Clinical Pharmacology in Drug Development最新文献

Bepirovirsen is an antisense oligonucleotide currently in Phase 3 development to treat chronic hepatitis B virus (HBV) infection. Given the importance of coadministration of bepirovirsen and standard-of-care nucleos(t)ide analogs (NAs), we evaluated drug-drug interactions (DDIs) between bepirovirsen, entecavir (ETV), and tenofovir (TFV) using in vitro and clinical data obtained through innovative study design and sampling strategy. Static models employing in vitro data indicated that bepirovirsen is not a direct inhibitor or inducer of most drug-metabolizing enzymes or an inhibitor or substrate of drug transporters and poses no clinical DDI risk against NAs. Bepirovirsen plasma pharmacokinetic parameters and concentration-time profiles in patients with chronic HBV in the CS3 study (NCT02981602) were similar with or without ETV or TFV coadministration, indicating no effect of NA coadministration on bepirovirsen pharmacokinetics. In patients with chronic HBV receiving both bepirovirsen and ETV or TFV in the B-Clear study (NCT04449029), NA plasma concentrations and pharmacokinetic parameters were similar to those published without bepirovirsen coadministration, suggesting no effect of bepirovirsen coadministration on NA pharmacokinetics. This analysis demonstrated no DDI potential between bepirovirsen and NAs, suggesting that dedicated clinical DDI studies are not required. Bepirovirsen is currently being evaluated in Phase 3 studies in combination with NA.

This open-label, multicenter study (NCT03010982) evaluated the absolute bioavailability, characterized the disposition and metabolism, and investigated the metabolic profile of tazemetostat, a US Food and Drug Administration-approved inhibitor of enhancer of zeste homolog 2, following intravenous and oral [¹⁴C]-labeled and unlabeled tazemetostat in patients with B-cell lymphomas or advanced solid tumors. Patients received oral tazemetostat 800 mg twice daily for 14 days. On Day 15, patients received tazemetostat 800-mg tablets in a fasted state followed by an intravenous microdose of 12 µg [¹⁴C]-tazemetostat. On Day 16, patients received a [¹⁴C]-tazemetostat 800-mg solution with a meal, then continued tazemetostat 800 mg twice daily. Blood, plasma, urine, and fecal samples were collected for pharmacokinetic analyses, and recovery and excretion of the radioactivity of [¹⁴C]-labeled/unlabeled tazemetostat and its metabolites. The median absolute bioavailability was 31.8% (range, 20.2%-49.8%). Notable plasma components were EPZ-6930, unchanged tazemetostat, EPZ006931, and EPZ034163, accounting for 31.8%, 22.4%, 11.0%, and 3.5% of total drug-related exposure, respectively. Recovery of radiolabeled material ranged from 93.2% to 94.7%, with most excreted doses recovered within 48 hours in urine and by 96 hours in feces. Fecal elimination represented the principal route of elimination with a mean of 78.9% of the administered radioactive dose and renal excretion accounted for 15.4%.

Rusfertide, a peptide hepcidin mimetic, has shown efficacy in polycythemia vera. This trial investigated the multiple-dose pharmacokinetics, pharmacodynamics, and safety of once-weekly rusfertide 60 mg for 5 weeks in healthy subjects. Subjects were randomized to subcutaneous injection in the abdomen, upper arm, or thigh. Eighteen subjects were enrolled, and 15 completed the study. Geometric mean peak rusfertide plasma concentrations (C_max) following the first dose were 547, 387, and 560 ng/mL following injection in the abdomen, thigh, and arm, respectively (P = .0054). There was no difference between injection sites in the rusfertide area under the plasma concentration-time curve (AUC) following the first dose (P ≥ .179) or in the C_max or AUC during the dosing interval following the last dose (P ≥ .238). Geometric mean accumulation (Dose 5/Dose 1) for AUC and C_max was 1.5 and 1.2, respectively, and similar across injection sites. Mechanism-based decreases in serum iron, transferrin-iron saturation, hemoglobin, and hematocrit were noted following multiple doses. There were no differences between injection sites in the pharmacodynamic effect as measured by change from baseline in hematocrit values. There were no serious adverse events. Treatment-emergent adverse events in 2 or more subjects were injection-site reactions (erythema, induration, pruritus), fatigue, and headache. There were no clinically relevant findings in the safety laboratory parameters, vital signs, electrocardiograms, or physical examination. While a higher incidence of treatment-emergent adverse events was noted in these healthy participants following multiple doses of 60 mg, rusfertide was generally well tolerated. There were no clinically meaningful differences in rusfertide pharmacokinetics or pharmacodynamics between injection sites.

