Single‐dose of LC51‐0255, a selective S1P1 receptor modulator,showed dose‐dependent and reversible reduction of absolute lymphocyte count in humans

Reducing the peripheral absolute lymphocyte count (ALC) is a promising therapeutic approach in treating autoimmune diseases. LC51‐0255 is a sphingosine‐1‐phosphate 1 receptor modulator, which is known to decrease the peripheral ALC. We aimed to assess the pharmacokinetics (PKs), pharmacodynamics (PDs), safety, and tolerability profiles of LC51‐0255 after a single oral administration in healthy subjects. A randomized, double‐blind, placebo‐controlled, dose‐escalation study was conducted in 50 healthy subjects. Each subject orally received LC51‐0255 (0.25, 0.5, 1, 2, or 4 mg) or its matching placebo in an 8:2 ratio. Blood and urine samples were collected to assess the PKs, and PDs was evaluated using peripheral ALC and 24‐h hourly heart rate data. Safety and tolerability were assessed by monitoring treatment emergent adverse events (TEAEs), vital signs, 12‐lead electrocardiogram (ECG), continuous 24‐h ECG (via Holter monitoring), clinical laboratory tests, ophthalmologic tests, pulmonary function tests, and physical examinations. A single dose of LC51‐0255 reduced ALC and heart rate in a reversible and dose‐dependent manner. Systemic exposure of LC51‐0255 increased dose‐dependently and its half‐life ranged from 72.2 to 134.0 h. ALC and the systemic exposure of LC51‐0255 seemed to be negatively correlated. LC51‐0255 was well‐tolerated up to 2 mg, and the most common TEAE was bradycardia. The results of this study suggest that LC51‐0255 can be developed into a beneficial treatment option for autoimmune disease.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Reducing the peripheral absolute lymphocyte count (ALC) is a promising therapeutic approach to treat autoimmune diseases. Sphingosine‐1‐phosphate 1 (S1P₁) receptor modulator reduces peripheral ALC by preventing the recirculation of lymphocytes from lymphatic tissue to target organs.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We performed this study to assess the pharmacokinetics, pharmacodynamics, safety, and tolerability profiles of LC51‐0255, a novel S1P₁ receptor modulator, in humans.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our results showed that LC51‐0255 has a relatively long half‐life, is well‐tolerated, and reduces ALC in a dose‐dependent and reversible manner.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our results provide evidence that a single dose of LC51‐0255 can be further developed into a beneficial treatment option for patients with autoimmune disease.     

Comprehensive in vitro pro‐arrhythmic assays demonstrate that omecamtiv mecarbil has low pro‐arrhythmic risk

Omecamtiv mecarbil (OM) is a myosin activator (myotrope), developed as a potential therapeutic agent for heart failure with reduced ejection fraction. To characterize the potential pro‐arrhythmic risk of this novel sarcomere activator, we evaluated OM in a series of International Conference on Harmonization S7B core and follow‐up assays, including an in silico action potential (AP) model. OM was tested in: (i) hERG, Nav1.5 peak, and Cav1.2 channel assays; (ii) in silico computation in a human ventricular AP (hVAP) population model; (iii) AP recordings in canine cardiac Purkinje fibers (PF); and (iv) electrocardiography analysis in isolated rabbit hearts (IRHs). OM had low potency in the hERG (half‐maximal inhibitory concentration [IC₅₀] = 125.5 µM) and Nav1.5 and Cav1.2 assays (IC₅₀ > 300 µM). These potency values were used as inputs to investigate the occurrence of repolarization abnormalities (biomarkers of pro‐arrhythmia) in an hVAP model over a wide range of OM concentrations. The outcome of hVAP analysis indicated low pro‐arrhythmia risk at OM concentration up to 30 µM (100‐fold the effective free therapeutic plasma concentration). In the isolated canine PF assay, OM shortened AP duration (APD)₆₀ and APD₉₀ significantly from 3 to 30 µM. In perfused IRH, ventricular repolarization (corrected QT and corrected JT intervals) was decreased significantly at greater than or equal to 1 µM OM. In summary, the comprehensive proarrhythmic assessment in human and non‐rodent cardiac models provided data indicative that OM did not delay ventricular repolarization at therapeutic relevant concentrations, consistent with clinical findings.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

A new therapeutic agent, omecamtiv mecarbil (OM), increases cardiac contractility by prolonging systolic ejection time, however, there is no published data assessing its pro‐arrhythmic risks.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Pro‐arrhythmic risk assessment of OM in in vitro and ex vivo safety pharmacology models compliant with International Conference on Harmonization S7B guideline and Comprehensive In Vitro Proarrhythmia Assay initiative.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Comprehensive in vitro pro‐arrhythmic risk assays demonstrate that OM has low pro‐arrhythmic risk and translate into clinical safety observations.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Low pro‐arrhythmic risks consistently identified in preclinical in vitro models translate well into clinical observations (i.e., negative preclinical pro‐arrhythmic findings can predict negative clinical outcomes).     

