alternative for dose individualisation for patients with NSCLC with low crizotinib exposure appears to be safe and is cost‐effective and feasible.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Crizotinib is an oral inhibitor of anaplastic lymphoma kinase, prolonging progression‐free survival and overall survival in patients with non‐small cell lung cancer. There is considerable variability in exposure and the lowest exposure quartile is associated with worse outcome.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ Does inhibition of CYP3A, the enzyme metabolizing crizotinib, significantly increase crizotinib exposure and is it safe?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Experience from a single case suggests that cobicistat can substantially and cost‐effectively boost crizotinib exposure in patients with low plasma concentrations.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ These data expand the concept of pharmacoenhancement into the indication of oncology. Inhibition of CYP3A‐mediated drug metabolism can increase plasma crizotinib concentration and hence possibly improve outcome.

Non‐small cell lung cancer (NSCLC) is the predominant type of lung cancer and a leading cause of death worldwide. Anaplastic lymphoma kinase (ALK) is a druggable driver mutation of NSCLC. ¹ Targeting ALK with the small molecule inhibitor crizotinib demonstrated significant clinical benefit improving progression‐free survival, overall response rate (ORR), lung cancer symptoms, and global quality of life. ² , ³ Oral crizotinib exhibits substantial variability in steady‐state plasma trough concentrations (C_min,ss), associated with a concentration‐dependent variability in ORR ⁴ ; the ORR was only 24–47% in the quartile with the lowest C_min,ss (< 310 ng/mL) as opposed to 60–75% in the quartile with the highest C_min,ss. ⁴ The benefit in ORR translates into longer progression‐free survival of patients with higher exposure. The model suggested a higher hazard in the lowest quartile vs. the combined upper three quartiles with a hazard ratio of 3.2 (90% confidence interval: 1.62–6.36). ⁴ The high rate of isolated intracranial disease progression under crizotinib has been linked to reduced local central nervous concentrations due to poor penetration. ⁵ , ⁶ Based on preclinical and clinical considerations, a lower effective plasma concentration limit of 235 ng/mL for C_min,ss has been proposed. ⁷ Interestingly, no exposure‐response relationship was observed for adverse events related to respiratory or liver function, albeit a dose reduction strategy is recommended in the drug label. ⁸ In patients experiencing disease progression, an ALK mutation explaining crizotinib resistance is found in only 30%. ⁹ Subtherapeutic exposure is a possible explanation for some of the remaining cases, suggesting that fixed standard doses might not meet the needs of these patients and exposure should be monitored early in therapy. Crizotinib is the primary active circulating moiety. ⁸ , ¹⁰ Its lactam metabolite (PF‐06260182), which consists of two diastereoisomers, is formed by CYP3A‐dependent oxidation but does not contribute significanty to pharmacological activity despite ALK‐inhibiting activity (4–8%). ⁸ , ¹⁰ Crizotinib exposure critically depends on the highly variable CYP3A activity: ⁸ , ¹⁰ , ¹¹ Co‐administration of CYP3A‐inducing rifampin decreases the area under the concentration‐time curve (AUC) by 72% and, conversely, the strong CYP3A inhibitor ketoconazole increases crizotinib AUC by 220%. ⁸ , ¹² Therefore, we screened patients with ALK‐positive metastasized NSCLC for subtherapeutic drug levels. Patients within the lowest quartile of exposure (i.e., C_min,ss < 310 ng/mL) were eligible to participate in a pharmacokinetic (PK) drug trial and were to receive the CYP3A inhibitor cobicistat to determine whether pharmacoenhancement will boost crizotinib exposure in the range of patients previously reported to have a better outcome.     

Early M‐Protein Dynamics Predicts Progression‐Free Survival in Patients With Relapsed/Refractory Multiple Myeloma

This study aimed to predict long‐term progression‐free survival (PFS) using early M‐protein dynamic measurements in patients with relapsed/refractory multiple myeloma (MM). The PFS was modeled based on dynamic M‐protein data from two phase III studies, POLLUX and CASTOR, which included 569 and 498 patients with relapsed/refractory MM, respectively. Both studies compared active controls (lenalidomide and dexamethasone, and bortezomib and dexamethasone, respectively) alone vs. in combination with daratumumab. Three M‐protein dynamic features from the longitudinal M‐protein data were evaluated up to different time cutoffs (1, 2, 3, and 6 months). The abilities of early M‐protein dynamic measurements to predict the PFS were evaluated using Cox proportional hazards survival models. Both univariate and multivariable analyses suggest that maximum reduction of M‐protein (i.e., depth of response) was the most predictive of PFS. Despite the statistical significance, the baseline covariates provided very limited predictive value regarding the treatment effect of daratumumab. However, M‐protein dynamic features obtained within the first 2 months reasonably predicted PFS and the associated treatment effect of daratumumab. Specifically, the areas under the time‐varying receiver operating characteristic curves for the model with the first 2 months of M‐protein dynamic data were ~ 0.8 and 0.85 for POLLUX and CASTOR, respectively. Early M‐protein data within the first 2 months can provide a prospective and reasonable prediction of future long‐term clinical benefit for patients with MM.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ M‐protein is a biomarker for tumor burden and its levels in the serum and urine have been used to assess treatment responses for patients with multiple myeloma (MM).

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ Whether early M‐protein data in the first several months can provide a prospective prediction for long‐term benefit and treatment effect.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ By using clinical data collected from two pivotal phase III trials of daratumumab in relapsed or refractory MM, we demonstrated that M‐protein dynamic data collected during the first 2 months of therapy can provide a prospective and reasonable prediction for not only long‐term progression‐free survival (PFS) but also the treatment effects of daratumumab on PFS compared with other active controls.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ Early M‐protein dynamic data within the first 2 months of therapy may enable the designers of clinical trials to predict the probability of treatment success, and thus facilitate decision making in developing new drugs for MM.

Daratumumab is a human immunoglobulin G (IgGκ) monoclonal antibody that targets CD38 and kills malignant plasma cells via direct antitumor and immunomodulatory mechanisms of action. ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ Daratumumab induces antitumor activity through several CD38 immune‐mediated actions, including complement‐dependent cytotoxicity, antibody‐dependent cellular cytotoxicity, antibody‐dependent cellular phagocytosis, apoptosis, and modulation of CD38 enzymatic activity. ¹ , ² , ³ , ⁴ , ⁵ Daratumumab also induces an immunomodulatory effect by minimizing the immune‐suppressive functions of CD38⁺ myeloid‐derived suppressor cells, regulatory T cells, and regulatory B cells, and increasing T‐cell clonality. ⁶ In the phase III clinical studies POLLUX (MMY3003) and CASTOR (MMY3004), daratumumab in combination with standards of care regimens lenalidomide and dexamethasone (Rd), and bortezomib and dexamethasone (Vd), respectively, reduced the risk of disease progression or death by ≥ 50%, doubled the rates of complete response or better, and more than tripled the rates of minimal residual disease negativity based on next‐generation sequencing at the 10^–5 sensitivity threshold vs. standard of care alone in patients with relapsed/refractory multiple myeloma (MM). ⁸ , ⁹ , ¹⁰ , ¹¹ These findings led to the approval of daratumumab (16 mg/kg) in combination with Rd, and Vd in patients with relapsed and refractory MM in many countries worldwide. Daratumumab has also been approved as monotherapy in many countries and in combination with pomalidomide and dexamethasone in the United States.In MM, tumor plasma cell produces a large amount of monoclonal IgG or IgG free light chain (FLC), known as M‐protein. M‐protein is a biomarker for tumor burden and its levels in the serum and urine have been used to assess treatment responses for patients with MM. ¹² Dispenzieri et al. ¹³ demonstrated the utility of FLC after 2 months of therapy to predict the overall response. Furthermore, several other studies have shown retrospective association between FLC/M‐protein reduction and the long‐term benefit, such as progression‐free survival (PFS) or overall survival, ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ which is critical for predicting antitumor activities for new agents and personalizing therapy for patients with myeloma.To date, the retrospective studies of the association between M‐protein dynamics and PFS or overall survival have been mainly based on complete M‐protein dynamic data collected up to the time of disease progression. ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ Therefore, the prospective ability of M‐protein, particularly early measurements within 2–3 months of therapy, to predict long‐term survivals remains unknown. Moreover, because most of existing association studies were performed based on nonrandomized, single‐arm phase II studies, ¹³ , ¹⁴ , ¹⁵ , ¹⁷ , ¹⁹ translation of the significant association between M‐protein and survival in these studies to treatment effects compared with control arms in the randomized phase III studies is still challenging. Furthermore, existing association studies have mainly focused on reduction in the M‐protein level at a static single time point (e.g., end of 8 weeks) without considering dynamic information or features of M‐protein (e.g., variation in M‐protein levels over time, and rate of M‐protein changes). ¹³ , ¹⁴ , ¹⁸ Here, we investigated the usefulness of early M‐protein dynamic data collected during the first several months after treatment initiation as a predictor of PFS and the effects of treatment on PFS. This analysis is based on the clinical data of two, large‐scale phase III studies, POLLUX and CASTOR for daratumumab. We evaluated different features of M‐protein dynamics in addition to M‐protein reduction and compared the predictive performance of M‐protein dynamic data within different periods after treatment. With this analysis, we hypothesized that an early interim analysis based on M‐protein dynamics within a couple of months after treatment could prospectively predict the future long‐term treatment effect on PFS. Such predictions would contribute greatly to predictions of the probability of success of future clinical trials, decision making in drug development, and the prevision of individualized guidance for treatment and patient care.     