This Phase I, randomized, multicenter, open-label, parallel-group, single-dose study assessed the relative bioavailability of the anti-interleukin-5 antibody depemokimab (100 mg) when administered subcutaneously via either a safety syringe device (SSD) or an autoinjector (AI). Healthy adult participants were randomized I:I to SSD or AI treatment arms and I:I:I to the injection site (upper arm, abdomen, or thigh). Participants were followed up for 30 weeks; blood samples were collected for pharmacokinetic (PK) assessment before dosing on Day 1 and up to Week 26. Depemokimab concentration profile as measured by plasma maximum concentration (C_max), the area under the concentration-time curve from time zero extrapolated to infinity (AUC_0-inf), PK parameters, immunogenicity, and safety were assessed. Overall, 140 participants were enrolled (n = 70 per arm). Mean plasma concentration-time profiles of depemokimab were similar in both treatment arms, regardless of the injection site, adjusted geometric mean AI:SSD ratios for C_max and AUC_0-inf were 1.03 and 1.03, respectively, with all 90% confidence intervals within the bioequivalence bounds of 0.80-1.25. PK parameters were comparable across treatment arms. Treatment-related adverse events were reported in 19% of SSD and 20% of AI participants, with headache being the most common across both arms; no adverse events led to study withdrawal. These results support the use of either SSD or AI for subcutaneous administration of depemokimab.

Bedaquiline is employed to treat multidrug-resistant and extensive drug-resistant tuberculosis by inhibiting the proton pump of adenosine triphosphate synthase in Mycobacterium tuberculosis. This study aims to investigate the effect of high-fat diets on the pharmacokinetics of bedaquiline through a single-center, open-label, randomized trial in healthy Chinese participants. Bedaquiline fumarate tablets were administered at a dosage of 100 mg under both fasted conditions and high-fat diet conditions. The concentrations were determined using liquid chromatography-tandem mass spectrometry, and the pharmacokinetic parameters were calculated using a noncompartmental model. The high-fat diet group showed a maximum plasma concentration that exceeded that of the fasted group by more than 4-fold and an area under the concentration-time curve from time 0 to the last measurable point that was more than twice as high. Moreover, compared to the fasted group, the high-fat diet group exhibits significantly lower levels of apparent clearance, indicating that the high-fat diet markedly enhances the rate and extent of gastrointestinal absorption of bedaquiline. To optimize drug bioavailability and absorption and ensure safety, the administration of bedaquiline with food is recommended in accordance with clinical usage guidelines and expert consensus.

Lenacapavir is a potent, long-acting HIV-1 capsid inhibitor used in combination with other antiretrovirals to treat HIV-1 infection. The pharmacokinetics of orally administered drugs may be affected by food intake or coadministration of acid-reducing agents (ARA). Two Phase 1 studies were conducted on healthy participants to evaluate the effect of food and the impact of the histamine H₂-receptor antagonist famotidine in parallel cohorts. In Study 1, oral lenacapavir (300 mg) was administered under fasting conditions, after a standardized high-fat meal, and after a low-fat meal (n = 8/cohort). In Study 2, lenacapavir 300 mg was administered alone (n = 27) and 2 hours after famotidine (40 mg; n = 25), each under fasting conditions. For the high-fat meal versus fasted comparison, the percentage geometric least-squares mean (%GLSM) ratios for the lenacapavir area under the curve to infinity (AUC_inf) and maximum concentration (C_max) were 115.2 and 145.2, respectively. For the low-fat meal, the %GLSM ratios for lenacapavir AUC_inf and C_max were 98.6 and 115.8, respectively, versus the fasted state. In the famotidine study, the %GLSM ratio for lenacapavir AUC from time zero to the last quantifiable concentration was 137.4, and for C_max was 100.6. Based on available clinical safety data, the exposure increases observed in these studies were not expected to be clinically relevant. Overall, these data support the dosing of oral lenacapavir without regard to food intake or coadministration with ARAs.

A randomized, partially blinded, placebo-controlled, crossover study in 48 healthy adults assessed the effect of momelotinib on the heart rate-corrected QT interval (QTc) using the Fridericia formula (QTcF). QTc was evaluated for momelotinib 200 mg (therapeutic dose), momelotinib 800 mg (supratherapeutic dose), moxifloxacin 400 mg (positive control), and placebo. Pharmacokinetic profiles of momelotinib and its active metabolite M21 were evaluated. Momelotinib did not prolong QTcF, as the upper bounds of the 2-sided 90% confidence intervals (CIs) for the mean difference between doses of momelotinib and placebo were <10 milliseconds at all time points. The lower limit of the 2-sided 98% CI for the mean difference in QTcF between moxifloxacin versus placebo was >5 milliseconds at 2, 3, and 4 hours after dosing, demonstrating assay sensitivity. There was no positive relationship between momelotinib plasma concentrations and QTcF. Adverse events (AEs) were more frequent with the supratherapeutic dose of momelotinib, but none were considered severe. There were no deaths, serious AEs, or AEs leading to study discontinuation. Neither therapeutic nor supratherapeutic doses of momelotinib led to clinically significant effects on the QTc interval, supporting a negative finding for QTc prolongation from this thorough QT study.

