Angiotensin 1‐7 protects against ventilator‐induced diaphragm dysfunction

Mechanical ventilation (MV) is a life‐saving instrument used to provide ventilatory support for critically ill patients and patients undergoing surgery. Unfortunately, an unintended consequence of prolonged MV is the development of inspiratory weakness due to both diaphragmatic atrophy and contractile dysfunction; this syndrome is labeled ventilator‐induced diaphragm dysfunction (VIDD). VIDD is clinically important because diaphragmatic weakness is an important contributor to problems in weaning patients from MV. Investigations into the pathogenesis of VIDD reveal that oxidative stress is essential for the rapid development of VIDD as redox disturbances in diaphragm fibers promote accelerated proteolysis. Currently, no standard treatment exists to prevent VIDD and, therefore, developing a strategy to avert VIDD is vital. Guided by evidence indicating that activation of the classical axis of the renin‐angiotensin system (RAS) in diaphragm fibers promotes oxidative stress and VIDD, we hypothesized that activation of the nonclassical RAS signaling pathway via angiotensin 1‐7 (Ang1‐7) will protect against VIDD. Using an established animal model of prolonged MV, our results disclose that infusion of Ang1‐7 protects the diaphragm against MV‐induced contractile dysfunction and fiber atrophy in both fast and slow muscle fibers. Further, Ang1‐7 shielded diaphragm fibers against MV‐induced mitochondrial damage, oxidative stress, and protease activation. Collectively, these results reveal that treatment with Ang1‐7 protects against VIDD, in part, due to diminishing oxidative stress and protease activation. These important findings provide robust evidence that Ang1‐7 has the therapeutic potential to protect against VIDD by preventing MV‐induced contractile dysfunction and atrophy of both slow and fast muscle fibers.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Prolonged mechanical ventilation results in ventilator‐induced diaphragm dysfunction (VIDD). This is significant because VIDD is a major risk factor for problems in weaning patients from the ventilator. Currently, no standard treatment exists to prevent VIDD. However, emerging evidence reveals that pharmacological inhibition of the classical axis of the renin‐angiotensin system (RAS) protects against VIDD. Although angiotensin 1‐7 (Ang1‐7) activates the nonclassical arm of the RAS and antagonizes classical RAS signaling, the therapeutic potential of Ang1‐7 to protect against VIDD remains unknown.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Is Ang1‐7 a viable therapy to prevent VIDD?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Treatment of animals with Ang1‐7 protected the diaphragm against both MV‐induced diaphragmatic contractile dysfunction and fiber atrophy. Importantly, Ang1‐7 protected against MV‐induced atrophy of both fast and slow‐type fibers and contractile dysfunction.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These new findings provide a foundation for future testing of Ang1‐7, a potential therapy to protect against VIDD.     

Comparative Efficacy of Angiotensin II Type 1 Receptor Blockers Against Ventilator‐Induced Diaphragm Dysfunction in Rats

Mechanical ventilation (MV) is a life‐saving intervention for many critically ill patients. Unfortunately, prolonged MV results in the rapid development of inspiratory muscle weakness due to diaphragmatic atrophy and contractile dysfunction (termed ventilator‐induced diaphragm dysfunction (VIDD)). Although VIDD is a major risk factor for problems in weaning patients from MV, a standard therapy to prevent VIDD does not exist. However, emerging evidence suggests that pharmacological blockade of angiotensin II type 1 receptors (AT1Rs) protects against VIDD. Nonetheless, the essential characteristics of AT1R blockers (ARBs) required to protect against VIDD remain unclear. To determine the traits of ARBs that are vital for protection against VIDD, we compared the efficacy of two clinically relevant ARBs, irbesartan and olmesartan; these ARBs differ in molecular structure and effects on AT1Rs. Specifically, olmesartan blocks both angiotensin II (AngII) binding and mechanical activation of AT1Rs, whereas irbesartan prevents only AngII binding to AT1Rs. Using a well‐established preclinical model of prolonged MV, we tested the hypothesis that compared with irbesartan, olmesartan provides greater protection against VIDD. Our results reveal that irbesartan does not protect against VIDD whereas olmesartan defends against both MV‐induced diaphragmatic atrophy and contractile dysfunction. These findings support the hypothesis that olmesartan is superior to irbesartan in protecting against VIDD and are consistent with the concept that blockade of mechanical activation of AT1Rs is a required property of ARBs to shield against VIDD. These important findings provide a foundation for future clinical trials to evaluate ARBs as a therapy to protect against VIDD.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Prolonged mechanical ventilation results in ventilator‐induced diaphragm dysfunction (VIDD). This is significant because VIDD is a major risk factor for problems in weaning patients from the ventilator. Currently, no standard treatment exists to prevent VIDD. However, emerging evidence reveals that pharmacological blockade of angiotensin II type 1 receptors (AT1Rs) protects against VIDD. Nonetheless, the specific properties of angiotensin receptor blockers (ARBs) required to protect against VIDD remain unknown.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ What characteristics of ARBs are vital for protection against VIDD?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ ARBs that prevent angiotensin II binding to AT1Rs alone do not protect against VIDD. In contrast, ARBs that block mechanical activation of AT1Rs are protective against VIDD.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ These new findings provide a foundation for future testing of ARBs in clinical trials.

