To characterize the relationship between cendakimab exposure and the longitudinal efficacy endpoint dysphagia days (DD), E-R analyses were performed using data from the EE-001 study (N = 427) with eosinophilic esophagitis. DD-a bounded, discrete endpoint assessed over 14-day period via modified daily symptom diary (mDSD)-was modeled using a latent variable indirect response (IDR) model coupled with a combined uniform-binomial (CUB) distribution. The latent variable, representing the underlying disease status, was dynamically modulated by placebo and drug effects (a function of individual-predicted exposure) to govern the binomial probability of DD, while the uniform component captured the residual variability in patient-reported outcomes. Inter-individual variability was estimated for baseline DD, maximum placebo effect, and maximum drug effect. Covariates, including steroid inadequate response or intolerance (Steroid IR/I) status and baseline DD, were incorporated in the final model based on the clinical relevance. The estimated placebo half-life was ~28 weeks, estimated EC50 was 76.5 μg/mL, corresponding to an EC90 of ~688 μg/mL, indicating steepness of the Emax curve. Model-based simulations showed that both 360 mg QW and QW-to-Q2W regimens reduced DD compared to placebo at Week 48, with mean reductions of ~1.65 and ~1.36 days, respectively. Covariate-stratified simulations suggested consistent responses across sex, age, and race. Steroid IR/I and baseline DD influenced treatment response magnitude but did not warrant dose modification. These findings support QW-to-Q2W as an effective maintenance posology and the utility of latent variable IDR models with appropriate likelihoods for modeling bounded, discrete longitudinal endpoints in E-R analyses.

This study uses a population pharmacokinetic (PPK) approach to provide abatacept dosing recommendations in pediatric patients 2 to < 6 years of age receiving unrelated donor hematopoietic stem cell transplantation (HSCT) due to hematologic malignancies (HMs), for the prophylaxis of acute graft-versus-host disease (aGVHD). An intermediate PPK model was developed and refined to include data from 904 patients aged 2-17 years with juvenile idiopathic arthritis administered with subcutaneous abatacept. Then, PK simulations were performed using the final PPK model for virtual pediatric patients aged 2 to < 6 years administered with either intravenous abatacept, fixed abatacept doses, or loading doses followed by maintenance dosing. The final model characterized abatacept exposure well using a linear, two-compartment model including absorption parameters (KA and F1), and generated parameter estimates comparable to previously published models. Further simulations of abatacept exposure in 10,000 virtual patients aged 2 to <6 years revealed that a 15-mg/kg loading dose followed by 12-mg/kg maintenance doses achieved exposure levels similar to adults at risk of aGVHD, and therefore was selected for these patients. Additionally, an exposure-response (E-R) safety analysis in patients aged ≥6 years with HMs undergoing HSCT showed no significant relationship between abatacept exposure and occurrence of infection, confirming the safety of abatacept in these patients. The recommended dosing regimen for pediatric patients aged 2 to <6 years at risk of aGVHD is a 15-mg/kg loading dose on Day -1, followed by 12 mg/kg for the remaining doses on Days 5, 14, and 28.

Apixaban is an oral direct inhibitor of factor Xa (FXa) that could be a treatment option for thromboembolism prevention in children with congenital or acquired heart disease (CAHD). Data from SAXOPHONE, a phase II pediatric study, were used to update a previously developed population pharmacokinetics (PPK) model and to assess the covariate effect of patient type on PK parameters while retaining previous covariates. Stochastic simulations were performed to assess whether the proposed dosing regimens in pediatric patients aged 28 days to < 18 years matched adult exposures. The relationship between anti-Factor Xa (AXA) and apixaban concentration, as well as apixaban concentration and chromogenic FX, were evaluated. Apixaban dose adjustment in response to the growth of pediatric patients and changes in age and weight were also assessed. Apixaban PK in pediatric patients with CAHD was well characterized by a 2-compartment model with first-order absorption, dose-dependent F1, and first-order elimination. Apixaban apparent clearance (CL/F) and apparent volume of distribution in the central compartment (Vc/F) increased with increasing body weight. Apixaban CL/F was lower in pediatric patients with CAHD compared to adults and other pediatric patients. The fixed dose by weight-tiered dosing regimen for pediatric patients with CAHD (28 days to < 18 years) achieved target exposures similar to adult VTE treatment and nonvalvular atrial fibrillation populations. A linear PK/PD relationship between apixaban and AXA was observed. Inhibition of FXa was observed across weight tiers. Apixaban dose adjustment in response to weight gain resulted in exposures similar to target adult exposures.