First‐in‐human development of a pharmacodynamic biomarker for PAC1 receptor antagonists using intradermal injections of maxadilan

Maxadilan, a potent vasodilator peptide, selectively activates the PAC₁ receptor, a promising target for migraine therapy. Therefore, maxadilan has been suggested as a tool to study the pharmacodynamics (PDs) of PAC₁ receptor antagonists. The objectives of this first‐in‐human study were to: (1) determine the safety, tolerability, dose response, and time course of the dermal blood flow (DBF) changes after intradermal (i.d.) injections of maxadilan in the human forearm, and (2) assess the inter‐arm and inter‐period reproducibility of this response. This was a single‐center, open‐label study in healthy subjects, comprising three parts: (1) dose–response (n = 25), (2) response duration (n = 10), and (3) reproducibility (n = 15). DBF measurements were performed using laser Doppler imaging (LDI) up to 60 min postinjection, or up to 5 days for the response duration assessments. To assess reproducibility, the intraclass correlation coefficient (ICC) and sample sizes were calculated. The i.d. maxadilan (0.001, 0.01, 0.1, 0.9, 3, and 10 ng) produced a well‐tolerated, dose‐dependent increase in DBF, with a half‐maximal effective concentration fitted at 0.0098 ng. The DBF response to 0.9 ng maxadilan was quantifiable with LDI up to 72 h postinjection. The inter‐period reproducibility of the DBF response was better upon 0.9 ng (ICC > 0.6) compared to 0.01 ng (ICC < 0.4) maxadilan. However, irrespective of the study design or maxadilan dose, a sample size of 11 subjects is sufficient to detect a 30% difference in DBF response with 80% power. In conclusion, intradermal maxadilan provides a safe, well‐tolerated, and reproducible PD biomarker for PAC₁ receptor antagonists in vivo in humans.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Selective target engagement biomarkers have proven to be successful in guiding go/no‐go decisions in early clinical drug development. Recently, the PAC₁‐receptor gained interest as novel target for anti‐migraine drugs. Intradermal injections of maxadilan, a selective and potent PAC₁ receptor agonist, have been proposed as a pharmacodynamic (PD) biomarker tool to assess PAC₁ receptor activation.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the safety and applicability of intradermal maxadilan injection in humans by characterizing the induced vascular changes in terms of safety, dose response, and reproducibility.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Intradermal injection of maxadilan induces a robust, dose‐dependent increase in dermal blood flow with low variability. Hence, it can be used in the early clinical drug development of PAC₁ receptor antagonists.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Implementation of this novel PD biomarker will support the early clinical development of PAC₁ receptor antagonists, thereby reducing the costs and time invested to translate promising results in rodent pain models to human conditions.     

First‐in‐human trial assessing the pharmacokinetic‐pharmacodynamic profile of a novel recombinant human chorionic gonadotropin in healthy women and men of reproductive age

The purpose of this first‐in‐human trial was to examine the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel recombinant human chorionic gonadotropin (rhCG; FE 999302, choriogonadotropin beta) to support its clinical development for various therapeutic indications. The single and multiple dose PK of choriogonadotropin beta (CG beta) were evaluated in women and the single dose PK and PD of CG beta were compared to those of CG alfa in men. CG beta was safe and well‐tolerated in all 84 healthy subjects. In women, the area under the curve (AUC) and the peak serum concentration (C_max) increased approximately dose proportionally following single and multiple doses of CG beta. The apparent clearance (CL/F) was ~ 0.5 L/h, the mean terminal half‐life (t_½) ~ 45 h and the apparent distribution volume (V_z/F) ~ 30 L. After single administration in men, the mean AUC was 1.5‐fold greater for CG beta than for CG alfa. Mean C_max and V_z/F were comparable for the 2 preparations. In accordance with the differences in AUC, the CL/F was lower for CG beta (CL/F 0.5 vs. 0.8 L/h), explained by a longer t_½ (47 vs. 32 h). Serum testosterone levels induced by a single dose rhCG reflected the PK profiles with a slight delay, resulting in 59% higher AUC for CG beta. The PK parameters for CG beta were comparable in men and in women. In conclusion, the PK differs between the two rhCG preparations, causing higher exposure and a higher PD response for CG beta, which may require relatively lower therapeutic doses.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Recombinant human chorionic gonadotropin (hCG) is indicated for the treatment of male or female infertility and administered by single or multiple subcutaneous injections.

• WHAT QUESTION DID THIS STUDY ADDRESS?

A new recombinant hCG (rhCG; choriogonadotropin [CG] beta) produced by a human‐derived cell line (PER.C6) is currently in clinical development. The amino acid sequence of the α‐ and β‐chains are identical to the natural sequences and also to that of rhCG expressed by Chinese Hamster Ovary (CHO) cell line (CG alfa), but the glycosylation provided by the PER.C6 and CHO cells is different. In this trial, the pharmacokinetics (PK) of choriogonadotropin beta were assessed in women and men and the PKs and pharmacodynamics (PDs) were compared in men to those of CG alfa.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

It is concluded that the PK of the two rhCG preparations are different, due to a slower clearance of CG beta resulting in a higher PD response.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Further development of CG beta may require lower doses of this potent hCG compared to current therapeutic hCG preparations.     