YH12852, a Potent and Selective Receptor Agonist of 5‐hydroxytryptamine,Increased Gastrointestinal Motility in Healthy Volunteers and Patients With Functional Constipation

Gastrointestinal (GI) motility disorders are common, decreases quality of life, and imposes a substantial economic burden. YH12852 is a novel agonist of 5‐hydroxytryptamine for the treatment of GI motility disorders. This phase I/IIa study assessed the tolerability, pharmacodynamic (PD) and pharmacokinetic (PK) profiles of YH12852. In the multiple dose (MD) cohort, healthy subjects and patients with functional constipation were randomized and received orally YH12852 at 0.3, 0.5, 1, 2, or 3 mg or prucalopride 2 mg or their matching placebo, once daily for 14 days after breakfast. In the multiple low‐dose cohort (MLD), healthy subjects randomly received once‐daily oral doses of YH12852 at 0.05 or 0.1 mg for 14 days after breakfast. Questionnaires, gastric emptying breath test for PDs, and plasma samples for PKs were collected. In the MD cohort, a total of 56 subjects (29 healthy volunteers and 27 patients with functional constipation) were randomized, of whom 48 completed the study. In the MLD cohort, a total of 16 healthy subjects were randomized, and 15 subjects completed the study. YH12852 increased the average weekly frequency of spontaneous bowel movements and loosened the stool. In addition, YH12852 increased quality of life satisfaction, and decreased severity of constipation symptom and GI symptoms. YH12852 was safe and well‐tolerated up to 3 mg and showed nearly dose proportional PKs. In conclusion, YH12852 was safe and enhanced GI motility. YH12852 can be developed as an effective treatment option for GI motility disorders, including functional constipation. Further studies are warranted to confirm this possibility.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Five‐hydroxytryptamine (5‐HT) promotes gastrointestinal (GI) motility in the small and large intestines through the 5‐HT receptor such as 5‐HT₄ receptor. The 5‐HT receptor is considered an attractive drug target to treat patients with constipation. YH12852 is a novel and highly selective agonist of the 5‐HT₄ receptor.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ This phase I/IIa study evaluated the tolerability, pharmacodynamic and pharmacokinetic profiles of YH12852 after multiple oral administration in healthy volunteers and patients with functional constipation.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ YH12852 was safe and well‐tolerated. Multiple oral administration of YH12852 enhanced GI motility. Oral YH12852 was absorbed fast, and its exposure increased in a dose‐proportional manner over 0.05–3 mg.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ YH12852 appeared to have a more potent prokinetic effect than other 5‐HT₄ receptor agonists, such as velusetrag, tegaserod, cisaprid, and prucalopride. YH12852 can be developed as an effective treatment for functional constipation.

Chronic constipation, irritable bowel syndrome, and functional dyspepsia are collectively referred to as gastrointestinal (GI) motility disorders. GI motility disorders are a common and debilitating disease that profoundly decreases quality of life and imposes a substantial economic burden. ¹ Traditional medications, including bulk forming laxatives, osmotic laxatives, and stool softeners, have been used to treat GI motility disorders. Although laxatives are effective, some patients could experience adverse drug reactions. ² Constipation is one of the most common GI motility disorders in Western countries. ³ The prevalence of constipation is higher in adults > 50 years of age than in younger adults of 18–35 years, and severe constipation is common in elderly women. ⁴ , ⁵ Current treatment strategies for constipation primarily aim to restore the normal neurogenic regulation of gut function. Five‐hydroxytryptamine (5‐HT) or serotonin, an important signaling molecule in the brain‐gut axis, plays an important role in promoting GI motility, such as peristalsis, in the small and large intestines. ⁶ , ⁷ , ⁸ Although endogenous 5‐HT is not essentially required for peristalsis or colonic migrating motor complexes, exogenous 5‐HT agonists potently increase GI motility. ⁹ , ¹⁰ , ¹¹ Five‐HT signaling is mediated through the 5‐HT receptor, of which 5‐HT₁, 5‐HT₂, 5‐HT₃, 5‐HT₄, and 5‐HT₇ subtypes are known to affect GI motility. ¹² , ¹³ Particularly, the 5‐HT₄ receptor subtype has been intensively studied in association with GI motility because it is distributed along the gut and plays a role in mediating peristalsis and mucosal secretion. Thus, the 5‐HT₄ receptor is an attractive drug target to treat constipation. ¹⁴ To support this notion, 5‐HT₄ receptor agonists, such as cisapride, tegaserod, and prucalopride, have been demonstrated to stimulate both whole gut transit and colonic transit, and were approved to treat patients with gastro‐esophageal reflux disease, dyspepsia, or constipation. ¹⁵ , ¹⁶ , ¹⁷ However, several 5‐HT₄ receptor agonists were withdrawn from the market due to cardiovascular concerns. For example, cisapride was withdrawn from the global market in 2000 after multiple reports of life‐threatening arrhythmias associated with prolonged corrected QT syndrome. ¹⁸ Likewise, tegaserod was withdrawn in 2007, although its relation with cardiovascular events remains inconclusive. ¹⁹ The limited selectivity of cisapride and tegaserod for the 5‐HT₄ receptor could have contributed to the cardiovascular adverse effects commonly seen in patients treated with them. ⁵ YH12852 is a novel, highly selective agonist of the 5‐HT₄ receptor. YH12852 has 84 times higher binding affinity for the 5‐HT₄ receptor than tegaserod. In the preclinical studies, YH12852 significantly improved motility in both upper and lower GI tracts, reduced visceral hypersensitivity, and showed an excellent safety profile. ²⁰ YH12852 was also approximately three times more potent than prucalopride for contractile activity in the distal colon of guinea pigs (mean half maximal effective concentration: 4.2 vs. 13 nM). ²⁰ , ²¹ Furthermore, all electrocardiogram (ECG) outputs were qualitatively and quantitatively normal in cynomolgus monkeys, which received a single oral dose of YH12852 up to at 60 mg/kg/day. YH12852 exhibited high selectivity for the human 5‐HT₄ receptors, whereas YH12852 had no significant affinity for other 5‐HT (5‐HT_1A, 5‐HT_1B, 5‐HT_2A, 5‐HT_2B, or 5‐HT₃) and non 5‐HT receptors or channels. Consistent with the very low affinity of YH12852 with the hERG channel, it had no meaningful effect on blood pressure, heart rate, or ECG, as measured in male cynomolgus monkeys using a telemetry system after single oral administration of YH12852 up to 60 mg/kg. Furthermore, no significant QT prolongation was observed in a previous human study (ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT01870674","term_id":"NCT01870674"}}NCT01870674). These findings suggest that the clinical use of YH12852 would be associated with a low cardiac safety risk.The objective of this study was to evaluate the tolerability, pharmacodynamic (PD) and pharmacokinetic (PK) profiles of YH12852 after multiple oral administration in humans. To this end, we performed a phase I/IIa study in healthy volunteers and patients with functional constipation after multiple oral administrations of YH12852.     