Apixaban could be a potential treatment option for the prevention of venous thromboembolism (VTE) in children with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL). This analysis describes an updated two-compartment population pharmacokinetic (PPK) model that characterizes the PK variability of apixaban in pediatric patients with ALL or LL treated with asparaginase using PK data from a phase III study (PREVAPIX). Patient type of ALL or LL was found to be a significant covariate on the apparent central volume of distribution (Vc/F) and first-order absorption rate (Ka). Pediatric patients (aged 9 months to < 18 years) with ALL or LL had a 52.4% lower Ka compared with adults; this was 81.1% lower than other pediatric patients (9 months to < 18 years) at risk of VTE. Apixaban Vc/F was estimated to be 43.1% lower in pediatric patients compared with adult patients. The updated PPK model was used to simulate and confirm apixaban fixed-dose by weight-tiered regimen-achieved target exposures in pediatric patients (aged 28 days to < 18 years) with ALL or LL. In addition, a PK/pharmacodynamic (PD) analysis was performed using a linear regression model to characterize the relationship between anti-FXa activity (AXA) and apixaban concentration in pediatric patients with ALL or LL. The characterization of apixaban PK and PK/PD in this analysis contributes to evidence that apixaban could be a potential antithrombotic option in pediatric patients.

Mavacamten, a cardiac myosin inhibitor, is primarily metabolized by the cytochrome P450 (CYP) enzymes CYP2C19 and CYP3A4, and coadministration with strong CYP3A4 or CYP2C19 inhibitors was contraindicated in patients with obstructive hypertrophic cardiomyopathy (HCM) in the US Prescribing Information. This study assessed the safety and efficacy of modifying mavacamten posology to accommodate coadministration with strong CYP3A4 and strong/moderate CYP2C19 inhibitors. Simulations of 5000 virtual patients with obstructive HCM with an equal distribution of CYP2C19 metabolizer phenotypes were performed using population pharmacokinetic and exposure-response modeling approaches. A reference posology and variations thereof were simulated to evaluate long-term (chronic) and short-term (1-week) coadministration with CYP3A4 or CYP2C19 inhibitors. Proportions of patients with left ventricular ejection fraction (LVEF) <50% and Valsalva left ventricular outflow tract gradient (VLVOTg) <30 mm Hg were evaluated to assess safety and efficacy, respectively. Compared with the reference posology, a modified posology, which used a 2.5-mg starting dose with coadministration being stopped if LVEF was <50% at any time when receiving 2.5 mg, resulted in a similar peak proportion of CYP2C19 poor metabolizers and CYP2C19 ultrarapid metabolizers with LVEF <50% when initiating mavacamten with a CYP3A4 or CYP2C19 inhibitor, respectively. Achievement of optimal efficacy was delayed in some patients owing to dose reduction. Initiation of CYP3A4 or CYP2C19 inhibitor treatment in patients receiving stable mavacamten therapy was accommodated through mavacamten dose reduction by one level. Interruption of mavacamten during short-term administration of inhibitors transiently increased VLVOTg for the duration of interruption, with no effect on LVEF.