Short‐ and long‐term effects of body weight loss following calorie restriction and gastric bypass on CYP3A‐activity – a non‐randomized three‐armed controlled trial

It remains uncertain whether pharmacokinetic changes following Roux‐en‐Y gastric bypass (RYGB) can be attributed to surgery‐induced gastrointestinal alterations per se and/or the subsequent weight loss. The aim was to compare short‐ and long‐term effects of RYGB and calorie restriction on CYP3A‐activity, and cross‐sectionally compare CYP3A‐activity with normal weight to overweight controls using midazolam as probe drug. This three‐armed controlled trial included patients with severe obesity preparing for RYGB (n = 41) or diet‐induced (n = 41) weight‐loss, and controls (n = 18). Both weight‐loss groups underwent a 3‐week low‐energy‐diet (<1200 kcal/day) followed by a 6‐week very‐low‐energy‐diet or RYGB (both <800 kcal/day). Patients were followed for 2 years, with four pharmacokinetic investigations using semisimultaneous oral and intravenous dosing to determine changes in midazolam absolute bioavailability and clearance, within and between groups. The RYGB and diet groups showed similar weight‐loss at week 9 (13 ± 2.4% vs. 11 ± 3.6%), but differed substantially after 2 years (−30 ± 7.0% vs. −3.1 ± 6.3%). At baseline, mean absolute bioavailability and clearance of midazolam were similar in the RYGB and diet groups, but higher compared with controls. On average, absolute bioavailability was unaltered at week 9, but decreased by 40 ± 7.5% in the RYGB group and 32 ± 6.1% in the diet group at year 2 compared with baseline, with no between‐group difference. No difference in clearance was observed over time, nor between groups. In conclusion, neither RYGB per se nor weight loss impacted absolute bioavailability or clearance of midazolam short term. Long term, absolute bioavailability was similarly decreased in both groups despite different weight loss, suggesting that the recovered CYP3A‐activity is not only dependent on weight‐loss through RYGB.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The current literature indicates an inverse relationship between body mass index (BMI) and CYP3A‐activity, and that systemic clearance of the CYP3A‐probe midazolam increases after Roux‐en‐Y gastric bypass (RYGB). However, the knowledge regarding changes in drug disposition following weight loss in general, and bariatric surgery in particular, is sparse and inconclusive, making drug dosing challenging. In addition, it remains uncertain whether pharmacokinetic changes following bariatric surgery are attributed to the gastrointestinal alterations per se and/or the subsequent weight loss.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Do body weight, weight loss, and RYGB impact CYP3A‐activity in vivo?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study shows that neither short‐term weight loss induced by RYGB or very‐low‐energy‐diet, nor RYGB per se, impact absolute bioavailability or systemic clearance of midazolam.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our results suggests that dose adjustments of CYP3A substrate drugs, 30–50% of all drugs on the market, may not be necessary following nonsurgical and surgical weight loss neither in a short‐ nor long‐term perspective.     

A randomized,controlled, feasibility study of RD‐X19 in subjects with mild‐to‐moderate COVID‐19 in the outpatient setting

The RD‐X19 is an investigational, handheld medical device precisely engineered to emit blue light through the oral cavity to target the oropharynx and surrounding tissues. At doses shown to be noncytotoxic in an in vitro three‐dimensional human epithelial tissue model, the monochromatic visible light delivered by RD‐X19 results in light‐initiated expression of immune stimulating cytokines IL‐1α and IL‐1β, with corresponding inhibition of severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) replication. A single exposure of 425 nm blue light at 60 J/cm² led to greater than 99% reductions against all SARS‐CoV‐2 strains tested in vitro, including the more transmissible (Alpha) and immune evasive (Beta) variants. These preclinical findings along with other studies led to a randomized, double‐blind, sham‐controlled early feasibility study using the investigational device as a treatment for outpatients with mild to moderate coronavirus disease 2019 (COVID‐19). The study enrolled 31 subjects with a positive SARS‐CoV‐2 antigen test and at least two moderate COVID‐19 signs and symptoms at baseline. Subjects were randomized 2:1 (RD‐X19: sham) and treated twice daily for 4 days. Efficacy outcome measures included assessments of SARS‐CoV‐2 saliva viral load and clinical assessments of COVID‐19. There were no local application site reactions and no device‐related adverse events. At the end of the study (day 8), the mean change in log₁₀ viral load was −3.29 for RD‐X19 and −1.81 for sham, demonstrating a treatment benefit of −1.48 logs (95% confidence internal, −2.88 to −0.071, nominal p = 0.040). Among the clinical outcome measures, differences between RD‐X19 and sham were also observed, with a 57‐h reduction of median time to sustained resolution of COVID‐19 signs and symptoms (log rank test, nominal p = 0.044).

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Visible blue light (400–470 nm) has previously been demonstrated to inhibit coronavirus replication in cultured cells and eliminate severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) from infected human epithelial tissue in a laboratory setting.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can precisely engineered doses of visible light inhibit replication of SARS‐CoV‐2 variants in a laboratory setting and lead to reductions of SARS‐CoV‐2 viral load in saliva in patients with coronavirus disease 2019 (COVID‐19)?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

In this randomized, double‐blind, sham‐controlled, early feasibility study, light administered in the outpatient setting by the investigational RD‐X19 device twice daily over 4 days resulted in clinically meaningful differences in both mean change in SARS‐COV‐2 viral load by day 8 (−1.48 log₁₀, nominal p = 0.040) and median time to sustained symptom resolution (57‐h advantage, nominal p = 0.044) compared to sham. Unlike the photodamage known to be caused by UV light, photobiomodulation via 425 nm blue light exhibited no cytotoxicity in oral mucosal tissues in vitro and no device‐related application site adverse events in the clinic.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Self‐administered visible light therapy in the outpatient setting may be capable of interrupting SARS‐CoV‐2 disease pathology (through inactivation of virus and/or stimulation of host immune response) and useful as a treatment for mild to moderate COVID‐19. These nonclinical and clinical findings help to inform dosing schedules for the optimal use of light as a therapeutic in future clinical trials.     