Mechanical ventilation (MV) is used annually in > 13 million patients in the intensive care unit. ¹ Although MV is a life‐saving intervention for many critically ill patients, an unintended consequence of prolonged MV is the rapid development of inspiratory muscle (i.e., diaphragm) weakness. This MV‐induced diaphragmatic weakness is due to both atrophy and contractile dysfunction of the diaphragm, collectively known as ventilator‐induced diaphragm dysfunction (VIDD). ² VIDD is clinically important because diaphragmatic weakness is a major risk factor for problems in “weaning” patients from the ventilator. ³ This failure to wean results in extended time on the ventilator along with increased morbidity and mortality. ⁴ Currently, no standard therapy exists to protect against VIDD.Recent studies into the pathogenesis of VIDD reveal that the renin angiotensin system is a potential therapeutic target to prevent VIDD. Specifically, treatment with the angiotensin II type 1 receptor (AT1R) blocker (ARB) losartan protects against VIDD. ⁵ Although this study reveals that ARBs are protective against VIDD, several classes of ARBs exist and the characteristics of ARBs that provide optimal protection against VIDD remain unknown. In principle, pharmacological blockade of AT1Rs via losartan can avert VIDD by one of three mechanisms. ⁶ , ⁷ , ⁸ First, losartan prevents activation of the classical RAS pathway by blocking angiotensin (AngII) binding to AT1Rs. Second, mechanical stress can activate AT1Rs and losartan blocks mechanical activation of AT1Rs. Indeed, it is feasible that mechanical activation of AT1Rs occurs during MV due to the mechanical stress placed on the receptor due to the passive, repetitive shortening/lengthening cycles of diaphragm fibers during ventilator support. Last, it is possible that losartan protects against VIDD by a combination of blocking both AngII binding and mechanical activation of the AT1R.Prior to clinical trials, additional preclinical studies are required to determine the characteristics of ARBs that are required to protect against VIDD; this forms the rationale for the current study. To delineate the properties of ARBs needed for protection against VIDD, we tested the efficacy of two US Food and Drug Administration (FDA) approved ARBs (i.e., olmesartan and irbesartan) that differ in both molecular structure and effects on the AT1R. Olmesartan blocks both AngII binding and mechanical activation of AT1Rs whereas irbesartan blocks only ligand binding to the receptor. We hypothesized that compared with irbesartan, olmesartan will provide superior protection against VIDD.     

Non‐synonymous alterations in AKR7A3 and ABCA6 correlate with bleeding in aged patients treated with rivaroxaban

Rivaroxaban is an oral anticoagulant that inhibits thrombin and blocks coagulation cascade through directly inactivating factors Xa. Despite rivaroxaban is widely used for prevention and treatment of venous thrombosis, and its common adverse reactions have been reported, including abnormal coagulation, mucosal hemorrhage, hematuria, and intracranial hemorrhage. To explore potential drivers of individual differences in adverse reactions induced by rivaroxaban, we performed whole‐exome sequencing and found that AKR7A3 rs1738023/rs1738025 and ABCA6 rs7212506 are susceptible sites for rivaroxaban‐related bleeding in aged patients treated with rivaroxaban. Gene functional annotation and signaling pathway enrichment indicated that homozygous mutations in AKR7A3 and ABCA6 might alter normal rivaroxaban transport and metabolism, and lead to continuous accumulation of activated drugs and toxic substances in vivo. Our results suggested that interindividual differences in bleeding events induced by rivaroxaban may be potentially driven by genetic alterations related to abnormal metabolism and transport of rivaroxaban.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Although rivaroxaban has been wildly used for the prevention and treatment of prevent of deep vein thrombosis without requiring routine coagulation monitoring, the adverse events, such as bleeding following rivaroxaban treatment, has not been fully addressed.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The correlation between genetic variations and rivaroxaban treatment‐induced side effects (e.g., bleeding).

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The AKR7A3 rs1738023/rs1738025 and ABCA6 rs7212506 confer susceptibility to adverse reactions caused by rivaroxaban.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY AND TRANSLATIONAL SCIENCE?

This study identified AKR7A3 and ABCA6 genes involved in drug metabolism and transport associated with susceptibility to rivaroxaban‐related bleeding events, and provided supporting evidence for the prevention and treatment of anticoagulant‐caused adverse effects.     

Pediatric growth patterns in youth‐onset type 2 diabetes mellitus: Implications for physiologically‐based pharmacokinetic models

An accurate understanding of the changes in height and weight of children with age is critical to the development of models predicting drug concentrations in children (i.e., physiologically‐based pharmacokinetic models). However, curves describing the growth of a typical population of children may not accurately characterize growth of children with various conditions, such as obesity. Therefore, to develop height and weight versus age growth curves for youth who were diagnosed with type 2 diabetes, we extracted data from electronic medical records. Robust nonlinear models were parameterized to the equations describing height and weight versus age as defined by the Centers for Disease Control and Prevention (CDC). CDC z‐scores were calculated using an internal program. The growth curves and z‐scores were compared to CDC norms. Youth with type 2 diabetes were increasingly heavier than CDC norms from early childhood. Except for a period around puberty, youth with type 2 diabetes were, on average, shorter than CDC norms, resulting in shorter average adult height. Deviations in growth were apparent in youth who develop type 2 diabetes; such deviations may be expected for other conditions as well, and disease‐specific growth curves should be considered during development of model‐informed drug development for pediatric conditions.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The Centers for Disease Control and other agencies have developed growth curves that represent typical children, but they do not extend beyond the 97th percentile. The growth of many children with type 2 diabetes is therefore not represented by these curves.