Therapeutic Opportunities for Intestinal Angioectasia‐ Targeting PPARγ and Oxidative Stress

Recurrent and acute bleeding from intestinal tract angioectasia (AEC) presents a major challenge for clinical intervention. Current treatments are empiric, with frequent poor clinical outcomes. Improvements in understanding the pathophysiology of these lesions will help guide treatment. Using data from the US Food and Drug Administration (FDA)’s Adverse Event Reporting System (FAERS), we analyzed 12 million patient reports to identify drugs inversely correlated with gastrointestinal bleeding and potentially limiting AEC severity. FAERS analysis revealed that drugs used in patients with diabetes and those targeting PPARγ‐related mechanisms were associated with decreased AEC phenotypes (P < 0.0001). Electronic health records (EHRs) at University of Cincinnati Hospital were analyzed to validate FAERS analysis. EHR data showed a 5.6% decrease in risk of AEC and associated phenotypes in patients on PPARγ agonists. Murine knockout models of AEC phenotypes were used to construct a gene‐regulatory network of candidate drug targets and pathways, which revealed that wound healing, vasculature development and regulation of oxidative stress were impacted in AEC pathophysiology. Human colonic tissue was examined for expression differences across key pathway proteins, PPARγ, HIF1α, VEGF, and TGFβ1. In vitro analysis of human AEC tissues showed lower expression of PPARγ and TGFβ1 compared with controls (0.55 ± 0.07 and 0.49 ± 0.05). National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) RNA‐Seq data was analyzed to substantiate human tissue findings. This integrative discovery approach showing altered expression of key genes involved in oxidative stress and injury repair mechanisms presents novel insight into AEC etiology, which will improve targeted mechanistic studies and more optimal medical therapy for AEC.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ The clinical detection of angioectasia (AEC) has increased using push‐enteroscopy, capsule enterography, colonoscopy, and esophagogastroduodenoscopy. Management is difficult. Currently, endoscopic ablation is an option for lesions within endoscopic reach, whereas angiogenesis inhibitors and octreotide are pharmacological agents additionally used in the treatment of AEC often with limited clinical benefit. The precise pathophysiology of AEC is unknown; however, AECs are known to result from an imbalance between the pro‐angiogenic and anti‐angiogenic factors.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ How do intestinal AEC develop and how can we design targeted therapeutic discovery for AEC.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Insight into the development of intestinal AEC and a targeted approach for novel therapeutic strategies.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ The results of this study demonstrate the complexity of AEC development and novel therapeutic directions that could impact patient care and treatment.

Angioectasia (AEC) lesions are common vascular abnormalities characterized by ectatic, dilated, and proliferated blood vessels, and are a significant source of obscure gastrointestinal (GI) bleeding. These aberrant blood vessels are typically < 10 mm in diameter, thin walled with little or no smooth muscle, malformed, and uncommunicative, ¹ , ² and symptomatically present with overt and occult GI hemorrhage, ¹ melena, hematochezia, and resulting anemia. ¹ , ³ The clinical procedure of endoscopy has shown the presence of AEC in the upper GI tract, ¹ small bowel, ¹ , ³ descending colon, ¹ , ⁴ and linked their existence to upper and lower GI hemorrhage. ¹ , ⁵ AECs are also significantly correlated with occurrence of synchronous lesions ⁶ , ⁷ , ⁸ and aging. ¹ , ⁹ The clinical detection of AEC has increased using push‐enteroscopy, capsule enterography, colonoscopy, and esophagogastroduodenoscopy, and management of these lesions is difficult with options for treatment being suboptimal. ¹ , ¹⁰ , ¹¹ Currently, endoscopic ablation is an option for lesions within endoscopic reach, whereas angiogenesis inhibitors, such as thalidomide, lenalidomide (thalidomide derivative), and octreotide, are pharmacological agents additionally used in the treatment of AEC often with limited clinical benefit. ¹¹ , ¹² The precise pathophysiology of AEC is unknown; however, AECs are known to result from an imbalance between the pro‐angiogenic and anti‐angiogenic factors and expression of growth factors, including VEGF in AECs, is suggestive of angiogenesis playing a role in their development. ¹ Angiogenesis promotes formation of new functional microvascular networks in human tissues in response to hypoxia or ischemia. ¹ AEC formation appears to be linked to patients with von Willebrand factor in Heyde’s syndrome and left ventricular assist device, whereas mutations in several genes in the TGFβ pathway are common in patients with hereditary hemorrhagic telangiectasia. ¹³ The VEGF‐dependent proliferation and migration represents an important angiogenesis‐hemostasis relationship that may have therapeutic implications in the management of AEC. ¹ , ¹⁴ , ¹⁵ , ¹⁶ Understanding the role of key mediators in AEC development will be important in identifying novel therapeutic strategies that will overcome this unmet clinical need.In this report, we describe a novel integrative systems biology‐based approach and clinical validation study that evaluates the pathophysiology of these lesions. We sought to identify if reduction in severity or decrease in rate of AEC and AEC‐correlated events occurred with use of specific drugs, hence using the medication’s own mechanism of action to ascertain a “first‐cut” of the inflammatory processes at work in vivo. To understand how therapeutic agents may impact AEC‐associated disease pathology, we used in silico drug discovery and gene regulatory networks analysis to identify key pathways/proteins involved in the pathophysiology of AEC and test candidate therapeutics for their protective mechanisms.     

Population Pharmacokinetics of Metoclopramide in Infants,Children, and Adolescents

