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.     

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.     

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.     

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.     

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.     

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.     

G970R‐CFTR Mutation (c.2908G>C) Results Predominantly in a Splicing Defect

In previous work, participants with a G970R mutation in cystic fibrosis transmembrane conductance regulator (CFTR) (c.2908G>C) had numerically lower sweat chloride responses during ivacaftor treatment than participants with other CFTR gating mutations. The objective of this substudy was to characterize the molecular defect of the G970R mutation in vitro and assess the benefit of ivacaftor in participants with this mutation. This substudy assessed sweat chloride, spirometry findings, and nasal potential difference on and off ivacaftor treatment in three participants with a G970R/F508del genotype. Intestinal organoids derived from rectal biopsy specimens were used to assess ivacaftor response ex vivo and conduct messenger RNA splice and protein analyses. No consistent or meaningful trends were observed between on‐treatment and off‐treatment clinical assessments. Organoids did not respond to ivacaftor in forskolin‐induced swelling assays; no mature CFTR protein was detected in Western blots. Organoid RNA analysis demonstrated that 3 novel splice variants were created by G970R‐CFTR: exon 17 truncation, exons 13–15 and 17 skipping, and intron 17 retention. Functional and molecular analyses indicated that the c.2908G>C mutation caused a cryptic splicing defect. Organoids lacked an ex vivo response with ivacaftor and supported identification of the mechanism underlying the CFTR defect caused by c.2908G>C. Analysis of CFTR mutations indicated that cryptic splicing was a rare cause of mutation misclassification in engineered cell lines. This substudy used organoids as an alternative in vitro model for mutations, such as cryptic splice mutations that cannot be fully assessed using cDNA expressed in recombinant cell systems.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Participants with the G970R mutation in the CFTR gene have lower sweat chloride responses to ivacaftor treatment than do participants with G551D or other non–G551D‐CFTR gating mutations.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ This substudy characterized the molecular defect of the G970R‐CFTR mutation in vitro and assessed the benefit of ivacaftor in participants with this mutation.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ The functional and molecular analyses revealed that the G970R‐CFTR mutation is not responsive to ivacaftor treatment and identified the mechanism of the CFTR defect as a cryptic splicing defect.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ For mutations that cannot be fully assessed using recombinant cell systems, such as cryptic splicing defects, organoid in vitro assessments and RNA analyses can be used as alternatives to characterize mutations.

Cystic fibrosis (CF) is an autosomal recessive hereditary disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that result in decreased quantity and/or function of the CFTR protein. ¹ , ² The CFTR protein is an epithelial chloride channel aiding in the regulation of salt and fluid absorption and secretion that is located in the epithelia of multiple organs, including the lungs, pancreas, intestinal tract, liver, and vas deferens. ³ , ⁴ , ⁵ , ⁶ CF is a multisystemic disease with clinical manifestations, including lung function decline, chronic airway infections, pancreatic insufficiency, and malnutrition. ⁷ Ivacaftor (Kalydeco^(R); Vertex Pharmaceuticals, Boston, MA) is a CFTR modulator that increases chloride transport by potentiating the channel open probability (P₀ (or gating)) of the CFTR protein at the epithelial cell surface. ⁸ Currently, ivacaftor is indicated in the United States for people aged ≥ 4 months with CF with ≥ 1 CFTR mutation that is responsive to ivacaftor based on clinical and/or in vitro assay data ⁹ ; the approved genotypes and ages vary in other regions. ¹⁰ , ¹¹ , ¹² In clinical studies of people with CF with eligible genotypes, ivacaftor treatment has been shown to achieve improvements in CFTR function, lung function, risk of pulmonary exacerbations, pancreatic function, and nutritional status. ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ Among > 340 known CF‐causing CFTR mutations identified, 10 have historically been classified as class III mutations that result in severe defects in CFTR channel gating: G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, and G1349D. ² , ¹⁸ , ¹⁹ , ²⁰ , ²¹ In Fischer rat thyroid (FRT) cells engineered to individually express complementary DNAs (cDNAs) that express CFTR proteins coding each of these mutations, chloride transport as determined by electrophysiological studies was < 5% of normal CFTR, despite the presence of mature CFTR protein at levels similar to those of normal CFTR. Ivacaftor increased the channel P₀ of these 10 CFTR forms and caused an increase in CFTR‐mediated chloride transport to levels equivalent to > 10% above baseline. These in vitro data supported investigation of the potential clinical benefit with ivacaftor in people with CF with severe gating mutations. ⁸ In a clinical study of ivacaftor in participants with CF who had a non‐G551D severe gating mutation, participants with a G970R‐CFTR mutation had a numerically lower treatment response than participants with the other gating mutations. ¹⁴ Given this result, the molecular defect of the G970R mutation was further evaluated as part of the completed open‐label extension study KONTINUE. ¹⁵ Organoids, a cell culture technology platform, ²² enabled generation of an in vitro model from each participant that expresses the CFTR protein based on the genomic DNA rather than on a cDNA construct. These organoids were used for in vitro functional CFTR experiments to evaluate the response with ivacaftor and for further mechanistic studies to help clarify the range of functional defects caused by the G970R mutation.     