• WHAT QUESTION DID THIS STUDY ADDRESS?

How does the height and weight of children who are diagnosed with type 2 diabetes change with age relative to a population of typically developing children?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Children who develop type 2 diabetes have growth patterns that deviate from the norm.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Given that physiologically‐based pharmacokinetic scaling factors, such as liver volume, are based on body surface area, which is, itself, derived from height and weight, disease‐specific growth curves should be considered for modeling and simulation of dosing for pediatric drug development and clinical applications.     

Machine learning approach to identify adverse events in scientific biomedical literature

Monitoring the occurrence of adverse events in the scientific literature is a mandatory process in drug marketing surveillance. This is a very time‐consuming and complex task to fulfill the compliance and, most importantly, to ensure patient safety. Therefore, a machine learning (ML) algorithm has been trained to support this manual intellectual review process, by automatically providing a classification of the literature articles into two types. An algorithm has been designed to automatically classify “relevant articles” which are reporting any kind of drug safety relevant information, and those which are not reporting an adverse drug reaction as “not relevant.” The review process is consisted of many rules and aspects which needed to be taken into consideration. Therefore, for the training of the algorithm, thousands of documents from previous screenings have been used. After several iterations of adjustments and fine tuning, the ML approach is definitively a great achievement in pre‐sorting the articles into “relevant” and “non‐relevant” and supporting the intellectual review process.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Using machine learning (ML) to make decisions based on previous decisions is becoming more prominent in the digital world. However, to implement such a workflow in a very regulated field is a big challenge.

• WHAT QUESTION DID THIS STUDY ADDRESS?

To what extend is it possible to replace human decisions needing intellectual input by ML?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

It shows that it is to a certain extent possible to detect drug safety‐related information to the drugs in focus in written text. Furthermore, it combines the methodologies to show which technical solutions are best.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Using ML in more and more processes will gain efficiency and will make drug discovery, drug development, and postmarketing surveillance more efficient and, most importantly, it will increase the patients’ safety.     

Type‐2 airway inflammation in mild asthma patients with high blood eosinophils and high fractional exhaled nitric oxide

Type‐2 (T2) inflammation is a characteristic feature of asthma. Biological therapies have been developed to target T2‐inflammation in asthma. IL‐13 is a key component of T2‐inflammation in asthma, driving mucus hypersecretion, IgE‐induction, and smooth muscle contraction. Early phase clinical trials for treatments that target T2‐inflammation require biomarkers to assess pharmacological effects. The aim of this study was to examine levels of IL‐13 inducible biomarkers in the airway epithelium of patients with mild asthma compared to healthy controls. Ten patients with mild asthma with high blood eosinophil and high fractional exhaled nitric oxide (FeNO) were recruited, and six healthy subjects. Blood eosinophil and FeNO reproducibility was assessed prior to bronchoscopy. Epithelial brushings were collected and assessed for IL‐13 inducible gene expression. Blood eosinophil and FeNO levels remained consistent in both patients with asthma and healthy subjects. Of the 11 genes assessed, expression levels of 15LOX1, POSTN, CLCA1, SERPINB2, CCL26, and NOS2 were significantly higher in patients with asthma compared to healthy controls. These six genes, present in patients with mild asthma with T2 inflammation, have the potential to be used in translational early phase asthma clinical trials of novel therapies as bronchial epithelial biomarkers.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Type 2 (T2) inflammation is found in many patients with asthma and is not always controlled by inhaled corticosteroids. T2‐specific biomarkers may be useful for measuring the pharmacological effects of novel anti‐T2 treatments.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We sought to identify IL‐13 associated biomarkers in the airways of patients with asthma with T2 inflammatory phenotype.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Six genes were identified in airway epithelium whose expressions were elevated in patients with T2‐high asthma compared to healthy subjects.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The six genes identified have the potential to be used as target engagement biomarkers in early phase clinical development for novel asthma treatments targeting T2‐inflammation.     

Effect of difelikefalin,a selective kappa opioid receptor agonist,on respiratory depression: A randomized,double‐blind,placebo‐controlled trial