Metoclopramide is commonly used for gastroesophageal reflux. The aims of the present study were to develop a pediatric population pharmacokinetic (PopPK) model, which was applied to simulate the metoclopramide exposure following dosing used in clinical practice. Opportunistic pharmacokinetic data were collected from pediatric patients receiving enteral or parenteral metoclopramide per standard of care and these data were simultaneously fitted using NONMEM. Allometric scaling with body weight was included a priori in the model. Using the final model, the steady‐state maximum concentrations (C_ss,max) and the area under the metoclopramide plasma concentration‐time curve at steady state from 0 to 6 hours (AUC_ss,0–6h) were simulated following 0.1 or 0.15 mg/kg orally every 6 hours in virtual patients, and compared with previously reported ranges associated with toxicity or the efficacy for gastroesophageal reflux in infants. A two‐compartment model with first‐order absorption best characterized 87 concentration measurements from 50 patients (median [range] postnatal age of 8.89 years [0.01–19.13]). There were 20 infants (≤ 2 years), 9 children (2 years to age ≤ 12 years), and 21 adolescents (> 12 years). Body weight was the only covariate included in the final model. For > 75% of virtual patients, simulated C_ss,max and AUC_ss,0–6h estimates were within the range associated with efficacy for gastroesophageal reflux in infants; however, slightly lower exposures were predicted in virtual patients < 2 years. Our study suggests that a metoclopramide enteral dose of 0.1 mg/kg every 6 hours, which was previously recommended for pediatric patients, results in simulated exposure generally within suggested ranges for the treatment of gastroesophageal reflux.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Metoclopramide is a dopamine receptor antagonist used off‐label in children for gastroesophageal reflux (GER), gastroparesis, nausea, and vomiting. Only one population pharmacokinetic (PopPK) study of metoclopramide has been performed, which included data from 47 patients with cancer 10–80 years of age.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ This study sought to characterize the PopPK of metoclopramide in pediatric patients, and to apply the model to evaluate simulated exposure following dosing used in clinical practice.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Our study suggests that a metoclopramide oral dose of 0.1 mg/kg every 6 hours, which was previously recommended for children, results in simulated exposure generally within suggested ranges for the treatment of GER.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ This study contributes to our understanding of metoclopramide pharmacokinetics and dosing in the pediatric population. When the dose‐response relationship of metoclopramide is further elucidated in future studies, our model could be used to further evaluate metoclopramide pediatric dosing. Metoclopramide is a drug with prokinetic and anti‐emetic properties that is prescribed for the treatment of gastrointestinal motility disorders, gastroesophageal reflux (GER), diabetic gastroparesis, nausea, and vomiting. ¹ , ² Metoclopramide injection is also used to facilitate small bowel intubation and radiological examination. ³ , ⁴ Metoclopramide''s peripheral gastrointestinal prokinetic effects and central anti‐emetic effects are mediated through antagonism of the dopamine 2 and 5‐hydroxytryptamine type 3 receptors, as well as through 5‐hydroxytryptamine type 4 receptor agonism. ⁵ , ⁶ In the United States, metoclopramide is not recommended by the US Food and Drug Administration (FDA) for use in children because its safety and effectiveness in this population have not been established except to facilitate small bowel intubation. ³ The FDA added a black box warning in metoclopramide''s product label related to tardive dyskinesia, a serious adverse event involving involuntary and repetitive body movement. Extrapyramidal side effects (e.g., dystonic reactions, tardive dyskinesia, and parkinsonian‐like symptoms) have also been reported with greater frequency in children compared with adults. ³ The European Medicines Agency recommends that metoclopramide not be used in children younger than 1 year of age, and as second‐choice treatment in children older than 1 year for short‐term use (up to 5 days) for the prevention of delayed nausea and vomiting after chemotherapy, as well as for the treatment of postoperative nausea and vomiting. ⁷ Although limited data are available to inform dosing in the pediatric population, metoclopramide is generally administered enterally or intravenously at a dosage of 0.1–0.2 mg/kg every 6–8 hours. ² , ⁸ , ⁹ , ¹⁰ The pharmacokinetics (PKs) of metoclopramide have been previously characterized in adults. ¹¹ , ¹² , ¹³ , ¹⁴ Metoclopramide undergoes metabolism via oxidation (primarily via cytochrome P450 2D6 (CYP2D6)) as well as glucuronide and sulfate conjugation. ¹⁵ , ¹⁶ Approximately 85% of the radioactivity of an orally administered dose is recovered in the urine, and half of it is present as parent or conjugated metoclopramide. Around 18–22% of the dose was recovered as free metoclopramide in urine. ⁴ Metoclopramide''s elimination half‐life in adults with normal renal function has been reported to be ~ 6 hours. ³ , ⁴ In adults with severe renal impairment, there is a reduction in metoclopramide clearance (CL), resulting in a prolongation in the terminal elimination half‐life (7.7–17.8 hours), and a dose adjustment is recommended. ¹⁴ Only one population pharmacokinetic (PopPK) study of metoclopramide has been performed, which included data from patients 10–80 years old. ¹⁷ In this single PopPK analysis, a two‐compartment model with linear elimination was used, and it was reported that body weight and serum alkaline phosphatase activity were significant covariates that explained interindividual variability (IIV) in the CL of metoclopramide. Given that metoclopramide is extensively metabolized in the liver, this suggests that metoclopramide''s PKs may be impacted by liver function, which has been confirmed in studies of adults with liver cirrhosis. ¹⁸ , ¹⁹ Additional studies focused on characterizing the PKs of metoclopramide in adults have also been published. ¹¹ , ¹² , ¹³ , ¹⁸ In the pediatric population, few studies have evaluated metoclopramide''s PKs in neonates, ⁸ infants, ²⁰ and children. ²¹ Whether the PKs of metoclopramide in adults and the pediatric population are similar remains unclear. ³ One study in preterm infants reported a greater metoclopramide weight‐normalized CL (mean CL of 0.80 L/hour/kg) compared with adults (mean CL of 0.29–0.53 L/hour/kg). ⁸ , ¹¹ , ¹⁷ Nevertheless, in two other studies performed in infants and children, the weight‐normalized PK parameters were comparable to those in adults. ²⁰ , ²¹ Metoclopramide exposure targets for efficacy and toxicity have not been well established in adult or pediatric populations. Conflicting study results have been reported regarding the efficacy of metoclopramide as a prokinetic drug in children. In some studies, metoclopramide''s favorable efficacy for the treatment of GER or vomiting was demonstrated in a pediatric population, ²⁰ , ²² , ²³ , ²⁴ , ²⁵ whereas in other studies it was shown that the metoclopramide treatment was ineffective in children. ²⁶ , ²⁷ One study in infants treated for GER suggested that the beneficial effects were associated with steady‐state maximum concentrations (C_ss,max). In 6 infants with C_ss,max ranging from 26 to 94 ng/mL, 4 of them had a 75% reduction in reflux time ²⁰ ; however, significant correlations were not found between metoclopramide exposures and pharmacodynamic parameters. Data evaluating the relationship between exposure and safety are also limited. One study reported that the metoclopramide plasma concentration measured in a child who developed dystonia after i.v. injection was 143 ng/mL. ²¹ The objectives of this study were to develop a PopPK model using opportunistic PK data collected from infants, children, and adolescents receiving metoclopramide and to apply the model to evaluate simulated exposure following dosing used in clinical practice.     

Identification of BAG2 and Cathepsin D as Plasma Biomarkers for Parkinson’s Disease

The current diagnosis of Parkinson’s disease (PD) mostly relies on clinical rating scales related to motor dysfunction. Given that clinical symptoms of PD appear after significant neuronal cell death in the brain, it is required to identify accessible, objective, and quantifiable biomarkers for early diagnosis of PD. In this study, a total of 20 patients with idiopathic PD and 20 age‐matched patients with essential tremor according to the UK Brain Bank Criteria were consecutively enrolled to identify peripheral blood biomarkers for PD. Clinical data were obtained by clinical survey and assessment. Using albumin‐depleted and immunoglobulin G‐depleted plasma samples, we performed immunoblot analysis of seven autophagy‐related proteins and compared the levels of proteins to those of the control group. We also analyzed the correlation between the levels of candidate proteins and clinical characteristics. Finally, we validated our biomarker models using receiver operating characteristic curve analysis. We found that the levels of BCL2‐associated athanogene 2 (BAG2) and cathepsin D were significantly decreased in plasma of patients with PD (P = 0.009 and P = 0.0077, respectively). The level of BAG2 in patients with PD was significantly correlated with Cross‐Culture Smell Identification Test score, which indicates olfactory dysfunction. We found that our biomarker model distinguishes PD with 87.5% diagnostic accuracy (area under the curve (AUC) = 0.875, P < 0.0001). Our result suggests BAG2 and cathepsin D as candidates for early‐diagnosis plasma biomarkers for PD. We provide the possibility of plasma biomarkers related to the autophagy pathway, by which decreased levels of BAG2 and cathepsin D might lead to dysfunction of autophagy.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Although the current diagnostic method for Parkinson’s disease (PD) shows high accuracy, it is frequently inefficacious to diagnose early PD or predict PD onset. Several studies showed that the autophagy‐lysosomal pathway is altered in patients with early PD, suggesting autophagy‐related proteins could be potential biomarkers for early PD.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ We aimed to identify plasma biomarkers for PD by quantitative analysis of proteins related to the autophagy‐lysosomal pathway.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ This study showed that decreased levels of BCL2‐associated athanogene and cathepsin D could be used as PD biomarkers with high accuracy.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ The diagnostic model using biomarkers identified in this study can be used for more accurate and convenient PD diagnosis. This study also supports that the autophagy‐lysosomal pathway is fundamentally linked to the pathogenesis of PD.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder of insidious onset. PD is characterized by the presence of motor symptoms, including shaking, rigidity, bradykinesia, and postural disturbances, and non‐motor symptoms, including gait, speech, and swallowing difficulties. ¹ The motor symptoms of PD are caused by a significant decrease in dopamine levels in the brain due to the degeneration of dopaminergic (DA) neurons. ² Because the motor disturbance symptoms begin after a 60 to 80% loss of the DA neurons, it is critical to initiate the appropriate medical intervention at the early stage of disease progression. ³ Despite the rapid increase in PD prevalence, there are still no effective biological or imaging markers. The current diagnosis method of PD is made through the clinical criteria developed by the Brain Bank of the Parkinson’s Disease Society in the UK. ⁴ Even though these criteria are with a high degree of accuracy, it is still not effective to predict PD onset or diagnose patients with early PD without motor symptoms. Thus, the development of early PD biomarkers to predict PD is of importance.Identifying biomarkers is necessary as they can be administered in worldwide screening to predict PD progress and diagnose early PD. A biomarker should be applicable to all sexes and ages, easily accessible, noninvasive, and, most importantly, it should be a quantifiable value for clinical application. In this regard, using peripheral blood plasma is a promising way to develop biomarkers for PD. ⁵ Although several studies showed that the level of different types of α‐synuclein in the plasma of patients with PD could be used as a biomarker, it is still controversial whether the α‐synuclein level is a suitable biomarker for PD prediction or diagnosis, due to the inconsistency of the results. ⁶ , ⁷ Accordingly, the peripheral α‐synuclein level does not seem to have potential as a biomarker. Nonetheless, a promising finding is that the level of DJ‐1 decreased in the cerebrospinal fluid of patients with PD; however, DJ‐1 levels in the sera of patients with PD did not differ from those of control patients. ⁶ , ⁸ In addition, the levels of uric acid in sera and epidermal growth factor in plasma are reported to be decreased in patients with PD. ⁶ Thanks to the years of research on PD, it is now well‐known that several factors, including α‐synuclein, parkin, PINK1, LRRK2, and DJ‐1, are deeply related to the pathogenesis of PD. The α‐synuclein is a presynaptic neuronal protein, which is neuropathologically related to PD. ⁹ , ¹⁰ Several studies showed the implication of parkin and PINK1 in mitophagy that is thought to be one of the underlying pathogenic mechanisms of PD. ¹⁰ , ¹¹ , ¹² In addition, LRRK2 and DJ‐1 are reported to play important roles in autophagy‐mediated DA neuronal cell loss. ¹³ , ¹⁴ Most recently, Laperle et al. showed that lysosomal membrane proteins, such as LAMP1, were decreased in induced pluripotent stem cells of patients with young‐onset PD. ¹⁵ These studies, all together, suggest the deep implication of autophagy in PD.In this study, we aimed to identify autophagy‐related proteins as potential biomarkers for PD by quantitative analysis with patient plasma samples. In addition, we investigated the relationship between the potential biomarkers and clinical characteristics of the patients with PD.     