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.     

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.     

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.     

Evaluating Potential Disease‐Mediated Protein‐Drug Interactions in Patients With Moderate‐to‐Severe Plaque Psoriasis Receiving Subcutaneous Guselkumab

This open‐label, multicenter, phase I therapeutic protein‐drug interaction study was designed to evaluate the potential effect of guselkumab, a fully human anti‐interleukin‐23 immunoglobulin G1 lambda monoclonal antibody, on the pharmacokinetics of a cocktail of representative cytochrome P450 (CYP) probe substrates (midazolam (CYP3A4), S‐warfarin (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and caffeine (CYP1A2)). Fourteen participants with psoriasis received a single subcutaneous dose of guselkumab 200 mg on day 8 and an oral probe cocktail on days 1, 15, and 36. Blood samples were collected for measuring plasma concentrations of these probe substrates on days 1, 15, and 36. No consistent trends in observed maximum plasma concentration and area under the curve from time 0 to infinity values of each probe CYP‐substrate before (day 1) and after guselkumab treatment (days 15 and 36) could be identified in each individual patient, suggesting that the use of guselkumab in patients with psoriasis is unlikely to influence the systemic exposure of drugs metabolized by CYP isozymes (CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP1A2). The probe cocktail was generally well‐tolerated when administered in combination with guselkumab in patients with psoriasis.Clinicaltrials.gov Identifiers: {"type":"clinical-trial","attrs":{"text":"NCT02397382","term_id":"NCT02397382"}}NCT02397382.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Therapeutic proteins (TPs) that modulate cytokine concentrations and activity can indirectly influence expression of cytochrome P450 (CYP) isoenzymes and may alter CYP‐mediated metabolism of concomitantly administrated small molecule drugs. An in vitro study ¹ and two phase I studies ² , ³ were previously conducted to assess if interleukin (IL)‐23 modulates the expression or activity of multiple CYP isoenzymes (including CYP1A2, 2C9, 2C19, 2D6, and 3A4). These results suggest that potential TP‐drug interactions between guselkumab and drugs metabolized by CYP450 could be low.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ This phase I study evaluated whether treatment with guselkumab, which selectively binds and inhibits IL‐23, affects CYP450 isoenzyme activity in patients with moderate‐to‐severe psoriasis.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Subcutaneous administration of guselkumab to patients with psoriasis has no effect on the pharmacokinetics (PK) of the evaluated CYP substrates.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ These results suggest that guselkumab can be used for the treatment of psoriasis without significant PK interactions with drugs metabolized by CYP3A4, CYP2C9, CYP2C19, CYP2D6, or CYP1A2.