Difelikefalin, a selective kappa opioid receptor agonist designed to limit central nervous system (CNS) penetration, is under development for the treatment of pruritus. Its hydrophilic, small‐peptidic structure limits CNS entry, minimizing potential CNS‐mediated adverse events (AEs). This study assessed the effect of difelikefalin on key relevant measures of respiratory depression in healthy volunteers. This single‐center, randomized, double‐blind, placebo‐controlled, three‐way crossover study enrolled healthy, nonsmoking volunteers. Subjects were randomized to 1 of 3 treatment sequences of difelikefalin (1.0 or 5.0 mcg/kg i.v.) or placebo on sequential days with an intervening 24 (±2) h washout period. The primary end points included incidence of increased end‐tidal carbon dioxide (ETCO₂) greater than or equal to 10 mm Hg versus baseline or a level greater than 50 mm Hg sustained greater than or equal to 30 seconds, and incidence of reduction in saturation of peripheral oxygen (SpO₂) to less than 92% sustained greater than or equal to 30 seconds. Secondary end points included incidence of reduced respiratory rate and other safety assessments. Fifteen subjects were randomized and completed the study. No subject on placebo or difelikefalin met the increased ETCO₂ or reduced SpO₂ primary end point criteria for respiratory depression. All respiratory measures in each group remained near baseline values during 4‐h postdose observations. No subject met the reduced respiratory rate criterion or experienced clinically significant changes in ETCO₂, SpO₂, or respiratory rate. The most commonly reported treatment‐emergent AEs (TEAEs; ≥20% of subjects) were paresthesia, hypoesthesia, and somnolence in the difelikefalin arms. All TEAEs were mild and resolved without intervention. Difelikefalin 1.0 and 5.0 mcg/kg i.v. did not produce respiratory depression.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Severe respiratory depression is a life‐threatening complication of inappropriate use of mu opioid receptor agonists. Difelikefalin, a peripherally restricted kappa opioid receptor (KOR) agonist, has not demonstrated evidence of compromised respiratory safety.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated whether difelikefalin, a selective and potent KOR agonist, induces respiratory depression.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study helps to expand on the safety profile for difelikefalin. Difelikefalin did not produce respiratory depression in healthy volunteers at doses that were 2 to 10 times higher than those observed to be therapeutically effective in clinical trials of patients with chronic kidney disease–associated pruritus.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

KOR agonists may be potentially safe and effective therapeutics. Difelikefalin is currently being evaluated for chronic kidney disease‐associated pruritus and other chronic pruritic conditions.     

A randomized,double‐blind,placebo‐ and positive‐controlled crossover study of the effects of durlobactam on cardiac repolarization in healthy subjects

Durlobactam (formerly ETX2514) is a diazabicyclooctane β‐lactamase inhibitor that inhibits class A, C, and D β‐lactamases. Sulbactam combined with durlobactam has in vitro and in vivo activity against Acinetobacter baumannii including carbapenem‐ and colistin‐resistant isolates and is being developed for treating serious infections due to A. baumannii. The effect of a single supratherapeutic dose of durlobactam on the heart rate corrected QT interval (QTc) was evaluated in healthy subjects in a placebo‐ and active‐controlled, single‐infusion, three‐way crossover study. Subjects were randomized to 1 of 6 sequences that included a single 3‐h i.v. infusion of durlobactam 4 g (supratherapeutic dose), a single 3‐h i.v. infusion of placebo, and a single 3‐h i.v. infusion of placebo plus a single oral dose of moxifloxacin 400 mg given open‐label at the end of the i.v. infusion. In each treatment period, Holter electrocardiogram (ECG) measurements were obtained from predose through 24 h post‐start of infusion. For the primary ECG end point, placebo‐corrected change‐from‐baseline corrected QT Fridericia’s formula (ΔΔQTcF), no significant change was observed with durlobactam. A concentration‐QT analysis demonstrated no significant effect of durlobactam on ECG parameters, including QT interval prolongation. Thus, durlobactam has a low risk for prolonging the QT interval and is unlikely to produce any proarrhythmic effects.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Drug‐induced prolongation of the QT interval has the potential to cause severe, potentially fatal ventricular arrhythmias. A number of antimicrobial agents, including fluoroquinolones and macrolides, are associated with a low, but clinically significant increased risk of QT prolongation.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the effect of a single supratherapeutic dose of durlobactam on the heart rate corrected QT interval in healthy subjects to determine if there were any potentials for proarrhythmic effects.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study found that durlobactam had a low risk for prolonging the QT interval and is unlikely to produce any proarrhythmic effects.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Because durlobactam had a low risk for prolonging the QT interval alone and when co‐administered with sulbactam, clinicians should be confident in administering the combination without risk for proarrhythmic effects.     

Pharmacokinetics and safety of cenobamate,a novel antiseizure medication,in healthy Japanese,and an ethnic comparison with healthy non‐Japanese

Cenobamate (XCOPRI and ONTOZRY) is a novel antiseizure medication for the treatment of focal‐onset seizures. Nonetheless, there is limited information on the pharmacokinetics (PKs), safety, and efficacy of cenobamate in Asian people, including Japanese people. This study aimed to evaluate the PKs and safety of cenobamate after a single oral dose in healthy Japanese subjects and to compare the PKs with that reported in non‐Japanese subjects. A randomized, double‐blind, placebo‐controlled, single ascending dose study was conducted at four dose levels of 50, 100, 200, and 400 mg. Subjects were randomly assigned to cenobamate or placebo in a 6:2 ratio. Cenobamate was rapidly absorbed, reaching its maximum plasma concentration (C_max) in 0.75 to 2.25 h, and was eliminated with a mean half‐life of 37.0 to 57.7 h. The C_max increased dose proportionally, whereas area under the concentration‐time curve increased more than dose proportionally, which was consistent with the findings in non‐Japanese subjects. The systemic exposure of cenobamate was comparable between Japanese and non‐Japanese subjects at all dose levels evaluated. All adverse events were mild in severity, and their incidence did not show dose‐dependent trends. Furthermore, there were no clinically significant issues in safety parameters, including sedation tests, neurologic examinations, and Columbia Suicide Severity Rating Scale interviews. In conclusion, the systemic exposure of cenobamate after a single dose in Japanese subjects increased by dose, which was similar to the pattern in non‐Japanese subjects. In addition, a single dose of cenobamate was well‐tolerated in the dose range of 50 to 400 mg in healthy Japanese subjects.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Cenobamate is a novel antiseizure medication newly approved for the treatment of focal‐onset seizures in the United States and Europe. To date, properties of cenobamate including pharmacokinetics (PKs) have not been extensively studied in Asian people including Japanese people.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the PKs and safety of a single oral dose of cenobamate in healthy Japanese subjects and compared the PKs with that in non‐Japanese subjects previously reported.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Cenobamate showed similar PK profiles in Japanese and non‐Japanese subjects, which suggests its negligible ethnic sensitivity. In addition, a single dose of cenobamate was well‐tolerated in healthy Japanese subjects. Our results indicate that the currently approved dosing regimen of cenobamate may also be applicable to Japanese patients with reasonable exposure and tolerability profiles.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our study bridged the clinical pharmacology gap between ethnicities by providing new findings on the ethnic sensitivity as well as the PKs and safety of cenobamate in Asian people including Japanese people.     