A permeability‐ and perfusion‐based PBPK model for improved prediction of concentration‐time profiles

To improve predictions of concentration‐time (C‐t) profiles of drugs, a new physiologically based pharmacokinetic modeling framework (termed ‘PermQ’) has been developed. This model includes permeability into and out of capillaries, cell membranes, and intracellular lipids. New modeling components include (i) lumping of tissues into compartments based on both blood flow and capillary permeability, and (ii) parameterizing clearances in and out of membranes with apparent permeability and membrane partitioning values. Novel observations include the need for a shallow distribution compartment particularly for bases. C‐t profiles were modeled for 24 drugs (7 acidic, 5 neutral, and 12 basic) using the same experimental inputs for three different models: Rodgers and Rowland (RR), a perfusion‐limited membrane‐based model (K_p,mem), and PermQ. K_p,mem and PermQ can be directly compared since both models have identical tissue partition coefficient parameters. For the 24 molecules used for model development, errors in V_ss and t _1/2 were reduced by 37% and 43%, respectively, with the PermQ model. Errors in C‐t profiles were reduced (increased EOC) by 43%. The improvement was generally greater for bases than for acids and neutrals. Predictions were improved for all 3 models with the use of parameters optimized for the PermQ model. For five drugs in a test set, similar results were observed. These results suggest that prediction of C‐t profiles can be improved by including capillary and cellular permeability components for all tissues.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Compared to compartmental models, concentration‐time profiles of drugs are often not well‐predicted by perfusion‐limited PBPK models.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can C‐t profiles be better predicted by including capillary, cellular and membrane permeability in a new PBPK framework?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study suggests that variable capillary permeability for different tissues is an important anatomical component for drug distribution. Apparent permeability and membrane partitioning can be used to model clearances in and out of membranes. Early distribution kinetics observed in the C‐t profile of basic drugs indicates that an additional shallow distribution compartment is necessary. Parameters optimized for input into the new PermQ framework also decrease the prediction errors in perfusion‐limited PBPK models.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Improved prediction of drug concentration‐time profiles with new modeling frameworks such as the PermQ model can result in improved therapeutic outcomes for healthy and special populations.     

Tilidine and dipyrone (metamizole) in cold pressor pain: A pooled analysis of efficacy,tolerability, and safety in healthy volunteers

The cold pressor test (CPT) is widely implemented and offers a simple, experimental acute pain model utilizing cold pain. Previous trials have frequently paired the CPT with opioids in order to investigate the mechanisms underlying pharmacological analgesia, due to their known analgesic efficacy. However, opioid side effects may lead to unblinding and raise concerns about the safety of the experimental setting. Despite the established clinical efficacy of dipyrone (metamizole), its efficacy, tolerability, and safety in cold pressor pain has not been systematically addressed to date. This pooled analysis included data of 260 healthy volunteers from three randomized, placebo‐controlled, double‐blind substudies using the CPT following a pre‐test‐post‐test‐design. These substudies allow for comparing a single dose of 800 mg dipyrone with two different doses of the opioid tilidine/naloxone (50/4 mg and 100/8 mg, respectively). Outcomes included pain intensity ratings, pain tolerance, medication‐attributed side effects, as well as changes of blood pressure and heart rate. We demonstrate that both opioid doses and dipyrone had a comparable, significant analgesic effect on cold pressor pain. However, dipyrone was associated with significantly less self‐reported adverse effects and these were not significantly different from those under placebo. These results indicate that the combination of dipyrone and the CPT provides a safe, tolerable, and effective experimental model for the study of pharmacological analgesia. In combination with a CPT, dipyrone may be useful as a positive control, or baseline medication for the study of analgesic modulation.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The cold pressor test (CPT) has frequently been paired with opioids to investigate analgesia, but opioids are often associated with side effects. Although the pyrazalone derivate dipyrone (metamizole) is used for clinical analgesia, its efficacy, tolerability, and safety in experimental cold pain has not been systematically addressed to date.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Which efficacy, tolerability, and safety provide 800 mg dipyrone compared to 50/4 mg and 100/8 mg tilidine/naloxone in a cold pain experiment?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Both opioid doses and dipyrone had a comparable analgesic effect on cold pain. Importantly, dipyrone was associated with less adverse effects.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Combining dipyrone with the CPT offers an effective and safe model of pharmacological analgesia and might be of particular interest to explore contextual modulations of analgesia.     

First‐in‐human study of milvexian,an oral,direct, small molecule factor XIa inhibitor