Objectives: Danicamtiv is an investigational drug that works as a cardiac myosin activator and could be a potential treatment option for heart failure with reduced ejection fraction (HFrEF). Successful development in this potential indication is contingent on a favorable benefit-risk profile, favorable pharmacokinetic profile and identifying an exposure-response relationship using key echocardiograph (ECHO) parameters indicative of improving systolic function. Population pharmacokinetic (PK) and PK/pharmacodynamic (PK/PD) modeling were performed to better understand the potential of danicamtiv.Methods: Data from 29 patients in the phase 2a HFrEF PoC study1 was used to perform population PK and PK/PD modeling in NONMEM 7.4. ECHO parameters such as systolic ejection time (SET) and stroke volume were evaluated as PD endpoints using a linear or Emax model. Model performance was evaluated using goodness of fit plots. Final parameter estimates from the population PK-PD model were used to perform simulations using mrgsolve in R to assess dosing. 1000 simulation runs were performed at each evaluated dose. Results: A one compartment model with zero-order absorption described the concentration data well. The inter-individual variability on apparent clearance and apparent volume of distribution was 23.6% and 18.1%. Among ECHO parameters evaluated, SET demonstrated the strongest relationship to danicamtiv exposure, which was described by an Emax model. Heart rate (HR) was a significant, physiologically relevant covariate on baseline SET. Subjects with lower HR had higher SET. Exposure-response relationship with stroke volume data was characterized indirectly through the linear relationship between SET and stroke volume previously described in literature2.Conclusion: Population PK analysis demonstrated relatively low variability and minimal complexities in the PK of danicamtiv. The exposure-response analysis suggests 25-100 mg BID is the optimal clinical dose range to be further evaluated in future studies without the need of therapeutic drug monitoring. Danicamtiv exposure has an indirect relationship with stroke volume through its relationship with SET, which supports the hypothesis that danicamtiv increases contractility. Overall, danicamtiv appears to have favorable properties within the context of other agents with similar mechanism of action in the literature.Citations: 1 Voors AA, et al. Eur J Heart Fail. 2020; 22(9):1649-1658.2Weissler AM, et al. Am Heart J. 1961; 62(3):367-378.

OBJECTIVE:To determine whether higher serum exposure during subcutaneous (SC) abatacept (ABA) treatment was associated with an increased infection risk in adult patients with early rheumatoid arthritis (RA). METHODS:Data from Assessing Very Early Rheumatoid Arthritis Treatment-2 (AVERT2; ClinicalTrials.gov: NCT02504268), a randomized, placebo-controlled study in anticitrullinated protein antibody-positive patients with early RA, were analyzed. A post hoc population pharmacokinetic (PPK) analysis was performed. The association between steady-state ABA concentration exposures (ie, steady-state time-averaged serum concentration, steady-state trough serum concentration, steady-state maximum serum concentration) and first infection was evaluated using Kaplan-Meier plots of probability vs time receiving treatment and Cox proportional hazards models. RESULTS:The PK model of SC ABA was defined as a linear 2-compartment model with first-order absorption and elimination, and higher body weight was the only covariate with a clinically relevant effect in the final PPK model. Infections occurred in 330/693 patients treated with ABA + methotrexate (MTX; 47.6%; 11/693 [1.6%] with serious infections) and 134/301 of those treated with ABA placebo + MTX (44.5%; 4/301 [1.3%] with serious infections). Exposure-response analysis demonstrated no exposure relationship for an increased risk of first infection for patients with concomitant use of MTX and glucocorticoids (GCs) during the induction period, baseline GC use, or higher-than-median body weight (> 70 kg) at baseline. CONCLUSION:This exposure-response analysis of AVERT-2 showed no increase in the risk of first infection, regardless of ABA exposure level, in patients with RA treated with SC ABA. Similarly, no effect on the risk of first infection was found for concomitant MTX and GC use in patients with RA treated with SC ABA + MTX.