Identification of small molecules that mitigate vincristine‐induced neurotoxicity while sensitizing leukemia cells to vincristine

Vincristine (VCR) is one of the most widely prescribed medications for treating solid tumors and acute lymphoblastic leukemia (ALL) in children and adults. However, its major dose‐limiting toxicity is peripheral neuropathy that can disrupt curative therapy. Peripheral neuropathy can also persist into adulthood, compromising quality of life of childhood cancer survivors. Reducing VCR‐induced neurotoxicity without compromising its anticancer effects would be ideal. Here, we show that low expression of NHP2L1 is associated with increased sensitivity of primary leukemia cells to VCR, and that concomitant administration of VCR with inhibitors of NHP2L1 increases VCR cytotoxicity in leukemia cells, prolongs survival of ALL xenograft mice, but decreases VCR effects on human‐induced pluripotent stem cell‐derived neurons and mitigates neurotoxicity in mice. These findings offer a strategy for increasing VCR’s antileukemic effects while reducing peripheral neuropathy in patients treated with this widely prescribed medication.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Vincristine (VCR) is a widely prescribed drug, but its use is limited by its main side effect, neurotoxicity. There are currently no strategies to mitigate VCR neurotoxicity without altering its antileukemic effects.

• WHAT QUESTION DID THIS STUDY ADDRESS?

How to improve VCR efficacy while reducing its main side effect, neurotoxicity?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The present study shows for the first time the possibility of reduced VCR ‐induced neurotoxicity while improving VCR anti‐leukemia effect by using small molecules.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The current translational study could permit a safer and more efficient use of VCR.     

Phase I and scintigraphy studies to evaluate safety,tolerability, pharmacokinetics,and lung deposition of inhaled GDC‐0214 in healthy volunteers

Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo‐controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC‐0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule‐based inhaler. An accompanying open‐label gamma scintigraphy study in HVs examined the lung deposition of a single dose of inhaled Technetium‐99m (^99mTc)‐radiolabeled GDC‐0214. GDC‐0214 plasma concentrations were linear and approximately dose‐proportional after both single and multiple doses. Peak plasma concentrations occurred at 15–30 min after dosing. The mean apparent elimination half‐life ranged from 32 to 56 h across all single and multiple dose cohorts. After single and multiple doses, all adverse events were mild or moderate, and none led to treatment withdrawal. There was no clear evidence of systemic toxicity due to JAK1 inhibition, and systemic exposure was low, with plasma concentrations at least 15‐fold less than the plasma protein binding‐corrected IC50 of JAK1 at the highest dose. Scintigraphy showed that approximately 50% of the emitted dose of radiolabeled GDC‐0214 was deposited in the lungs and was distributed well to the peripheral airways. ^99mTc‐radiolabeled GDC‐0214 (1 mg) exhibited a mean plasma C_max similar to that observed in phase I at the same dose level. Overall, inhaled GDC‐0214 exhibited pharmacokinetic properties favorable for inhaled administration.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Many factors drive asthma pathogenesis, including several cytokines that signal through the Janus kinase 1 (JAK1) pathway. Inhibition of JAK1 is a possible target for asthma treatments, but previous studies show oral JAK1 inhibitors lead to increased risk of severe infections, malignancy and cardiovascular events.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study investigated the safety, pharmacokinetics, and lung deposition of GDC‐0214, an inhaled JAK1 inhibitor designed to target the lungs.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Inhaled delivery of a JAK inhibitor for 14 days exhibited low systemic exposure, leading to few adverse events and limited systemic toxicity, while demonstrating high deposition in the lungs.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Local pulmonary application of JAK inhibitors may be an effective treatment for asthma with limited systemic risks.     