Milvexian (BMS‐986177/JNJ‐70033093) is a small molecule, active‐site inhibitor of factor XIa (FXIa) being developed to prevent and treat thrombotic events. The safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of milvexian were assessed in a two‐part, double‐blind, placebo‐controlled, sequential single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy adults. Participants in SAD panels (6 panels of 8 participants; n = 48) were randomized (3:1) to receive milvexian (4, 20, 60, 200, 300, or 500 mg) or placebo. The 200‐ and 500‐mg panels investigated the pharmacokinetic impact of a high‐fat meal. Participants in MAD panels (7 panels of 8 participants; n = 56) were randomized (3:1) to receive milvexian (once‐ or twice‐daily) or placebo for 14 days. All milvexian dosing regimens were safe and well‐tolerated, with only mild treatment‐emergent adverse events and no clinically significant bleeding events. In SAD panels, maximum milvexian plasma concentration occurred 3 h postdose in all fasted panels. The terminal half‐life (T_1/2) ranged from 8.3 to 13.8 h. In fasted panels from 20 to 200 mg, absorption was dose‐proportional; results at higher doses (300 and 500 mg) were consistent with saturable absorption. Food increased milvexian bioavailability in a dose‐dependent fashion. In MAD panels, steady‐state milvexian plasma concentration was reached within 3 and 6 dosing days with once‐ and twice‐daily dosing, respectively. Renal excretion was less than 20% in all panels. Prolongation of activated partial thromboplastin time was observed and was directly related to drug exposure. These results suggest that the safety, tolerability, PK, and PD properties of milvexian are suitable for further clinical development.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Factor XI (FXI) amplifies thrombin generation and has a limited role in hemostasis. Targeted FXI inhibition may reduce the burden of vascular and thromboembolic diseases while preserving hemostasis.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the safety/tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the selective, direct, small molecule FXIa inhibitor milvexian.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Single and multiple ascending doses of milvexian up to 500 mg were generally safe and well‐tolerated, with no clinically significant bleeding events. Milvexian plasma concentration was dose proportional at doses up to 200 mg q.d. The milvexian half‐life is suitable for q.d. or b.i.d. dosing. Milvexian exhibited low renal excretion and low overall variability in PK and PD parameters.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These results can inform the future clinical development of milvexian.     

Safety,tolerability, and pharmacokinetics of oral baicalein tablets in healthy Chinese subjects: A single‐center,randomized, double‐blind,placebo‐controlled multiple‐ascending‐dose study

Baicalein is a biologically important flavonoid in extracted from the Scutellaria baicalensis Georgi, which can effectively inhibit the influenza virus. This study aimed to analyze the safety and pharmacokinetic (PK) characteristics of baicalein tablets in healthy Chinese subjects and provide more information for phase II clinical trials. In this multiple‐ascending‐dose placebo‐controlled trial, 36 healthy subjects were randomized to receive 200, 400, and 600 mg of baicalein tablet or placebo once daily on day 1 and day 10, 3 times daily on days 4–9. All groups were intended to produce safety and tolerability outcomes (lowest dose first). Blood and urine samples were collected from subjects in the 600 mg group for baicalein PK analysis. Our study had shown that Baicalein tablet was generally safe and well‐tolerated. All adverse events were mild and resolved without any intervention except one case of fever reported in the 600 mg group, which was considered as moderate but not related with baicalein as judged by the investigator. Oral baicalein tablets were rapidly absorbed with peak plasma levels being reached within 2 h after multiple administration. The highest urinary excretion of baicalein and its metabolites peaked in 2 h, followed by 12 h, with a double peak trend.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Many studies have shown that baicalin has an anti‐influenza effect in cell and animal experiments. The primary mechanism of action is that baicalein has a strong inhibitory effect on the sialidase of the influenza virus.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study aimed to analyze the safety and pharmacokinetic (PK) characteristics of baicalein tablets in healthy Chinese subjects and provide more information for phase II clinical trials.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our study results have shown that baicalein tablets were administered multiple times within the studied dose range were safe and well‐tolerated in healthy Chinese subjects with no serious or severe adverse effects. The highest urinary excretion of baicalein and its metabolites peaked in 2 h, followed by 12 h, with a double peak trend. Oral baicalein tablets were rapidly absorbed with peak plasma levels reached within 2 h after multiple administration.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our study addresses the safety outcomes of baicalein tablets and emphasizes the PKs of baicalein, which provides a better understanding and a scientific basis of the clinical application of baicalein for further evaluation.     

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.     

Assessment of the impact of Japanese‐specific long‐term safety data on new drug approval

Under the International Council for Harmonization (ICH)‐E1 guideline for drugs intended for chronic or repeated intermittent use in non‐life‐threatening diseases, data from 100 patients exposed for a minimum of 1 year are required to be included in the safety data base of a new drug application. In response to the recent globalization of drug development, the Ministry of Health, Labour, and Welfare of Japan requires that the data according to the ICH‐E1 guideline should be collected from 100 Japanese patients by the administrative notice of Basic Principles on Global Clinical Trials (reference cases) by considering ethnic differences in safety between Japanese and foreigners. In this study, we assessed Pharmaceuticals and Medical Devices Agency (PMDA) review reports of new drugs from 2016 to 2020 that include safety data for 100 Japanese patients exposed to these drugs for a minimum of 1 year to see if the study data led to the detection of Japanese‐specific safety issues. The result showed that the safety data from these patients provided only marginal value to identify Japanese‐specific safety issues, and no drugs were subjected to regulatory measures. Based on these studies and the fact that Japanese‐specific safety differences detected for a few drugs did not lead to adaptations of drug regulatory measures, we would like to propose not to make it a rule to collect safety data from 100 Japanese patients exposed at least 1 year, while keeping the ICH‐E1 guideline.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Given long‐term repeated administration of drug/s for non‐life‐threatening diseases, a safety study on 100 or more patients with 1‐year administration is required by the ICH‐E1 guidelines. The administrative notice by the Ministry of Health, Labour, and Welfare (MHLW) requires that the long‐term safety data should be collected from Japanese patients. The usefulness of this requirement has not been confirmed by systematic examination of the results.

• WHAT QUESTION DID THIS STUDY ADDRESS?