Mavacamten is a potential inducer of cytochrome P450 (CYP) 3A4 and could reduce the effectiveness of concomitant drugs that are metabolized by CYP3A4, such as midazolam. This study aimed to determine if repeat doses of mavacamten achieving clinically relevant exposures affected midazolam exposure. This was a single-center, open-label study in healthy participants. Participants received: on day 1, midazolam 5 mg; on days 2-3, mavacamten 25 mg; on days 4-16, mavacamten 15 mg; and on day 17, mavacamten 15 mg and midazolam 5 mg. Plasma concentrations of mavacamten, midazolam, and the midazolam metabolite 1'-hydroxymidazolam were measured. A physiologically based pharmacokinetic (PBPK) model was used to simulate the effect of mavacamten-mediated CYP3A4 induction on midazolam exposure by CYP2C19 phenotype. Thirteen adult participants were enrolled (46.2% were female; mean [SD] age: 34.0 [9.0] years). Compared with midazolam alone, midazolam coadministered with mavacamten decreased the maximum observed plasma concentration (Cmax), area under the drug concentration-time curve (AUC) from time zero to infinity (AUC0-inf), and AUC from time zero to last measurable concentration (AUC0-last) for midazolam by 7%, 13%, and 24%, respectively; for 1'-hydroxymidazolam, AUC0-inf and AUC0Ȁlast increased by 20% and 11%, respectively. Ten participants experienced adverse events and the majority were mild in severity. The PBPK model predicted the clinical trial data well. The PBPK simulation assessed that the overall impact of mavacamten on midazolam Cmax and AUC was predicted to be weak regardless of CYP2C19 phenotype. At clinically relevant exposures, mavacamten had a negligible effect on midazolam exposure.

OBJECTIVE:To assess the effect of activated charcoal on the single-dose pharmacokinetics of mavacamten when administered 2 h or 6 h after mavacamten dosing. METHODS:In this open-label, randomized, parallel-group study, healthy adults were randomized into three groups to receive mavacamten 15 mg alone or mavacamten 15 mg plus activated charcoal 50 g administered either 2 h or 6 h after mavacamten dosing. Pharmacokinetic parameters were derived from plasma concentration-time data using noncompartmental methods. RESULTS:Of the 45 participants randomized, 37 completed the study. When activated charcoal was administered 2 h after mavacamten dosing, mavacamten absorption and exposure were reduced compared with when mavacamten was administered alone: the area under the concentration-time curve from 0 to 72 h (AUC0-72) and area under the concentration-time curve from time 0 extrapolated to infinity (AUCINF) were reduced by 14% and 34%, respectively. The maximum plasma concentration (Cmax) was also slightly lower when activated charcoal was administered 2 h after mavacamten dosing than with mavacamten alone. Pharmacokinetic profiles were similar for mavacamten alone and mavacamten plus activated charcoal administered 6 h after mavacamten dosing. CONCLUSIONS:Activated charcoal was successful in reducing mavacamten absorption and exposure when administered as soon as possible after identification of a need for adsorption (2 h after mavacamten dosing). No change in exposure was observed when activated charcoal was administered 6 h after mavacamten dosing. CLINICAL TRIAL REGISTRATION:NCT05320094.

In patients with heart failure (HF) who respond inadequately to loop diuretic therapy, BMS-986308, an oral, selective, reversible renal outer medullary potassium channel (ROMK) inhibitor may represent an effective diuretic with a novel mechanism of action. We present data from the first-in-human study aimed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) following single ascending doses of BMS-986308 in healthy adult participants. Forty healthy participants, aged from 20 to 55 years, and body mass index (BMI) from 19.8 to 31.6 kg/m2 were assigned to 1 of 5 dose cohorts (1, 3, 10, 30, and 100 mg) and randomized (6:2) to receive BMS-986308 oral solution or matching placebo. Following administration, BMS-986308 was rapidly absorbed with a median time to maximum concentration (Tmax) of 1.00 to 1.75 h and exhibiting a mean terminal half-life (t1/2) of approximately 13 h. Dose proportionality was evident in BMS-986308 area under the concentration-time curve (AUC), while maximum concentration (Cmax) was slightly greater than dose-proportional. We observed that urine output (or diuresis; mL) and urinary sodium excretion (or natriuresis; mmol) increased in a dose-dependent manner, starting at a minimum pharmacologically active dose of 30 mg. The largest mean changes from baseline in diuresis and natriuresis occurred in both the 6- and -24 h post-dose period following administration of 100 mg (1683.0 mL and 2055.3 mL, and 231.7 mmol and 213.7 mmol, respectively; ***P < 0.001). Overall, single-dose BMS-986308 was found to be safe, well-tolerated, with an excellent PK profile, and substantial diuretic and natriuretic activity.