Pharmacometric dose optimization of buprenorphine in neonatal opioid withdrawal syndrome

Results from Blinded Buprenorphine OR Neonatal morphine solution (BBORN), a previous phase III trial in infants with neonatal opioid withdrawal syndrome (NOWS), demonstrated that sublingual buprenorphine resulted in a shorter duration of treatment and shorter length of hospital stay than the comparator, oral morphine. Objectives of Buprenorphine Pharmacometric Open Label Research study of Drug Exposure (BPHORE), a new trial with buprenorphine in a similar population, were to (1) optimize initial dose, up‐titration to achieve symptom control and weaning steps of pharmacologic treatment and (2) investigate safety of the revised regimen. A pharmacodynamic model linked buprenorphine exposure to NOWS symptom scores. Adaptive dose regimens were simulated using BBORN results to compare dosing regimens for times to stabilization, weaning, and cessation. A clinical trial using model informed doses (BPHORE), was conducted. Simulations indicated benefits in time to stabilization and weaning when up‐titration rates increased to 30%. Stabilization time was not greatly impacted by the starting dose. Time to wean and time to cessation were dose dependent. A weaning rate of 25% shortened time to cessation. Ten infants were enrolled in BPHORE using buprenorphine starting dose of 24 µg/kg/day, 33% titration, and 15% wean rate. Five subjects required adjuvant therapy. Half‐maximal effective concentration (EC₅₀) values indicated maximum buprenorphine doses did not generate maximal effect size, suggesting potential efficacy of a further increased dose if a goal was to reduce the use of adjunct agents. Simulations indicated that further benefits can be gained by increasing starting doses of buprenorphine and increasing wean rates. Use of a model‐based analysis to provide focused guidelines for care can be used with goals of reducing treatment time and hospital stays in infants with NOWS.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Buprenorphine has demonstrated efficacy for the pharmacologic treatment of neonatal opioid withdrawal syndrome (NOWS).

• WHAT QUESTION DID THIS STUDY ADDRESS?

The study sought to explore a variety of buprenorphine dose regimens using modeling and simulation. A revised dose approach was explored in an open label clinical trial.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The study explored the exposure response of buprenorphine in controlling the symptoms of NOWS. The exposure response relationship was described.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The model of buprenorphine response will allow the optimization of dose regimens that may reduce the length of pharmacologic treatment and length of stay for infants treated for NOWS.     

Prediction of human pharmacokinetics for low‐clearance compounds using pharmacokinetic data from chimeric mice with humanized livers

Development of low‐clearance (CL) compounds that are slowly metabolized is a major goal in the pharmaceutical industry. However, the pursuit of low intrinsic CL (CL_int) often leads to significant challenges in evaluating the pharmacokinetics of such compounds. Although in vitro–in vivo extrapolation is widely used to predict human CL, its application has been limited for low‐CL_int compounds because of the low turnover of parent compounds in metabolic stability assays. To address this issue, we focused on chimeric mice with humanized livers (PXB‐mice), which have been increasingly reported to accurately predict human CL in recent years. The predictive accuracy for nine low‐CL_int compounds with no significant turnover in a human hepatocyte assay was investigated using PXB‐mouse methods, such as single‐species allometric scaling (PXB‐SSS) approach and a novel physiologically based scaling (PXB‐PBS) approach that assumes that the CL_int per hepatocyte is equal between humans and PXB‐mice. The percentages of compounds with predicted CL within 2‐ and 3‐fold ranges of the observed CL for low‐CL_int compounds were 89% and 100%, respectively, for both PXB‐SSS and PXB‐PBS approaches. Moreover, the predicted CL was mostly consistent among the methods. Conversely, the percentages of compounds with predicted CL within 2‐ and 3‐fold ranges of the observed CL for low‐CL_int compounds were 50% and 63%, respectively, for multispecies allometric (MA) scaling. Overall, these PXB‐mouse methods were much more accurate than conventional MA scaling approaches, suggesting that PXB‐mice are useful tools for predicting the human CL of low‐CL_int compounds that are slowly metabolized.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

It is important to identify low‐clearance (CL) compounds that are slowly metabolized during the drug discovery process, but the ability of in vitro–in vivo extrapolation to predict human CL decreases as the value of intrinsic CL (CL_int) decreases. Although chimeric mice with humanized livers (PXB‐mice) have been reported to be useful for predicting human CL, their applicability to low‐CL_int compounds with no significant turnover in human hepatocyte assays has not been clarified.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study examined the predictive accuracy of PXB‐mouse methods for low‐CL_int compounds.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

In addition to the previously reported single‐species allometric scaling approach, we proposed a novel physiologically based scaling approach. Both methods displayed much greater predictive accuracy for low‐CL_int compounds than conventional multispecies allometric scaling approaches.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The findings should improve the accuracy of human pharmacokinetic prediction and enable efficient and safe first‐in‐human studies.     

Application of a PBPK model to elucidate the changes of systemic and liver exposures for rosuvastatin,carotegrast, and bromfenac followed by OATP inhibition in monkeys