To what extent do the long‐term safety data on at least 100 Japanese patients required by the administrative notice contribute to the identification of new safety signals that result in package insert adaptation?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study on the long‐term safety data from 100 Japanese patients shows that no unique safety signals specific to Japanese patients were detected and no regulatory measures were introduced. Thus, the long‐term safety data on 100 Japanese patients has only marginal impact for the new drug reviews, and the data from total 100 patients, including foreign patients, might be able to replace the data of 100 Japanese patients.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The result of this study may lead to the amendment of the administrative notice by the MHLW requiring the long‐term safety data from 100 Japanese patients so that the data are not necessary in principle with the consideration of the recent strengthened postmarket safety management.     

Evaluation of a blockchain‐based dynamic consent platform (METORY) in a decentralized and multicenter clinical trial using virtual drugs

Blockchain is a novel data architecture characterized by a chronological sequence of blocks in a decentralized manner. We aimed to evaluate the real‐world feasibility of a blockchain‐based dynamic consent platform (METORY) in a decentralized and multicenter trial. The study consisted of three visits (i.e., screening and 2 follow‐up visits) with a 2‐week interval. Each subject was required to report the self‐measured body temperatures and take a virtual investigational drug by entering the unique drug code on the application. To simulate real‐world study settings, two major (i.e., changes in the schedule of body temperature measurement) and three minor protocol amendments (i.e., nonsignificant changes without any changes in the procedures) were set. Overall study completion rates, proportion of consent, and response time to each protocol amendment and adherence were evaluated. A total of 60 subjects (30 in each center) were enrolled in two study centers. All subjects completed the study, and the overall proportion of consent to each protocol amendment was 95.7 ± 13.7% (mean ± SD), with a median response time of 0.2 h. Overall, subjects took 90.8% ± 19.2% of the total drug, whereas compliance with the schedule was 69.1% ± 27.0%. Subjects reported 96.7% ± 4.2% of the total body temperature measurements whereas the adherence to the schedule was 59.0% ± 25.0%, which remarkably decreased after major protocol amendments. In conclusion, we evaluated a blockchain‐based dynamic consent platform in real clinical trial settings. The results suggested that major changes should be avoided unless subjects’ proper understanding is warranted.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Blockchain technology has recently drawn attention in ensuring data integrity in clinical trials due to its immutability and traceability of data. Dynamic consent is a feasible field where blockchain could be adopted. Decentralized clinical trials after coronavirus disease 2019 (COVID‐19) accelerated the adoption of blockchain in clinical trials.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The study evaluated the real‐world feasibility of METORY by conducting a decentralized and multicenter clinical trial using virtual drugs.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The results of our study revealed that the information given on the online platform could often be ignored or misunderstood, despite the prompt consent of the subjects. A system to verify the accurate understanding of the subjects should be incorporated in the platform.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Blockchain‐based dynamic consent could facilitate clinical trials in decentralized settings. The virtual drug approach could be used to evaluate drug behavior prior to the trials.     

Pharmacokinetics and pharmacodynamics of itepekimab in healthy adults and patients with asthma: Phase I first‐in‐human and first‐in‐patient trials

Itepekimab is a monoclonal antibody that targets interleukin (IL‐33) and has been shown to reduce airway inflammation and associated tissue damage in preclinical studies. We assessed the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamic profiles of single‐ascending and multiple‐ascending doses of itepekimab in two randomized, double‐blind, placebo‐controlled phase I studies. Healthy adults (N = 40) were randomized to the single‐dose study and patients with moderate asthma (N = 23) to the multiple‐dose study. Itepekimab was administered intravenously (0.3, 1, 3, or 10 mg/kg infusion) or subcutaneously (150 mg) in the single‐dose study and subcutaneously (75 or 150 mg weekly for 4 weeks) in the multiple‐dose study. Itepekimab exhibited linear PKs across studies and dose‐proportional increases in mean maximum concentration in serum and area under the concentration–time curve following single intravenous or multiple subcutaneous doses. Itepekimab demonstrated mean subcutaneous bioavailability of 59–73% and a long terminal half‐life (30.0–31.6 days). IL‐33 concentrations in most healthy participants and patients with asthma were undetectable at baseline. Following administration of itepekimab in both studies, total IL‐33 concentrations increased and blood eosinophils decreased, both with durable effect. Itepekimab was well‐tolerated in both studies with no detection of treatment‐emergent anti‐drug antibody responses.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Preclinical data suggest that itepekimab, a monoclonal antibody targeting IL‐33, may benefit patients with chronic inflammatory airway diseases by blocking IL‐33–mediated pathologic inflammation. Neither the pharmacokinetic (PK) profile of itepekimab nor its safety has been fully elucidated in first‐in‐human or first‐in‐patient studies.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The study evaluated the initial safety of itepekimab, and its PK and pharmacodynamic activity in healthy adults and patients with asthma.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Itepekimab demonstrated linear and dose‐proportional PKs in our studies and was well‐tolerated, with no evidence of immunogenicity. These findings have facilitated dose and regimen selection for subsequent clinical studies in patients with asthma and chronic obstructive pulmonary disease.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Itepekimab is one of a few anti‐alarmin biologics under development; if successful, it may provide an alternative mechanism of action with which to target chronic inflammatory airway diseases, alone or in combination with other targeted therapies.     