Pizuglanstat is a novel hematopoietic prostaglandin D synthase inhibitor and investigational treatment for Duchenne muscular dystrophy. This Phase 1 mass balance study aimed to characterize the absorption, metabolism, and excretion of carbon-14 (¹⁴C)-labeled pizuglanstat in healthy adults (ClinicalTrials.gov, NCT04825431). After administering a single oral dose of [¹⁴C]pizuglanstat solution containing 400 mg of pizuglanstat and 1 megabecquerel of radioactivity to 6 healthy men (median age, 26 years), pizuglanstat in plasma reached a maximal concentration after a median of 0.5 hour and declined with a geometric mean half-life of 7.7 hours. Pizuglanstat and its metabolites were primarily excreted via the fecal route; on average, 66.1% of administered radioactivity was excreted in feces after 168 hours, compared with 32.2% excreted in urine. Pizuglanstat was mostly present as the unchanged parent molecule in plasma, urine, and feces, while the sulfate conjugate of hydroxyl pizuglanstat was the major metabolite in each sample type. Two adverse drug reactions of urticaria were reported in 2 participants (33.3%); both events were nonsevere and manageable with treatment, and no other clinically significant safety events were observed. Overall, this study provides important pharmacokinetic, mass balance, and safety data to support the development of pizuglanstat as a new treatment for Duchenne muscular dystrophy.

Bedaquiline fumarate tablets are a novel oral antimycobacterial drug. This study assessed the bioequivalence of a generic bedaquiline fumarate tablet compared to a reference tablet under fasting (n = 44) and fed (n = 24) conditions. Conducted as a single-center, randomized, open-label, 2-sequence, crossover trial, 68 participants were randomly assigned to receive a 100-mg dose of either the test or reference tablet, with a 42-day washout period between doses. Blood samples were collected at prespecified time points from 0 hour (before administration) to 984 hours after administration. Plasma concentrations of bedaquiline were measured using a validated ultra-performance liquid chromatography-tandem mass spectrometry method. Safety was monitored throughout the study. Key pharmacokinetic parameters included maximum plasma concentration, area under the plasma concentration-time curve (AUC) from 0 to 72 hours, AUC from time 0 to the last measurable concentration, AUC from 0 to 336 hours, and AUC from time 0 to infinity. The 90% confidence intervals for the geometric mean ratios of the test/reference formulations for maximum plasma concentration, AUC from 0 to 72 hours, AUC from 0 to 336 hours, AUC from time 0 to the last measurable concentration, and AUC from time 0 to infinity fell within the bioequivalence acceptance range of 80%-125%. confirming bioequivalence between the 2 formulations in healthy Chinese volunteers. Moreover, a high-fat diet can significantly elevate the exposure of bedaquiline. No serious adverse events occurred, and both formulations were well tolerated across all participants.

To evaluate the bioequivalence and safety of oral rivaroxaban tablets between a test formulation and a reference formulation in healthy Chinese subjects, a randomized, open, 2-formulation, 4-cycle, complete repeat crossover study was conducted under both fasting and fed states. Thirty-six healthy participants were enrolled separately for the fasting and fed groups, and each subject received a single oral dose of 20 mg of the test or reference formulation of rivaroxaban tablets per cycle. Blood samples were collected at specified intervals, and rivaroxaban was analyzed using liquid chromatography-tandem mass spectrometry. Under fasting and fed conditions, the 90% confidence intervals (CIs) for the geometric mean ratios of the maximum concentration (C_max), the area under the plasma concentration-time curve from time 0 to the last measurable time point (AUC_0-t), and the area under the curve extrapolated to infinity from time 0 (AUC_0-∞) all fell within the 80%-125% CI, and the upper limit of the 90% CIs for the test-to-reference ratio of the within-subject variability was <2.5. This indicated that the test formulation of rivaroxaban is bioequivalent to the reference formulation. Compared to the fasted state, the C_max, AUC_0-t, and AUC_0-∞ of rivaroxaban increased significantly by factors of 2, 1.6, and 1.5, respectively, following oral administration of 20 mg of rivaroxaban in the fed state. This suggests that a high-fat diet significantly enhances the exposure to rivaroxaban. No serious adverse events were reported under fasting or fed conditions.