The pharmacokinetics (PK) of intravenous (i.v.) nivolumab is well characterized. A subcutaneous (s.c.) nivolumab formulation with and without recombinant human hyaluronidase PH20 enzyme is being evaluated in CheckMate 8KX (NCT03656718). A model‐based analysis was conducted to characterize the PK of nivolumab s.c. and predict systemic exposures after i.v. and s.c. administration to guide dosing regimen selection for nivolumab s.c. A prior i.v. model was modified to incorporate an s.c. extravascular compartment and estimate the absorption rate constant and bioavailability of nivolumab s.c. Serum concentration–time data from 82 patients treated with nivolumab s.c. 720, 960, or 1,200 mg were pooled with existing i.v. data from multiple studies for model development. Prediction‐corrected visual predictive check (pcVPC) plots assessed the model's performance. Stochastic simulations were conducted to predict exposures for i.v. and s.c. administration. The data were described by a two‐compartment model with time‐varying clearance, zero‐order infusion into the central compartment after i.v. dosing, and first‐order absorption from the extravascular compartment after s.c. dosing. The pcVPC suggested that the model adequately described the observed nivolumab s.c. data. Predicted nivolumab exposures at 1,200 mg s.c. every 4 weeks (q4w) were higher than those at the approved dose of 3 mg/kg i.v. q2w and lower than those at the highest tested safe dose of 10 mg/kg i.v. q2w. Nivolumab PK is well‐characterized using the combined s.c./i.v. population PK model. The model‐based analysis facilitated a comprehensive benefit–risk assessment of nivolumab s.c. and informed selection of 1,200 mg s.c. q4w for phase III evaluation.

Abstract Milvexian, an oral activated Factor XI (FXIa) inhibitor, is in clinical studies where it may be combined with antiplatelet agents, including aspirin and/or clopidogrel, to prevent thromboembolic diseases. This phase I trial assessed safety, pharmacokinetics, and pharmacodynamics of milvexian coadministration with aspirin and/or clopidogrel in healthy participants through 3 drug-drug interaction studies using a 3-period, 3-treatment, crossover design. A total of 113 participants were randomized to receive milvexian (200 mg; twice daily for 5 days) or matched placebo coadministered with once-daily aspirin (325 mg for 5 days) and/or clopidogrel (Day 1: 300 mg; Days 2–5: 75 mg). Milvexian was safe and well tolerated, with and without aspirin and/or clopidogrel. Eight mild bleeding adverse events (AEs) were reported in 5 of 113 participants across various treatment arms. Peak and total exposures of milvexian were similar with or without clopidogrel and/or aspirin. Exposure-dependent prolongation of activated partial thromboplastin time and reduction of FXI clotting activity by milvexian were similar with coadministration of aspirin and/or clopidogrel. Milvexian, with or without coadministration of aspirin and/or clopidogrel, did not affect bleeding time or platelet aggregation. Administration of milvexian alone or with aspirin and/or clopidogrel was safe and well tolerated without increased incidence of AEs, including bleeding. Pharmacokinetic and pharmacodynamic effects of milvexian, including bleeding time, were similar with or without aspirin and/or clopidogrel. ClinicalTrials.gov Identifier: NCT03698513.