Utility of the 13C‐pantoprazole breath test as a CYP2C19 phenotyping probe for children

The ¹³C‐pantoprazole breath test (PAN‐BT) is a safe, noninvasive, in vivo CYP2C19 phenotyping probe for adults. Our objective was to evaluate PAN‐BT performance in children, with a focus on discriminating individuals who, according to guidelines from the Clinical Pharmacology Implementation Consortium (CPIC), would benefit from starting dose escalation versus reduction for proton pump inhibitors (PPIs). Children (n = 65, 6–17 years) genotyped for CYP2C19 variants *2, *3, *4, and *17 received a single oral dose of ¹³C‐pantoprazole. Plasma concentrations of pantoprazole and its metabolites, and changes in exhaled ¹³CO₂ (termed delta‐over‐baseline or DOB), were measured 10 times over 8 h using high performance liquid chromatography with ultraviolet detection and spectrophotometry, respectively. Pharmacokinetic parameters of interest were generated and DOB features derived using feature engineering for the first 180 min postadministration. DOB features, age, sex, and obesity status were used to run bootstrap analysis at each timepoint (T_i) independently. For each iteration, stratified samples were drawn based on genotype prevalence in the original cohort. A random forest was trained, and predictive performance of PAN‐BT was evaluated. Strong discriminating ability for CYP2C19 intermediate versus normal/rapid metabolizer phenotype was noted at DOB_T30 min (mean sensitivity: 0.522, specificity: 0.784), with consistent model outperformance over a random or a stratified classifier approach at each timepoint (p < 0.001). With additional refinement and investigation, the test could become a useful and convenient dosing tool in clinic to help identify children who would benefit most from PPI dose escalation versus dose reduction, in accordance with CPIC guidelines.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

CYP2C19 genotype is a known determinant of drug disposition and response for proton pump inhibitors (PPIs). However, it is not the only determinant and genotype‐phenotype discordance can occur.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can the ¹³C‐pantoprazole breath test (PAN‐BT) be utilized as a noninvasive CYP2C19 phenotyping probe for children, and can the test discriminate the CYP2C19 intermediate metabolizer (IM) phenotype (i.e., children who would benefit from PPI starting dose reduction) from the normal and rapid metabolizer (NM and RM) phenotype (i.e., children who would benefit from PPI starting dose escalation)?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The PAN‐BT can discriminate CYP2C19 IMs from NMs and RMs in as little as 30 min (mean sensitivity 0.522, specificity 0.784), and is feasible in children as young as 6 years of age. Based on recently demonstrated receptiveness to drug dose individualization for PPIs in pediatrics, additional studies are warranted in pediatric populations.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

A convenient, noninvasive, in‐office, CYP2C19 phenotyping probe could aide appropriate drug dose selection for PPIs in pediatrics.     

Evaluation of the abuse potential of difelikefalin,a selective kappa‐opioid receptor agonist,in recreational polydrug users

Difelikefalin, a selective kappa‐opioid receptor agonist with limited central nervous system penetration, is being developed for the treatment of chronic pruritic conditions. This randomized, double‐blind, active‐ and placebo‐controlled, four‐way crossover study was designed to evaluate the abuse potential of difelikefalin in healthy recreational polydrug users. Using a 4 × 4 Williams design, nondependent adult users of opioids and hallucinogens (N = 44) were randomized to receive single intravenous (i.v.) injections of difelikefalin at supratherapeutic doses (5 and 15 mcg/kg); pentazocine (0.5 mg/kg), a schedule IV mu‐opioid partial agonist and kappa‐opioid receptor agonist; and placebo. The abuse potential of difelikefalin was compared with pentazocine and placebo using the maximal score (maximum effect [E_max]) of the Drug Liking visual analog scale (VAS; primary end point), along with multiple secondary end points of subject‐rated measures and pupillometry. Difelikefalin produced significantly lower Drug Liking VAS E_max, and lower peak positive, sedative, and perceptual effects compared with pentazocine. These effects of difelikefalin were small, brief, and not dose‐dependent, although marginally greater than those observed with placebo. Neither dose of difelikefalin elicited significant negative or hallucinogenic effects. On end‐of‐session measures of overall drug liking and willingness to take the drug again, difelikefalin did not differ from placebo, indicating subjects neither liked nor disliked the effects overall and did not feel motivated to take the drug again. Consistent with its lack of mu agonist activity, difelikefalin did not induce miosis compared with pentazocine. All treatments were generally well‐tolerated. This study indicates that difelikefalin presents a low potential for abuse.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Difelikefalin is a selective kappa‐opioid receptor agonist with limited central nervous system penetration being developed for the treatment of chronic pruritus. Difelikefalin has no affinity for other opioid receptors and therefore is different from opioid analgesics that predominantly bind to mu opioid receptors.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This randomized, double‐blind, active‐ and placebo‐controlled, four‐way crossover study addressed whether difelikefalin has abuse potential in healthy recreational polydrug users.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Intravenous difelikefalin, at supratherapeutic doses, had an abuse potential profile that was significantly lower than the schedule IV opioid pentazocine, and not meaningfully different from placebo. Difelikefalin did not elicit significant negative or hallucinogenic effects.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These findings suggest that difelikefalin should not be a target for diversion for recreational use. This has important clinical implications for patients who may require this treatment, and it demonstrates that peripherally restricted kappa‐opioid receptor exhibit fewer adverse effects and toxicities related to abuse over typical opioids.     

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.     