An Evaluation of Biometric Monitoring Technologies for Vital Signs in the Era of COVID‐19

The novel coronavirus disease 2019 (COVID‐19) global pandemic has shifted how many patients receive outpatient care. Telehealth and remote monitoring have become more prevalent, and measurements taken in a patient’s home using biometric monitoring technologies (BioMeTs) offer convenient opportunities to collect vital sign data. Healthcare providers may lack prior experience using BioMeTs in remote patient care, and, therefore, may be unfamiliar with the many versions of BioMeTs, novel data collection protocols, and context of the values collected. To make informed patient care decisions based on the biometric data collected remotely, it is important to understand the engineering solutions embedded in the products, data collection protocols, form factors (physical size and shape), data quality considerations, and availability of validation information. This article provides an overview of BioMeTs available for collecting vital signs (temperature, heart rate, blood pressure, oxygen saturation, and respiratory rate) and discusses the strengths and limitations of continuous monitoring. We provide considerations for remote data collection and sources of validation information to guide BioMeT use in the era of COVID‐19 and beyond.

In an effort to mitigate the spread of the novel coronavirus disease 2019 (COVID‐19), the disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), healthcare providers are increasingly using telehealth for remote patient visits. At the beginning of the pandemic, amidst fears of being infected and having to visit overcrowded hospitals, individuals were rapidly purchasing technologies, such as pulse oximeters, to use at home to monitor for early signs of infection. ¹ Entering early summer, the Centers for Disease Control and Prevention (CDC) reported an increase in cases in several regions of the United States; without a vaccine, experts are concerned for a second wave of the virus. ² , ³ , ⁴ , ⁵ As the healthcare system faces an unprecedented need for remote monitoring due to the COVID‐19 pandemic, Biometric Monitoring Technologies (BioMeTs) offer solutions for collecting disease‐related measurements from patients at home. ⁶ , ⁷ , ⁸ BioMeTs are internet‐connected digital medicine products, such as smart thermometers or heart rate monitors with Bluetooth connectivity, that process data captured by mobile sensors using algorithms to generate measures of behavioral and/or physiological function. ⁹ These connected technologies are used in a variety of contexts, including but not limited to healthcare delivery, ¹⁰ clinical trials, ¹¹ and public health. ¹² , ¹³ BioMeTs offer convenient opportunities to collect frequent and objective data and disease‐related measurements, which facilitates assessing trends ¹² and detecting changes in vital signs not traceable by conventional spot check data collection protocols. ¹⁴ In response to the COVID‐19 pandemic, BioMeTs can be used for many clinical needs, such as aiding preliminary patient physical assessments, assisting with triage of patients with COVID‐19 symptoms, and monitoring patients post‐hospital discharge for risks of readmission. ⁸ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ For clinical teams implementing remote monitoring for the first time or for those already familiar with these technologies and exploring new options, there is an overwhelming variety of BioMeTs available as the market has seen an exponential growth over the past 2 decades. ¹¹ Navigating engineering solutions, form factors (physical size and shape), corresponding data collection protocols, and knowing how to interpret generated values can be challenging, especially if a healthcare provider is unfamiliar with how a BioMeT compares with conventional clinical instruments. Healthcare providers may question the accuracy of measurements taken by patients at home without supervision and it may be unclear how a BioMeT collects and processes data. Understanding data quality and potential biases in data collection is key to drawing appropriate inferences, especially because some of the data may be used for clinical decision making.In this paper, we will discuss the following: (i) sources of information one can use to identify high‐quality BioMeTs, (ii) products and engineering solutions for remote vital sign monitoring, including temperature, heart rate, blood pressure (BP), oxygen saturation, and respiratory rate, and (iii) considerations for choosing a product, including form factors, usability and data collection protocols, and interfering factors that can produce altered readings. Although certain vital sign abnormalities have been associated with COVID‐19 and will be highlighted in this review, we believe the foundations of evaluating these BioMeTs can be applied broadly whenever remote vital sign monitoring is needed. Although overviews of wearable sensor applications for COVID‐19 have been published, ⁸ , ¹⁹ this paper provides a critical review of technologies and is intended as an aid to navigate the plethora of remote monitoring sensors.     

Evaluation of the Effect of Maribavir on Cardiac Repolarization in Healthy Participants: Thorough QT/QTc Study

Maribavir is an orally bioavailable benzimidazole riboside in clinical development for treatment of cytomegalovirus infection in patients who undergo transplantation. Maribavir was evaluated in a thorough QT (TQT) study to determine any effects on cardiac repolarization. The effect of maribavir 100 and 1,200 mg oral doses on the baseline‐adjusted and placebo‐adjusted corrected QT (QTc) interval (delta delta QTc (ddQTc)) and other electrocardiogram (ECG) parameters was assessed in a randomized, phase I, placebo‐controlled, four‐period crossover study in healthy participants (men and women ages 18–50 years). Additionally, maribavir pharmacokinetics, safety, and tolerability were investigated. Moxifloxacin (400 mg) was used as a positive control to demonstrate the study’s ability to detect QT prolongation. Digital 12‐lead Holter ECG monitoring was performed over 22 hours following study drug administration. Individual, Fridericia’s, and Bazett’s QTc intervals were calculated. Of 52 randomized participants (29 ± 8.1 years old; 31 men (60%)), 50 (96%) completed the study. For both 100‐mg and 1200‐mg doses of maribavir, analysis of ddQTc demonstrated that the upper bound of the two‐sided 90% confidence interval was below the 10‐ms threshold at all time points. The concentration–effect analysis demonstrated no relationship between ddQTc and plasma concentrations of maribavir (and its metabolite). There were no clinically meaningful changes in heart rate and systolic blood pressure. The most common adverse event was dysgeusia; no serious adverse events were reported. This TQT study demonstrated that maribavir did not have impact on cardiac repolarization.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ The effect of maribavir on the QT/corrected QT (QTc) interval in healthy participants is not known.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ Maribavir’s potential effect on the QT/QTc interval was investigated in healthy participants in accordance with International Conference on Harmonization E14 guidelines.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ The study provides the evidence of maribavir’s supratherapeutic dose of 1,200 mg in healthy adult participants.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ The study provides the evidence of cardiovascular safety of maribavir, an orally bioavailable benzimidazole riboside drug currently in phase III development for cytomegalovirus infection in patients who undergo transplantation.