Milvexian is an oral, small-molecule factor XIa inhibitor being developed to prevent thromboembolic events. This study assessed the absolute bioavailability (F) of milvexian following single doses of milvexian spray-dried dispersion (SDD) formulation under fed and fasted conditions, and milvexian solution, in healthy adult participants using an intravenous microtracer approach. This was a phase I, open-label, partially randomized, 4-sequence, 5-period crossover study. After fasting for ≥10 h, participants received milvexian 200-mg oral solution with a 100-μg 14C milvexian intravenous microtracer at the time of maximum observed plasma concentration. Following a 3-day washout, participants were randomized to 1 of 4 milvexian SDD treatment sequences in a crossover fashion: 25 mg fasted, 25 mg fed, 200 mg fasted, or 200 mg fed. Pharmacokinetic data were collected up to 72 h postdose. Seventeen participants were dosed, and 14 completed treatment. Under fasted conditions, milvexian F was ~100%, 58.2%, and 54.2% following administration of the oral solution, 25 mg SDD, and 200 mg SDD, respectively. Under fed conditions, milvexian F following 25 mg and 200 mg SDD was 44.3% and 75.6%, respectively. The milvexian SDD formulation at 25 mg and 200 mg resulted in similar F in a fasted state; under fed conditions, milvexian F decreased at 25 mg and increased at 200 mg. These findings clarify pharmacokinetic-related gaps observed in previous studies.

Introduction: Persistent congestion and edema remain an unmet need in heart failure (HF). BMS-986308, a novel inhibitor of the Renal Outer Medullary Potassium Channel (ROMK), is predicted to enhance potassium-sparring diuresis and natriuresis in HF patients with persistent congestion and edema despite SOC treatment. We present pharmacodynamics and biomarkers of kidney function and injury from a first-in-human study of BMS-986308 (NCT04763226). Method: Thirty-two adult healthy participants were assigned to 1 of 4 dose cohorts (3, 10, 30, and 100 mg) and randomized (6:2) to receive a single dose of BMS-986308 oral solution or matching placebo. Diuresis and natriuresis were measured in intervals over 24 h post dose and baseline-adjusted using matching intervals at Day -1. Serum creatinine, cystatin C, electrolytes (K, Ca, Cl, Mg), aldosterone, renin activity; and urinary protein and albumin to creatinine ratios (UPCR, APCR); and biomarkers of kidney injury Kim1, NAGASE, OPN, CLUST were measured up to Day 5. Statistical significance between BMS-986308 treatment groups and placebo was assessed using unpaired t tests. Results are mean (±SD). ** P<0.01, *** P<0.001 Results: BMS-986308 increased natriuresis and diuresis in a dose-dependent manner starting at the 30 mg dose. The table below presents change from baseline (CFB). No significant change in kaliuresis was observed (mean placebo and 100mg dose respectively 0.08 ± 0.03 and 0.05 ± 0.01 mmol/min over 24h). Aldosterone and renin activity peaked at 24h at 30 mg and 100 mg (CFB 132 ± 102% and 405 ± 129%***, 121 ± 130% and 783 ± 282%** respectively). A transient rapid dose-dependent increase in serum creatinine was observed at the 100 mg dose (CFB 44 ± 12% at 6h***, 28 ± 13% at Day2***, 11 ± 9% at Day4**, 100 mg dose) as well as a less pronounced increase in serum cystatin C (peak at 30 ± 6% at 12h***, 100 mg dose). No meaningful change was observed for the other biomarkers tested. Conclusion: BMS-986308 significantly increased diuresis and natriuresis in healthy participants while sparing potassium. In line with the substantial natriuresis, activation of the RAAS pathway and transient elevations of serum creatinine and cystatin C (with no change in kidney injury markers) was observed.