Psoriasis is a chronic inflammatory disease affecting 1–3% of the world’s population. ⁴ Traditional systemic therapies for psoriasis have not fully met patients’ needs. ⁵ Highly effective antibody‐based or fusion protein‐based biologics targeting key inflammatory mediators have been developed for psoriasis treatment. ⁶ Based on their mechanisms of action, biological psoriasis therapies can be classified as: (i) T‐cell modulating agents, (ii) tumor necrosis factor (TNF)‐α antagonists, (iii) interleukin (IL)‐12/23 and/or IL‐23 inhibitors, and (iv) IL‐17 inhibitors. ⁴ , ⁷ Guselkumab (Tremfya, Janssen Research & Development, Spring House, PA) is a fully human immunoglobulin G1 lambda (IgG1λ) monoclonal antibody (mAb) that selectively binds and inhibits IL‐23, a critical driver of pathogenic T cells in chronic plaque psoriasis. Clinical trials have demonstrated that guselkumab had favorable efficacy and safety profiles for the treatment of moderate‐to‐severe plaque psoriasis. ⁸ , ⁹ , ¹⁰ As a fully human IgG1λ mAb, guselkumab is expected to be metabolized in the same manner as any other endogenous IgG antibody (degraded into small peptides and amino acids via catabolic pathways) and subject to similar routes for elimination. ¹¹ Therefore, the likelihood of direct therapeutic protein (TP)‐drug interaction occurring during co‐administration of guselkumab and other concomitant small molecule medications is assumed to be low. In line with this, clinically relevant information has been published about potential TP‐drug interactions, ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ and supports that mAbs do not elicit a direct effect on the metabolic/clearance pathways of small molecular therapeutics. However, the immunomodulatory properties of mAbs may indirectly alter the clearance of certain small molecules through noncatabolic hepatic metabolism pathways. ¹⁴ , ¹⁵ An in vitro study ¹ using cryopreserved human hepatocytes to assess whether IL‐12 and/or IL‐23 modulate the expression or activity of multiple cytochrome P450 (CYP) enzymes (i.e., CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) suggested that TP‐drug interactions between guselkumab and CYP450 substrates are unlikely. However, in vitro studies may have limitations in predicting clinical interactions between TPs and small molecule drugs. ¹⁷ To confirm these findings, we conducted a phase I study in patients with moderate‐to‐severe plaque psoriasis to determine if blocking IL‐23 with guselkumab for treatment of psoriasis would clinically alter the metabolism of probe substrates metabolized by CYP isozymes (CYP3A4, CYP2C9, CYP2C19, CYP2D6, or CYP1A2).     

Bromhexine Hydrochloride Tablets for the Treatment of Moderate COVID‐19: An Open‐Label Randomized Controlled Pilot Study

This open‐label randomized controlled pilot study aimed to test the study feasibility of bromhexine hydrochloride (BRH) tablets for the treatment of mild or moderate coronavirus disease 2019 (COVID‐19) and to explore its clinical efficacy and safety. Patients with mild or moderate COVID‐19 were randomly divided into the BRH group or the control group at a 2:1 ratio. Routine treatment according to China’s Novel Coronavirus Pneumonia Diagnosis and Treatment Plan was performed in both groups, whereas patients in the BRH group were additionally given oral BRH (32 mg t.i.d.) for 14 consecutive days. The efficacy and safety of BRH were evaluated. A total of 18 patients with moderate COVID‐19 were randomized into the BRH group (n = 12) or the control group (n = 6). There were suggestions of BRH advantage over placebo in improved chest computed tomography, need for oxygen therapy, and discharge rate within 20 days. However, none of these findings were statistically significant. BRH tablets may potentially have a beneficial effect in patients with COVID‐19, especially for those with lung or hepatic injury. A further definitive large‐scale clinical trial is feasible and necessary.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Bromhexine hydrochloride (BRH) is capable of inhibiting transmembrane protease serine 2 (TMPRSS2) and TMPRSS2‐specific viral entry and is theoretically regarded to be effective against severe acute respiratory syndrome‐coronavirus 2.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ This open‐label randomized controlled pilot study evaluated the study feasibility of BRH tablets for the treatment of coronavirus disease 2019 (COVID‐19) and to explore its clinical efficacy and safety.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ The study of BRH tablets for the treatment of COVID‐19 is feasible and necessary.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ BRH tablets may potentially have a beneficial effect against COVID‐19, especially for patients with lung and hepatic injury. A further large‐scale clinical trial is warranted to confirm our findings.