The impact of organic anion‐transporting polypeptide (OATP) inhibition on systemic and liver exposures of three OATP substrates was investigated in cynomolgus monkeys. A monkey physiologically‐based pharmacokinetic (PBPK) model was constructed to describe the exposure changes followed by OATP functional attenuation. Rosuvastatin, bromfenac, and carotegrast were administered as a single intravenous cassette dose (0.5 mg/kg each) in monkeys with and without predosing with rifampin (RIF; 20 mg/kg) orally. The plasma exposure of rosuvastatin, bromfenac, carotegrast, and OATP biomarkers, coproporphyrin I (CP‐I) and CP‐III were increased 2.3, 2.1, 9.1, 5.4, and 8.8‐fold, respectively, when compared to the vehicle group. The liver to plasma ratios of rosuvastatin and bromfenac were reduced but the liver concentration of the drugs remained unchanged by RIF treatment. The liver concentrations of carotegrast, CP‐I, and CP‐III were unchanged at 1 h but increased at 6 h in the RIF‐treated group. The passive permeability, active uptake, and biliary excretion were characterized in suspended and sandwich‐cultured monkey hepatocytes and then incorporated into the monkey PBPK model. As demonstrated by the PBPK model, the plasma exposure is increased through OATP inhibition while liver exposure is maintained by passive permeability driven from an elevated plasma level. Liver exposure is sensitive to the changes of metabolism and biliary clearances. The model further suggested the involvement of additional mechanisms for hepatic uptakes of rosuvastatin and bromfenac, and of the inhibition of biliary excretion for carotegrast, CP‐I, and CP‐III by RIF. Collectively, impaired OATP function would not reduce the liver exposure of its substrates in monkeys.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Challenges remain in understanding the impact of hepatic uptake transporter, OATPs, on plasma and liver concentrations for OATP substrate drugs with distinct pharmacokinetic (PK) profiles and elimination routes.

• WHAT QUESTION DID THIS STUDY ADDRESS?

How do hepatic active transport, metabolism, biliary excretion, and passive permeability impact the systemic and liver exposure?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study elucidates the important roles of hepatic active transport in determining drug plasma and liver concentrations and the translation of in vitro data to in vivo using the physiologically‐based PK modeling approach.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The disconnection between plasma concentration and liver exposure followed by OATP activity reduction can explain the PK/pharmacodynamic relationship for the liver‐targeted drugs.     

Pharmacokinetics and tolerability of apremilast in healthy Korean adult men

We performed a two‐part study to evaluate the pharmacokinetics, safety, and tolerability of oral apremilast, a phosphodiesterase 4 inhibitor indicated for the treatment of psoriasis, in healthy Korean adult men. In part 1, there were 12 subjects who randomly received a single oral dose of apremilast at 20, 30, or 40 mg in each of 3 periods in a crossover fashion. In part 2, there were 16 subjects who randomly received 30 mg of apremilast or its matching placebo in a ratio of 3:1 twice daily for 14 days. Apremilast was rapidly absorbed (maximum concentration: ~2–3 h postdose), and eliminated according to a monoexponential pattern with a terminal‐phase elimination half‐life of 8–9 h. The exposure to apremilast increased in a dose‐proportional manner and accumulation was 1.6‐fold at steady‐state. Apremilast was well‐tolerated after a single oral administration and multiple oral administrations in Korean adult men; all of the treatment‐emergent adverse events were mild and recovered without sequelae. In conclusion, apremilast was safe and well‐tolerated in healthy Korean adult men when administered single oral doses of 20, 30, or 40 mg or when administered multiple oral doses of 30 mg b.i.d. for 14 days. Overall exposures increased in an approximate dose proportional manner in healthy Korean adult men.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Apremilast, a phosphodiesterase 4 inhibitor, has been approved to treat patients with psoriasis in many countries, including the United States, Canada, and Japan. Although apremilast has shown a linear pharmacokinetic (PK) profile and little ethnic sensitivity, apremilast has never been studied specifically in Koreans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This two‐part study evaluated differences in PKs and tolerability of apremilast between healthy Korean adult men and previously studied ethnic populations.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our results clearly showed that apremilast was safe and well‐tolerated after single and multiple oral administrations in healthy Korean adult men. Linear PK profiles of apremilast were consistently observed in healthy Korean adult men.

• HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS?

Our results support the notion that recommended apremilast dose of 30 mg b.i.d., after a first week of titration, would be also appropriate in Koreans.     

Safety,tolerability, pharmacokinetics,and pharmacodynamics of a TLR7 agonist prodrug RO6870868 in healthy volunteers

RO6870868 is an oral prodrug of the toll‐like receptor 7 (TLR7) specific agonist, RO6871765. TLR7 agonists augment host immune activity and are in development to treat hepatitis B infection. We evaluated the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of RO6870868 in a first‐in‐human, phase I, randomized, single ascending oral dose study in 60 healthy volunteers at 6 dose levels (200–2000 mg). Single oral doses were generally well‐tolerated with a predictable safety profile associated with dose‐dependent increases in systemic interferon. No serious adverse events (AEs) were reported and no subject withdrew from the study due to an AE. No clinically significant changes were observed in vital signs, electrocardiograms, or laboratory parameters. Following oral RO6870868 doses, plasma RO6871765 concentrations increased rapidly, exhibiting mean terminal half‐life ranging 2–6 h across all cohorts, with area under the plasma concentration versus time curve extrapolated to infinity (AUC_0‐∞) increasing proportionally with dose. A pattern of dose and time‐dependent PD activity was demonstrated consistent with engagement of the TLR7 system. Single RO6870868 doses activated components of the TLR innate immune system in a dose‐dependent manner with adequate safety and tolerability. Single‐dose data in healthy volunteers are useful to evaluate safety, PK, and PD activity of TLR7 agonists and help to guide dose and regimen selection for further trials in patients with chronic hepatitis B.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Toll‐like receptor 7 (TLR7) agonists induce broad immune‐enhancing effects and may play a role in overcoming the adaptive and innate immune defects in chronic hepatitis B infection.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of RO6870868 (a prodrug of the specific TLR7 agonist RO6871765) in healthy volunteers.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

RO6870868 was safe and acceptably tolerated across the dose range in healthy volunteers. Oral administration results in the rapid appearance of the active TLR7 agonist RO6871765 and leads to a profile of gene expression typical for TLR7 agonism, including activation of interferon and interferon‐response genes. Gene activation occurs at RO6871765 exposure associated with single RO6870868 doses greater than or equal to 800 mg, with a plateau for several markers at doses between 1200 mg and 1600 mg.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The study results help to guide dose and regimen selection for clinical trials with RO6870868 and other potent TLR7 activators.     