Cytomegalovirus (CMV) infection or reactivation is a significant complication following both hematopoietic stem cell transplantation (HSCT) and solid organ transplantation, and it is associated with increased morbidity and reduced long‐term survival. ¹ , ² Use of approved anti‐CMV agents may carry risks of treatment‐limiting toxicities or of significant drug interactions leading to contraindication or requiring dose adjustment and monitoring. ³ , ⁴ , ⁵ , ⁶ , ⁷ Such drawbacks may contribute to failure to prevent CMV infection and disease, or to the development of drug resistance. ⁸ , ⁹ , ¹⁰ Maribavir (1263W94, GW 1263, GW 1263W94, VP 41263, SHP620, and TAK‐620) is a potent and selective, orally bioavailable, benzimidazole riboside drug with a novel mechanism of action that exerts its effects primarily on viral DNA assembly and on egress of CMV viral capsids from the nuclei of infected cells. ¹¹ , ¹² Maribavir is metabolized to its primary metabolite VP 44469 by cytochrome (CYP) P450 isoenzymes CYP3A4 (and, to a minor extent, CYP1A2 and CYP2C19). ¹³ , ¹⁴ Originally developed for CMV prophylaxis in transplant recipients, ¹⁵ , ¹⁶ maribavir is now in phase III clinical development for the treatment of CMV infection and disease. In January 2018, the US Food and Drug Administration (FDA) granted maribavir a “breakthrough therapy” designation based on data from phase II studies for the treatment of CMV infection and disease ({"type":"clinical-trial","attrs":{"text":"NCT00223925","term_id":"NCT00223925"}}NCT00223925 and {"type":"clinical-trial","attrs":{"text":"NCT01611974","term_id":"NCT01611974"}}NCT01611974).Maribavir is rapidly absorbed, and peak plasma concentration (C_max) is generally achieved between 1 and 3 hours after dosing. In single‐dose studies in healthy participants (50–1,600 mg) and patients with HIV (100–1,600 mg), the pharmacokinetics (PKs) of maribavir and VP 44469 were approximately linear. ¹⁷ In an ascending, multiple‐dose study in patients with HIV, there was a dose‐proportional increase in plasma maribavir area under the curve to infinity (AUC_∞), C_max, and area under the concentration‐time curve over 24 hours steady‐state (AUC_24,ss) over the dose range tested on the first day of maribavir administration (100–200 mg) and following 28 days of drug administration (100, 200, or 400 mg t.i.d., or 600, 900, or 1,200 mg b.i.d.). ¹⁸ In phase II studies, maribavir at doses ranging from 400 mg b.i.d. to 1,200 mg b.i.d. was generally well‐tolerated; taste disturbance (dysgeusia), nausea, and diarrhea were notable treatment‐emergent adverse events (TEAEs) that seemed to be associated with maribavir. ¹⁹ , ²⁰ , ²¹ Currently, maribavir at a dose of 400 mg b.i.d. is under investigation in two phase III studies for the treatment of transplant recipients with CMV infection, including resistant or refractory CMV and CMV disease ({"type":"clinical-trial","attrs":{"text":"NCT02927067","term_id":"NCT02927067"}}NCT02927067 and {"type":"clinical-trial","attrs":{"text":"NCT02931539","term_id":"NCT02931539"}}NCT02931539).The potential of maribavir to prolong ventricular repolarization was previously evaluated in an in vitro study according to the International Conference on Harmonisation (ICH) S7B guidelines. ²² In line with the ICH E14 guidance, ²³ this study was conducted in healthy participants to determine the effect of maribavir on the corrected QT (QTc) interval prolongation when compared with placebo as a negative control and moxifloxacin as a positive control. In addition, the PK of maribavir and its metabolite VP 44469, as well as the safety and tolerability of maribavir were evaluated.     

Atogepant Is Not Associated With Clinically Meaningful Alanine Aminotransferase Elevations in Healthy Adults

Atogepant is a potent, selective, oral calcitonin gene–related peptide (CGRP) receptor antagonist in development for migraine prevention. The chemical structure of atogepant is distinct from previous CGRP receptor antagonists, which were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report the safety, tolerability, and pharmacokinetics (PKs) of a once‐daily supratherapeutic dose (170 mg) of atogepant for 28 days from a randomized, double‐blind, placebo‐controlled phase I trial in healthy participants. Overall safety, hepatic safety, and plasma PK parameters were evaluated. Thirty‐four participants aged 23–55 years enrolled; 28 (82.4%) completed the study in accordance with the protocol. Multiple doses of 170 mg atogepant for 28 consecutive days were generally well‐tolerated. All adverse events (AEs; reported in 87.0% of the atogepant group; 72.7%, placebo) were mild in severity except one serious AE of subarachnoid hemorrhage due to a bicycle accident and not considered related to treatment. There were two discontinuations due to AEs, both with atogepant, one considered possibly related to treatment. Over 28 days of treatment, no participant receiving atogepant had an ALT elevation above 1.5 × upper limit of normal. Change from baseline in serum ALT levels was not different between atogepant and placebo. Atogepant is rapidly absorbed (median time to maximum plasma concentration, ~ 2 hours) with an apparent terminal half‐life of ~ 11 hours, and no evidence of accumulation after once‐daily dosing. Overall, atogepant at a high oral dose is safe and well‐tolerated in healthy participants with no clinically meaningful elevations in ALT.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Atogepant is a potent, selective, oral calcitonin gene–related peptide (CGRP) receptor antagonist in development for migraine prevention. The impact of atogepant on changes in alanine aminotransferase (ALT) has not yet been evaluated in a dedicated clinical trial.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ The potential impact of once‐daily supratherapeutic doses (170 mg) of atogepant for 28 days on ALT levels in healthy adult participants.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Once‐daily supratherapeutic doses of atogepant for 28 days were found to be safe and well‐tolerated in healthy participants with no clinically meaningful elevations in ALT.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ These findings will provide clinicians with the knowledge that atogepant, an oral CGRP receptor antagonist, is unlikely to be associated with drug‐induced liver injury.

Migraine is a highly prevalent and burdensome chronic neurological disease. ¹ , ² It is the second largest cause of disability worldwide, ³ and the leading cause of disability during the most productive ages of 15–49 years. ⁴ The disabling effects of migraine can also exert negative changes on many aspects of life, including work productivity, quality of life, and finances. ⁵ , ⁶ , ⁷ Effective and safe preventive treatment options are needed to help reduce the burden of migraine.Inhibition of calcitonin gene−related peptide (CGRP), a potent vasodilatory protein strongly implicated in the pathophysiology of migraine, has emerged as a targeted approach for migraine prevention and treatment. ⁸ Small‐molecule oral CGRP receptor antagonists (called gepants), such as ubrogepant ⁹ and rimegepant, ¹⁰ have demonstrated efficacy in the acute treatment of migraine attacks and were recently approved by the US Food and Drug Administration, ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ and rimegepant is being evaluated for prevention in adult patients with migraine ({"type":"clinical-trial","attrs":{"text":"NCT03732638","term_id":"NCT03732638"}}NCT03732638). Monoclonal antibodies that target CGRP or the CGRP receptor are currently available for adults in the United States and Europe. ⁸ Monoclonal antibodies require parenteral administration (subcutaneous or intravenous injection) and have a long elimination half‐life. ⁸ Therefore, the development of orally administered CGRP receptor antagonists may provide an alternative for people who prefer an oral route of administration over an injection.Atogepant is a potent, selective, small‐molecule antagonist of the CGRP receptor that is currently in development for the prevention of migraine, with a half‐life of ~ 11 hours. Atogepant is chemically distinct from prior oral CGRP receptor antagonists, notably telcagepant and MK‐3207, which were discontinued because of drug‐induced liver injury (DILI). ¹⁶ The efficacy and safety of atogepant in migraine prevention was demonstrated in a phase IIb/III clinical trial conducted subsequent to this trial in which treatment with atogepant, compared with placebo, significantly decreased monthly migraine days over 12 weeks. ¹⁷ Atogepant is in phase III development for migraine prevention (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03700320","term_id":"NCT03700320"}}NCT03700320, {"type":"clinical-trial","attrs":{"text":"NCT03777059","term_id":"NCT03777059"}}NCT03777059, {"type":"clinical-trial","attrs":{"text":"NCT03855137","term_id":"NCT03855137"}}NCT03855137, and {"type":"clinical-trial","attrs":{"text":"NCT03939312","term_id":"NCT03939312"}}NCT03939312).This study evaluated the safety, tolerability, and pharmacokinetics (PKs) of multiple oral 170 mg doses of atogepant in healthy adult participants. The 170 mg dose is substantially higher than doses being tested in phase III clinical trials (once daily 10, 30, and 60 mg, and twice daily 30 and 60 mg). The primary objectives were to evaluate the safety and tolerability, and the mean fold change from baseline of alanine aminotransferase (ALT) after 28 days of once‐daily atogepant dosing in healthy participants. The secondary objective was to obtain preliminary plasma PK data following multiple‐dose administration of atogepant. The primary safety end point was mean fold change from baseline in serum ALT.     