The epidemic novel coronavirus disease 2019 (COVID‐19) has now rapidly spread from China to around the world. ¹ , ² Among all infected patients, 80% of patients have been categorized as having moderate disease; and the overall fatality rate is ~ 2.3%, with the elderly experiencing a higher rate. ³ Asymptomatic carriers are also contagious, which contributes to the growing epidemic status. There is an urgent need for effective treatment to not only relieve the symptomatic patients but to curb viral transmission.The novel coronavirus mainly invades the human body through angiotensin‐converting enzyme 2/transmembrane protease serine 2 (TMPRSS2). ⁴ Previous studies on severe acute respiratory syndrome, Middle East respiratory syndrome, and other respiratory viruses have revealed that TMPRSS2 participates in the process of host cell entry, maturation, and release of the virus, which enhance the viral infectivity. ⁵ , ⁶ , ⁷ Therefore, inhibition of TMPRSS2 may be a promising therapeutic approach for COVID‐19. ⁴ The latest prophylactic and treatment option for severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) infection proposed by researchers from the Netherlands, the United States, Indonesia, South Africa, and Italy is the use of a TMPRSS2 inhibitor. ⁸ Bromhexine hydrochloride (BRH), a widely used mucolytic agent, has a specific inhibitory effect on TMPRSS2. ⁹ The half‐maximal inhibitory concentration value of BRH toward TMPRSS2 is merely 0.75 μM. ⁹ BRH at a dosage that selectively inhibits TMPRSS2 and TMPRSS2‐specific viral entry is regarded to be effective against SARS‐CoV‐2. ⁸ Therefore, the aim of this study was to conduct a clinical pilot study to test the study feasibility of BRH tablets for the treatment of moderate COVID‐19 and to explore its clinical efficacy and safety.     

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.     

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.     

Characterizing Pharmacogenetic Testing Among Children’s Hospitals

Although pharmacogenetic testing is becoming increasingly common across medical subspecialties, a broad range of utilization and implementation exists across pediatric centers. Large pediatric institutions that routinely use pharmacogenetics in their patient care have published their practices and experiences; however, minimal data exist regarding the full spectrum of pharmacogenetic implementation among children’s hospitals. The primary objective of this nationwide survey was to characterize the availability, concerns, and barriers to pharmacogenetic testing in children’s hospitals in the Children’s Hospital Association. Initial responses identifying a contact person were received from 18 institutions. Of those 18 institutions, 14 responses (11 complete and 3 partial) to a more detailed survey regarding pharmacogenetic practices were received. The majority of respondents were from urban institutions (72%) and held a Doctor of Pharmacy degree (67%). Among all respondents, the three primary barriers to implementing pharmacogenetic testing identified were test reimbursement, test cost, and money. Conversely, the three least concerning barriers were potential for genetic discrimination, sharing results with family members, and availability of tests in certified laboratories. Low‐use sites rated several barriers significantly higher than the high‐use sites, including knowledge of pharmacogenetics (P = 0.03), pharmacogenetic interpretations (P = 0.04), and pharmacogenetic‐based changes to therapy (P = 0.03). In spite of decreasing costs of pharmacogenetic testing, financial barriers are one of the main barriers perceived by pediatric institutions attempting clinical implementation. Low‐use sites may also benefit from education/outreach in order to reduce perceived barriers to implementation.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE OF THE TOPIC?

☑ Implementation of pharmacogenetic testing is well‐described at select institutions; however, it is poorly understood how widespread implementation is, particularly at pediatric hospitals.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ The primary objective of this survey was to characterize pharmacogenetic testing in addition to determining availability, concerns, and barriers to pharmacogenetic testing in pediatric hospitals.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Although this study gives a general sense of pharmacogenetic implementation among pediatric hospitals, it also highlights the considerable differences between sites with limited vs. more extensive implementation, in particular the need for additional education of providers.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ The results of this survey provide important information to institutions that have limited implementation of pharmacogenetic testing or for those considering implementation.