Introduction: Ozanimod (OZA) is a selective sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator approved for the treatment of moderately to severely active ulcerative colitis and relapsing multiple sclerosis. Treatment with OZA and other S1P receptor modulators has been associated with bradycardia likely due to the pharmacologic effect of S1P1 receptors on heart rate (HR). Thus, dose titration with OZA is implemented to mitigate this risk. Methods: This randomized, double-blind, placebo (PBO)–controlled, adaptive phase 1 study evaluated the effects of OZA reinitiation (0.92 mg) on HR after different washout intervals relative to dose escalation in healthy adults. Participants were randomized to receive once-daily OZA (dose titration: Days 1–4, 0.23 mg; Days 5–7, 0.46 mg; then 0.92 mg) or PBO for 28 days in Period 1, followed by a washout of 3, 7, or 14 days, and then treatment reinitiation with a single dose of OZA 0.92 mg or PBO in Period 2. Changes at Period 2 Day 1 from Period 1 Day 1 (CFP1) in the HRNadir from 0–12 h postdose were compared between OZA/OZA and PBO/PBO groups after each washout interval and were analyzed using an ANCOVA model with fixed effects for treatment, Period 1 Day 1 HRNadir (0–12 hours), sex, and treatment × Period 1 Day 1 HRNadir (0–12 hours); least squares (LS) mean differences between OZA/OZA and PBO/PBO with 90% CI were calculated. Safety was also assessed. Results: Of 64 participants, 15, 16, and 15 received OZA/OZA and completed the 3-, 7, and 14-day washout intervals, respectively; 18 participants received PBO/PBO (6 in each washout group, combined for all washout interval comparisons). LS mean CFP1 Day 1 HRNadir changes were generally similar between OZA/OZA and PBO/PBO groups at each washout interval: 3 days = 3.51 vs 1.73 beats per minute (bpm), 7 days = 0.85 vs 1.87 bpm, and 14 days = 0.27 vs 1.81 bpm, respectively. The CFP1 Day 1 HRNadir LS mean differences between OZA/OZA and PBO/PBO (90% CI) at each washout interval were 3 days = 1.78 bpm (–1.76 to 5.32), 7 days = –1.02 bpm (–3.88 to 1.85), and 14 days = –1.54 bpm (–4.20 to 1.11). There were no severe or serious adverse events during any period or washout interval. Conclusion: Overall, reinitiation of OZA at the maintenance dose of 0.92 mg once daily after dose interruption of 3, 7, or 14 consecutive days was not associated with meaningful changes in HR. OZA can be safely reinitiated at the 0.92 mg dose without repeating dose titration within 14 days of drug discontinuation.

Abstract This randomized, double‐blind, single‐ and multiple‐ascending dose study assessed the pharmacokinetics (PKs), pharmacodynamics, and safety of deucravacitinib (Sotyktu™), a selective and potent small‐molecule inhibitor of tyrosine kinase 2, in 100 (75 active, 25 placebo) healthy volunteers (NCT02534636). Deucravacitinib was rapidly absorbed, with a half‐life of 8–15 h, and 1.4–1.9‐fold accumulation after multiple dosing. Deucravacitinib inhibited interleukin (IL)‐12/IL‐18‐induced interferon (IFN)γ production ex vivo in a dose‐ and concentration‐dependent manner. Following in vivo challenge with IFNα‐2a, deucravacitinib demonstrated dose‐dependent inhibition of lymphocyte count decreases and expression of 53 IFN‐regulated genes. There were no serious adverse events (AEs); the overall frequency of AEs was similar in the deucravacitinib (64%) and placebo (68%) groups. In this first‐in‐human study, deucravacitinib inhibited IL‐12/IL‐23 and type I IFN pathways in healthy volunteers, with favorable PK and safety profiles. Deucravacitinib is a promising therapeutic option for immune‐mediated diseases, including Crohn's disease, psoriasis, psoriatic arthritis, and systemic lupus erythematosus.