Acceptability,Feasibility, and Utility of Integrating Pharmacogenetic Testing into a Child Psychiatry Clinic

Pharmacogenetic (PGx) testing is a tool to identify patients at a higher risk of adverse events or treatment failure. The concern for unwanted side effects can limit medication adherence, particularly in children and adolescents. We conducted a pragmatic study to evaluate the acceptability and feasibility and gather pilot data on the utility of PGx testing in a child and adolescent psychiatry clinic. Both physicians and families participated in the study and answered pre‐survey and post‐survey questionnaires to examine their attitudes toward PGx testing. Patients were randomized into implementation (N = 25) and control groups (N = 24) and underwent PGx testing at the beginning or end of the study, respectively. Clinical consult notes with genotype‐guided recommendations were provided to physicians for their consideration in clinical decisions. Patient‐reported symptom severity and antidepressant‐related side effects were assessed at baseline and for 12 weeks. Both participating physicians and families agreed that PGx testing is a useful tool to improve medication selection. The time from sample collection to having PGx test results was ~ 10 days and 15 days to having consult notes available, which may have impaired test utility in clinical decision making. There were no differences in any clinical end point between the implementation and control arms; however, there were higher antidepressant side effect scores for CYP2D6 poor and intermediate metabolizers after the eighth week of treatment. Our findings revealed benefits and pitfalls with the use of PGx testing in the real‐world clinical setting, which may inform the methodology of a larger trial focused on outcomes.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Previous studies have demonstrated that differences in CYP2D6 and CYP2C19 explains variability in drug response of psychiatric medications in adults. There is a need to assess the acceptability, feasibility, and clinical utility of psychiatric medications among the pediatric population in the real clinical setting.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ This study aimed to address whether pharmacogenetic (PGx) testing is accepted among parents and physicians, is feasible in a real world clinical setting, and is useful to choose optimal medications to treat depression in the pediatric population.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ This study found that PGx testing is feasible and well‐accepted among physicians and families of children with depression and anxiety and has the potential to identify patients at higher risk of experiencing side effects after 8 weeks of treatment. Our study also identified challenges for PGx testing implementation for treatment of pediatric psychiatric disorders in the real‐world clinical setting.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ Our findings informed the methodology for a large randomized clinical trial investigating PGx testing in both children and adults with psychiatric disorders.

Approximately one in every six children and adolescents suffers from a psychiatric illness, the most common being anxiety and depression. ¹ , ² Although psychosocial interventions are effective, pharmacological therapy is needed in more severe cases. The use of selective serotonin reuptake inhibitors (SSRIs) and serotonin‐norepinephrine reuptake inhibitors either alone ³ or in combination with cognitive behavioral therapy ⁴ is beneficial for the treatment of depression and anxiety disorders in children and adolescents. Nevertheless, these medications also carry a substantial potential side effect burden.Optimization of antidepressant therapy in children can be challenging given the potential for adverse events, particularly in the first few days of treatment, ⁵ consequently impacting treatment adherence. In fact, experiencing physical adverse events related to antidepressants is not uncommon in the pediatric population and may lead to visits to the emergency department. ⁶ Adherence may also be impacted by parents’ perceptions that the treatment may cause more harm than benefit. ⁷ Thus, identifying a medication that is most likely to be effective and/or has a lower risk of potential side effects in advance of treatment initiation could lead to an improvement in outcomes.One potential way to optimize medication choice and dosage is the use of pharmacogenetics (PGx), which involves testing specific variants in genes encoding for drug metabolizing enzymes (pharmacokinetics) or target proteins (pharmacodynamics). ⁸ CYP2D6 and CYP2C19 are the primary enzymes responsible for the metabolism of SSRIs, one of the most commonly used classes of antidepressants in adults and children. Polymorphisms in the genes that encode for CYP2D6 and CYP2C19 may contribute to interindividual differences in the pharmacokinetics of SSRIs. ⁹ The CYP2D6 and CYP2C19 genes are highly polymorphic, conferring normal metabolizer (NM), intermediate metabolizer (IM), poor metabolizer (PM), and rapid or ultra‐rapid metabolizer phenotypes (RM and UM, respectively). Although the sample size in most PGx association studies conducted in the pediatric population is limited, ¹⁰ several studies have shown an association between CYP2D6 and CYP2C19 genotypes and antidepressants response. ¹¹ , ¹² , ¹³ , ¹⁴ Nevertheless, there is still much work to be done regarding assessing the acceptability, feasibility, and utility of PGx testing in children with psychiatric disorders, particularly in the outpatient setting.This study was a prospective, randomized, pragmatic clinical trial comparing antidepressant therapy in children and adolescents using a genotype‐guided approach vs. the standard of care. The primary aim was to assess the acceptability and feasibility of PGx testing in a child psychiatry clinic. Our primary outcomes were: (i) attitudes of parents and physicians towards PGx testing (acceptability), and (ii) ease of and barriers to the implementation of PGx testing in a child psychiatry clinic (feasibility). As secondary outcomes, we evaluated the utility of PGx testing by measuring clinical end points related to medication response and psychiatric adverse events in the PGx implementation vs. the control arm (usual treatment).     

Annual Bleeding Rates: Pitfalls of Clinical Trial Outcomes in Hemophilia Patients

Emerging treatment options for hemophilia, including gene therapy, modified factor products, antibody‐based products, and other nonreplacement therapies, are in development or on their way to marketing authorization. For proof of efficacy, annual bleeding rates (ABRs) have become an increasingly important endpoint in hemophilia trials. We hypothesized that ABR analyses differ substantially between and within medicinal product classes and that the ABR observation period constitutes a major bias. For ABR characterization, an internal factor VIII (FVIII) treatment database has been built based on confidential clinical trial data submitted to the Paul‐Ehrlich‐Institut (PEI). Furthermore, anonymized data from 46 trial protocols submitted for review to the PEI were analyzed (FVIII replacement, n = 27; antibody‐based, n = 12; and gene therapy, n = 7) for methodology. Definitions of bleeding episodes and ABR observational periods differed substantially in clinical trials. In the initial observation phase, individual ABRs of patients, treated prophylactically for 1 year, vary by about 40% (P < 0.001), which finally led to a significant reduction of the ABR group mean by 20% (P < 0.05). Furthermore, the high variance in ABRs constitutes a major challenge in statistical analyses. In conclusion, considerable heterogeneity and bias in the ABR estimation in clinical trials was identified, which makes it substantially more difficult to compare the efficacy of different treatment regimens and products. Thus, awareness of the important pitfalls when using ABR as a clinical outcome is needed in the evaluation of hemophilia therapies for patients, physicians, regulators, and health technology assessment agencies.