The implementation of pharmacogenetic testing has made remarkable progress in recent years, with select institutions introducing preemptive or reactive clinical testing. ¹ , ² Widely available resources, such as PharmVar, ³ the Pharmacogenomics Knowledge Base (PharmGKB), ⁴ and Clinical Pharmacogenetic Implementation Consortium (CPIC) guidelines, ⁵ now provide laboratories with consolidated data on pharmacogenetic variants and clinicians with up‐to‐date clinical information in addition to formal dosing recommendations for drug‐gene pairs. The formalization of these resources has undoubtedly contributed to progress in pharmacogenetic implementation. The number of well‐characterized specific drug‐gene interactions (DGIs) is growing exponentially along with our ability to rapidly test for and act on clinically relevant gene variants, allowing for translation of laboratory knowledge into clinical practice. ⁶ Although not every DGI results in a medication or dosing change, there are institutions where genetic testing for clinically significant variants is part of routine care. CPIC first released guidelines for TPMT and thiopurines in March 2011, with subsequent updates in April 2013 ⁷ and most recently in November 2018, where the guideline was updated to include NUDT15. ⁸ Within pediatric oncology, patients with acute lymphoblastic leukemia are routinely tested for TPMT and NUDT15 variants prior to initiation of therapy with thiopurines. ⁹ TPMT is also routinely tested for in pediatric inflammatory bowel disease, which has improved dosing of thiopurines across pediatric centers participating in the ImproveCareNow network. ¹⁰ Recently, CPIC has also included pediatric‐specific genotype‐dosing recommendations for voriconazole based on CYP2C19 genotype and atomoxetine based on CYP2D6 genotype. ¹¹ , ¹² Implementation requires a collaboration of resources, including laboratories for genotyping, bioinformatics/information technology for interpretation and communication of results, and clinicians to incorporate the results into patient care. Historically, such resources were costly and often not sufficient for incorporation into clinical care, but current and evolving technologies are and will be available to make the process both possible and cost‐efficient. ¹³ The US Food and Drug Administration (FDA) has also made changes to facilitate the incorporation of pharmacogenetics into clinical practice. The FDA has implemented a voluntary program allowing companies to submit genomics data with new drug applications and has recently released a Table of Pharmacogenomic Associations that includes > 100 medications. The table includes subsections for those associations that they recommend therapeutic changes (dose or medication selection), associations that indicate an impact on safety or response, and associations that have an impact on pharmacokinetics only. Over 200 drug labels have been updated to include pharmacogenetic findings. There are several examples of newly approved targeted therapies with companion diagnostic tests (crizotinib and vemurafenib), drugs with required pharmacogenetic testing (eliglustat, pimozide, and tetrabenazine), and others with potential pharmacogenetic considerations included in the label.The increase in pharmacogenetic data and progress in implementation are encouraging to physicians and other clinicians eager to provide safer and more effective therapy for their patients through precision medicine. Although discovery and implementation of clinically relevant DGIs require considerable resources and effort, the benefits have the potential to make such expenditures worthwhile, especially as costs decrease with improved technology. Collaborative networks, such as the Pharmacogenomics Research Network (PGRN), ¹⁴ the Electronic Medical Records and Genomics (eMERGE) Network, ¹⁵ the Implementing Genomics in Practice (IGNITE) ¹⁶ and the Canadian Pharmacogenomics Network, ¹⁷ allow for distribution of knowledge and effort across multiple institutions. Despite these recent advances in the utility, feasibility, and cost efficacy of pharmacogenetic testing, there are still many institutions that have not implemented routine pharmacogenetic testing into clinical practice. Analysis of the barriers to pharmacogenetic implementation have found that information technology, ¹⁸ clinical utility concerns, ¹⁹ and training ²⁰ were major barriers to implementation in nonpediatric institutions. However, there has been no analysis of barriers to pharmacogenetic implementation specific to pediatric institutions. In order to assess this, we sought to better understand the landscape of pharmacogenetic testing in pediatric populations, and from there propose solutions to overcome these barriers. Thus, the primary objective of this survey was to characterize pharmacogenetic testing in addition to determining availability, concerns, and barriers to pharmacogenetic testing in pediatric hospitals.