Discovery of preventive drugs for cisplatin‐induced acute kidney injury using big data analysis

Cisplatin is effective against many types of carcinoma. However, a high rate of renal damage is a clinical problem. Thus, there is a need to establish a method to prevent it. Although various compounds have been reported to be effective against cisplatin‐induced renal injury, there are no examples of their clinical application. Therefore, we attempted to search for prophylactic agents with a high potential for clinical application. We used Cascade Eye to identify genes that are altered during cisplatin‐induced renal injury, Library of Integrated Network‐based Cellular Signatures (LINCS) to identify drugs that inhibit changes in gene expression, and a large database of spontaneous adverse drug reaction reports to identify drugs that could prevent cisplatin‐induced kidney injury in clinical practice. In total, 10 candidate drugs were identified. Using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), we identified drugs that reduce cisplatin‐induced kidney injury. Fenofibrate was selected as a candidate drug to prevent cisplatin‐induced kidney injury based on the FAERS analysis. A model was used to evaluate the efficacy of fenofibrate against cisplatin‐induced renal injury. Studies using HK2 cells and mouse models showed that fenofibrate significantly inhibited cisplatin‐induced renal injury but did not inhibit the antitumor effect of cisplatin. Fenofibrate is a candidate prophylactic drug with high clinical applicability for cisplatin‐induced renal injury. Analysis of data from multiple big databases will improve the search for novel prophylactic drugs with high clinical applicability. For the practical application of these findings, evaluation in prospective controlled trials is necessary.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Current coping strategies in clinical practice do not completely prevent cisplatin‐induced renal injury, warranting development of supportive care.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Many drugs and compounds have been reported to be effective against cisplatin‐induced renal injury in basic in vitro and in vivo studies, but none have been applied clinically. In this study, we used medical big data to identify candidate prophylactic drugs with high potential for clinical application.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study used an artificial intelligence tool called Cascade Eye and two large medical information databases, Library of Integrated Network‐based Cellular Signatures (LINCS) and US Food and Drug Administration Adverse Event Reporting System (FAERS), to identify candidate drugs that reduce cisplatin‐induced kidney injury and found that the candidate drug fenofibrate has the potential to prevent cisplatin‐induced kidney injury.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The developed methods can be applied to the development of prophylactic drugs against various adverse drug reactions and will have an impact on future clinical pharmacology and translational research.     

Data driven evaluation of healthy volunteer characteristics at screening for phase I clinical trials to inform on study design and optimize screening processes

Protocols for clinical trials describe inclusion and exclusion criteria based on general and compound‐specific considerations to ensure subject safety and data quality. In phase I clinical trials, healthy volunteers (HVs) are screened against these criteria that often specify predefined eligibility ranges for vital signs, electrocardiogram, and laboratory tests. HVs are excluded if baseline parameters deviate from these ranges even though this may not indicate underlying pathology, which could delay trial execution. Data from 3365 HVs participating in 9670 screening visits for 94 phase I HV trials, conducted between December 2008 and May 2019 at the Janssen Clinical Pharmacology Unit, were retrospectively analyzed. Commonly predefined protocol ranges were overlaid with HV data to estimate predicted screen failure rates (SFRs). Of the overall population, 91% was White and 64% were men with mean age of 42.8 ± 12.5 years. High predicted SFRs are related to cardiovascular/metabolic (body mass index, heart rate [HR], blood pressure [BP], and corrected QT Fridericia’s formula [QTcF]), renal (estimated glomerular filtration rate [eGFR]), liver (alanine aminotransferase [ALT], and total bilirubin), and coagulation (prothrombin time [PT]) parameters. Predicted SFRs increased with age for high systolic and diastolic BP, QTcF interval, and eGFR. In contrast, lower SFRs in the older age groups were seen for low diastolic BP, liver function test, ALT, PT, and total bilirubin. This analysis can be used to inform on study design, protocol inclusion and exclusion criteria, and to optimize the screening process. Data‐driven critical appraisal of proposed inclusion and exclusion criteria using a risk‐based approach may significantly reduce screen failure rates without compromising subjects’ safety.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

In contrast to those enrolled in phase I trials, healthy volunteer (HV) characteristics at screening are not well‐described.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What baseline characteristics of HVs at screening result in high screen failure rates based on different predefined protocol ranges?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This analysis can be used to inform on study design and protocol inclusion and exclusion criteria and optimizing the screening process.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Data‐driven critical appraisal of proposed inclusion and exclusion criteria using a risk‐based approach may significantly reduce screen failure rates without compromising subjects’ safety.