Hemophilia is an X‐linked rare bleeding disorder that is characterized by a deficiency of functional coagulation factor VIII (FVIII) or IX and can be categorized based on endogenous factor activity levels as severe (< 1% activity), moderate (1–5% activity), and mild (> 5–40% activity). Individuals with severe hemophilia experience frequent bleeding episodes (BEs) either spontaneously or following minor trauma, which can be acutely life‐threatening or lead to debilitating long‐term complications. For example, joint, muscle, mucosal, and gastrointestinal tract bleeding, and most severely, intracranial hemorrhage can result in disability and death. Current treatment of severe hemophilia mainly relies on replacement therapy with plasma‐derived or modified recombinant factor concentrates.New hemophilia treatment options are in development or have been approved recently, including gene therapy, bispecific monoclonal antibodies, anti‐tissue factor pathway inhibitor antibodies, and other nonreplacement therapies. ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ This is reflected by a large number of ongoing clinical trials (CTs) in this field. In fact, a search in the ClinicalTrials.gov database in June 2019 of phase I–III‐declared studies in congenital hemophilia yielded a total of 69 CTs comprising factor‐based (n = 26), gene therapy‐based (n = 23, including one trial referring to genome editing), antibody‐based (n = 12), RNAi‐based (n = 6), and stem cell‐based (n = 2) products. Importantly, these approaches intervene in different parts of the coagulation cascade and solely coagulation factor levels do not necessarily reflect therapeutic efficacy.Estimation of the annualized bleeding rate, also referred to as annual bleeding rate (ABR), has been introduced early as an efficacy variable for prophylactic replacement therapies in order to complement measures of FVIII or FIX trough levels. However, in contemporary CTs, ABRs are increasingly used as comparative and main outcome parameters.Estimation of bleeding rates has intricate challenges and depends on numerous patient‐related and external factors, including individual clotting factor level, pharmacokinetic profile and pain perception, the subject’s age, health status, activity level, dosing regimen, BE definition, time to follow‐up, and number of patients analyzed. ABR estimation is prone to subjective assessment, as patients as well as treating physicians have to define each bleed. This issue was also demonstrated in a musculoskeletal ultrasound study, which showed that pain perception as well as swelling and warmth is unreliable for bleed detection, resulting in substantial false‐positive and false‐negative bleeding rates. ⁹ Typically, mean total ABRs are in the low to mid‐single‐digit range, whereas specific ABRs, such as the annual joint bleed rate, are in the low single‐digit range. ¹⁰ It has been demonstrated that there is a substantial range of bleeding frequencies among patients with similar clotting factor levels, confirming the ABR as a more personalized parameter. In addition, there is ongoing discussion about the optimal outcome measure and suitability of ABR as an efficacy measure in patients with hemophilia with and without inhibitors. ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ In the European Medicine Agency (EMA) guidelines on core summary of product characteristics for human plasma derived and recombinant coagulation factor FVIII and FIX products, it is stated that ABR is not comparable between different factor concentrates and between different clinical studies. ¹⁶ , ¹⁷ This statement has been introduced empirically based on the long‐standing experience in the regulation of hemophilia therapeutics, however, there is lack of supportive and published evidence.We hypothesize that ABR analyses in CTs differ substantially and that the ABR observation period constitutes a major bias. For this approach, we constituted an internal database of confidential FVIII CT data at the Paul‐Ehrlich‐Institut (PEI) to determine basic characteristics of the ABR endpoint. In addition, we analyzed study protocols from contemporary hemophilia CTs comprising replacement and nonreplacement products as well as gene therapies to characterize differences in the methodology of ABR estimation. The results of this study should facilitate guidance on the minimum standards for bleeding rate estimation in CTs of rare bleeding disorders.     

Perioperative Dexmedetomidine Improves Outcomes of Kidney Transplant

Graft function is crucial for successful kidney transplantation. Many factors may affect graft function or cause delayed graft function (DGF), which decreases the prognosis for graft survival. This study was designed to evaluate whether the perioperative use of dexmedetomidine (Dex) could improve the incidence of function of graft kidney and complications after kidney transplantation. A total of 780 patients underwent kidney transplantations, 315 received intravenous Dex infusion during surgery, and 465 did not. Data were adjusted with propensity scores and multivariate logistic regression was used. The primary outcomes are major adverse complications, including DGF and acute rejection in the early post‐transplantation phase. The secondary outcomes included length of hospital stay (LOS), infection, overall complication, graft functional status, post‐transplantation serum creatinine values, and estimated glomerular filtration rate (eGFR). Dex use significantly decreased DGF (19.37% vs. 23.66%; adjusted odds ratio, 0.744; 95% confidence interval, 0.564–0.981; P = 0.036), risk of infection, risk of acute rejection in the early post‐transplantation phase, the risk of overall complications, and LOS. However, there were no statistical differences in 90‐day graft functional status or 7‐day, 30‐day, and 90‐day eGFR. Perioperative Dex use reduced incidence of DGF, risk of infection, risk of acute rejection, overall complications, and LOS in patients who underwent kidney transplantation.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Graft function is crucial for successful kidney transplantation. Dexmedetomidine (Dex) has been shown to have renal protective effect in preclinical and other surgeries.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ The objective of this study was to evaluate whether the perioperative Dex administration was associated with improved graft kidney function or decreased complications after kidney transplantation.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ This study demonstrated that perioperative Dex administration was associated with improved kidney function and outcomes in patients who underwent kidney transplantation.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ The results from this study suggest perioperative Dex administration could be beneficial to donor kidney grafts.

The cost to care for patients with chronic kidney disease and endstage renal disease (ESRD) is significant with total spending over US $120 billion for Medicare beneficiaries alone representing 33.8% of total Medicare fee‐for‐service spending according to the United States Renal Data System 2019 annual data report. ¹ There were nearly 500,000 patients receiving maintenance dialysis treatments and well over 200,000 living with a kidney transplant in the United States by the end of 2015. ² Thus, ESRD is a major public health problem due to its high morbidity and mortality as well as social and financial implications. ³ Treatment outcomes vary depending on different modalities like hemodialysis, peritoneal dialysis, and renal transplantation. Renal transplantation has an obvious survival advantage over dialysis treatments for patients with ESRD along with better quality of life. ⁴ , ⁵ , ⁶ However, the 5‐year graft survival rate was 74.4% in deceased‐donor transplants and 85.6% in living‐donor transplants. ⁷ The etiology of graft kidney dysfunction is multifactorial and involves immunologic factors, surgical techniques, hemodynamic alterations, inflammatory mechanisms, apoptosis, and ischemia/reperfusion (I/R) injury. ⁸ Although advances in immunosuppressive therapy and treatment of hypertension and hyperlipidemia have improved outcomes following kidney transplantation, poor initial graft function occurs in up to 5% of living donor recipients and up to 20% of deceased donor recipients. Infection occurs in up to 30% of renal transplant recipients during the first 3 months post‐transplantation. ⁹ , ¹⁰ The transplant population has expanded to older and sicker patients, and only about 7.3% candidates on the US kidney transplant waiting list received deceased donor kidney transplantations. ¹¹ Approximately 15% of procured kidneys were discarded despite long waiting lists. ¹¹ At the same time, graft rejection episodes occur in about 20% of low‐risk transplant recipients within the first 26 weeks post‐transplantation. ⁹ The probability of first‐year all‐cause graft failure (return to dialysis, repeat transplantation, or death with a functioning transplant) for deceased donor kidney transplant recipients was about 7.7%. ³ , ¹² , ¹³ It is important to identify factors responsible for decreased graft function and find appropriate interventions.It is well known that renal function is closely associated with hemodynamic performance, sympathetic activity, inflammatory responses, and I/R injury. The hemodynamic stabilizing and sympatholytic effects produced by alpha₂ agonists have been shown to prevent the deterioration of renal function after cardiac surgery. ¹² , ¹⁴ , ¹⁵ The mechanisms could be inhibition of renin release, increased glomerular filtration, and increased excretion of sodium and water via the kidneys. ¹⁶ Dexmedetomidine (Dex) is a short‐acting selective alpha₂ agonist in comparison to clonidine and has an alpha₂ to alpha₁ selectivity ratio of 1,600:1. ¹⁷ Dex has a stabilizing effect on hemodynamics mediated by reducing sympathetic tone, decreasing inflammatory response, alleviating I/R injury, inhibiting renin release, increasing glomerular filtration rate, increasing secretion of sodium and water by the kidneys, and decreasing insulin secretion. ¹⁸ , ¹⁹ Although Dex has been shown to alleviate acute kidney injury (AKI) in other surgeries, ¹⁴ , ¹⁵ no study has demonstrated the benefit of Dex on graft function in renal transplantation. Thus, this study was designed to determine whether the perioperative use of Dex is associated with improved graft kidney function and decreased incidence of complications after renal transplantation.