Safety,tolerability, and pharmacokinetics of single‐ and multiple‐dose administration of islatravir (MK‐8591) in adults without HIV

Islatravir (MK‐8591) is a nucleoside analogue in development for the treatment and prevention of HIV‐1. Two phase 1 trials were conducted during initial evaluation of islatravir: rising single doses (Study 1) and rising multiple doses (Study 2) of oral islatravir in male and female participants without HIV (aged 18–60 years). Safety, tolerability, and pharmacokinetics of islatravir (plasma) and islatravir‐triphosphate (peripheral blood mononuclear cells) were assessed. In Study 1, 24 participants, assigned to 1 of 3 panels, received alternating single doses of islatravir in a fasted state from 5 mg to 400 mg, or placebo, over 3 dosing periods; a 30 mg dose was additionally assessed following a high‐fat meal. In Study 2, 8 participants per dose received 3 once‐weekly doses of 10, 30, or 100 mg islatravir or placebo in a fasted state. For each panel in both trials, 6 participants received active drug and 2 received placebo. Islatravir was generally well‐tolerated, with no serious adverse events or discontinuations due to adverse events. Islatravir was rapidly absorbed (median time to maximum plasma concentration 0.5 hours); plasma half‐life was 49–61 h; intracellular islatravir‐triphosphate half‐life was 118–171 h. Plasma exposure increased in an approximately dose‐proportional manner; there was no meaningful food effect. There was a modest degree of intracellular islatravir‐triphosphate accumulation after multiple weekly dosing. After single oral doses of islatravir greater than or equal to 5 mg, intracellular islatravir‐triphosphate levels were comparable to levels associated with efficacy in preclinical studies. These results warrant continued clinical investigation of islatravir.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

​Current HIV treatment and prevention strategies have limitations, and novel agents that offer improved safety and tolerability, a high barrier to HIV resistance, and more convenient dosing regimens are required.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Two phase 1 studies in participants without HIV assessed safety and pharmacokinetics of rising single and multiple doses of oral islatravir, a nucleoside analogue, to support continued development for the treatment and prevention of HIV‐1 infection.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Islatravir was generally well‐tolerated at single doses up to 400 mg. Oral doses of islatravir greater than or equal to 10 mg resulted in intracellular peripheral blood mononuclear cell levels of the active form, islatravir‐triphosphate, comparable to those associated with antiviral efficacy in preclinical studies.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These studies provide important safety and pharmacokinetic information about islatravir in adults without HIV, which will be used to support further clinical investigation of islatravir for the treatment and prevention of HIV‐1 infection.     

Pharmacokinetics,bioavailability, and bioequivalence of lower‐sodium oxybate in healthy participants in two open‐label,randomized, crossover studies

American Academy of Sleep Medicine practice parameters designate sodium oxybate (SXB) as a standard of care for cataplexy, excessive daytime sleepiness (EDS), and disrupted night‐time sleep in narcolepsy. Recently, a lower‐sodium oxybate (LXB) with 92% less sodium than SXB was approved in the United States for the treatment of cataplexy or EDS in patients 7 years of age and older with narcolepsy. Two phase I, open‐label, randomized, single‐dose crossover pharmacokinetic studies in healthy adults were conducted. Single 4.5‐g oral doses of LXB and SXB were administered in a fasted or fed state. In the fasted state at equivalent oxybate doses, LXB, compared with SXB, had a lower maximum plasma concentration (C_max; study 1 [total aqueous volume, 240 ml]: 101.8 vs. 135.7 µg/ml; study 2 [60 ml]: 94.6 vs. 123.0 μg/ml), delayed time to C_max (T_max; study 1: 0.75 vs. 0.5 h; study 2: 1.0 vs. 0.5 h), but similar area under the curve (AUC; study 1: AUC_0‐t, 235.4 vs. 263.9 μg∙h/ml; AUC_0‐∞, 236.5 vs. 265.2 μg∙h/ml; study 2: AUC_0‐t, 241.5 vs. 254.7 μg∙h/ml; AUC_0‐∞, 243.1 vs. 256.3 μg∙h/ml). Bioequivalence criteria were met for AUC but not C_max (both studies). C_max and AUC were lower under fed than fasted conditions (LXB and SXB); differences between fed versus fasted were smaller for LXB than SXB. These pharmacokinetic differences between LXB and SXB are likely due to the lower sodium content in LXB. Pooled analyses demonstrated that a higher C_max is associated with a higher incidence of nausea and vomiting.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Sodium oxybate (SXB) and lower‐sodium oxybate (LXB) are approved in the United States for the treatment of cataplexy or excessive daytime sleepiness in patients greater than or equal to 7 years of age with narcolepsy. The pharmacokinetics (PK) of SXB includes a negative food effect (reduced maximum plasma concentration [C_max] and area under the curve [AUC]) and greater than dose‐proportional increase in exposure.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What are the relative bioavailability and bioequivalence of LXB and SXB in the fasted state, and how is the PK of LXB affected by food?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

At equivalent oxybate doses, in the fasted state, LXB had a lower C_max, delayed time to C_max, and similar AUC versus SXB (bioequivalence criteria met for AUC). C_max and AUC were lower under fed conditions (LXB and SXB); reduction in C_max with food was less for LXB compared with SXB. Lower oxybate C_max was associated with lower incidence of nausea and vomiting.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

PK differences between LXB and SXB may stem from reduced sodium. LXB represents a novel oxybate treatment for narcolepsy.     

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.