Clinical Pharmacology in Drug Development最新文献

Quizartinib is a potent, oral, second-generation, selective type II FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor. It has shown improved overall survival in a randomized, multinational, Phase 3 (QuANTUM-First) study in patients with FLT3-internal tandem duplication (ITD)-positive newly diagnosed acute myeloid leukemia. We conducted 2 Phase 1b studies in Japan and China to evaluate the safety, pharmacokinetics, and efficacy of quizartinib in combination with standard induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Quizartinib was started at a dose level of 20 mg/day and then escalated to 40 mg/day, the dose used in the Phase 3 study. Seven patients were enrolled according to the 3 + 3 dose-escalation method in each study, including 3 patients who were FLT3-ITD positive. No dose-limiting toxicities were observed at dose levels up to 40 mg/day in both studies. Grade 3 or higher, quizartinib-related, treatment-emergent adverse events included febrile neutropenia, hematologic toxicities, and infections. QT prolongation on electrocardiogram was observed in 5 patients. The pharmacokinetics of quizartinib and its metabolite AC886 were similar between the studies and consistent with previous findings in the United States. We confirmed the tolerability of Japanese and Chinese patients to the dose of quizartinib and chemotherapy regimens used in the QuANTUM-First study.

Ubrogepant is a calcitonin gene-related peptide receptor antagonist indicated for the acute treatment of migraine with or without aura in adults. The objectives of this study were to evaluate (1) single-dose pharmacokinetics (PK) and dose proportionality of ubrogepant in Japanese participants, (2) the safety and tolerability of ubrogepant in healthy Japanese and White participants, and (3) to compare the PK of ubrogepant in Japanese versus White participants. A total of 48 participants were enrolled into 4 cohorts (N = 12 [9 active + 3 placebo] per cohort). A single dose was administered on Day 1 following an overnight fast to assess the PK of ubrogepant at 3 dose levels and test dose proportionality between 25 and 100 mg in Japanese participants. White participants were randomly assigned to ubrogepant (100 mg) or placebo. Dose proportionality was observed in the dose range of 25-100 mg in Japanese participants. Systemic exposure was 20% lower in Japanese participants as compared with White participants, but this difference is unlikely to be clinically relevant. Single doses of ubrogepant (25-100 mg) had a safety profile similar to placebo, and no differences in the safety profile of ubrogepant 100 mg were observed between Japanese versus White participants.

Ganaxolone, a neuroactive steroid anticonvulsant that modulates both synaptic and extrasynaptic γ-aminobutyric acid type A (GABA_A) receptors, is in development for treatment of status epilepticus (SE) and rare epileptic disorders, and has been approved in the United States for treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder in patients ≥2 years old. This phase 1 study in 36 healthy volunteers evaluated the pharmacokinetics, pharmacodynamics, and safety of intravenous ganaxolone administered as a (i) single bolus, (ii) infusion, and (iii) bolus followed by continuous infusion. After a single bolus over 2 minutes (20 mg) or 5 minutes (10 or 30 mg), ganaxolone was detected in plasma with a median T_max of 5 minutes, whereas a 60-minute infusion (10 or 30 mg) or a bolus (6 mg over 5 minutes) followed by infusion (20 mg/h) for 4 hours achieved a median T_max of approximately 1 and 3 hours, respectively. C_max was dose and administration-time dependent, ranging from 73.8 ng/mL (10 mg over 5 minutes) to 1240 ng/mL (30 mg over 5 minutes). Bolus doses above 10 mg of ganaxolone markedly influenced the bispectral index score with a rapid decline; smaller changes occurred on the Modified Observer's Assessment of Alertness/Sedation scale and in quantitative electroencephalogram. Most adverse events were of mild severity, with 2 events of moderate severity; none were reported as serious. No effects on systemic hemodynamics or respiratory functions were reported. Overall, ganaxolone was generally well tolerated at the doses studied and demonstrated pharmacokinetic and pharmacodynamic properties suitable to treat SE.

Cedirogant (ABBV-157) is an orally bioavailable inverse agonist of retinoic acid-related orphan receptor gamma thymus. Data from 2 Phase 1 studies were used to characterize cedirogant pharmacokinetics and evaluate target engagement. Cedirogant plasma concentrations and ex vivo interleukin 17A (IL-17A) concentrations from healthy participants and participants with moderate to severe psoriasis (PsO) were analyzed in a population pharmacokinetic and pharmacodynamic modeling framework to characterize cedirogant pharmacokinetics following single and multiple doses and assess ex vivo IL-17A inhibition in relation to cedirogant exposure. Cedirogant population pharmacokinetics were best described by a 2-compartment pharmacokinetic model with delayed absorption and an enzyme turnover compartment to describe cytochrome P450 3A autoinduction. The pharmacokinetics of cedirogant were comparable between healthy participants and participants with PsO. Cedirogant steady-state average and maximum plasma concentrations were predicted to be 7.56 and 11.8 mg/L, respectively, for participants with PsO for the 375 mg once-daily regimen on Day 14. The apparent clearance and apparent volume of distribution for cedirogant were estimated to be 24.5 L/day and 28.2 L, respectively. A direct maximum inhibition model adequately characterized the exposure-response relationship of cedirogant and ex vivo IL-17A inhibition, indicating no temporal delay between exposure and response with a saturable inhibition of IL-17A. Model-estimated half-maximal inhibitory concentration and maximum inhibition values for cedirogant inhibition of ex vivo IL-17A were 0.56 mg/L and 0.76, respectively. The established relationship between cedirogant exposure and biomarker effect supported dose selection for the Phase 2 dose-ranging study in patients with PsO.

To determine the pharmacokinetics (PK), safety, and bioequivalence profiles of 0.5-g calcium dobesilate capsules in both fasting and fed states for the test drug and reference drug. A randomized-sequence, single-dose, open-label, 2-period crossover study was conducted in fasted and fed healthy Chinese volunteers (Chinese Clinical Trials Registry identifier: CTR202000268-01). The fasting and fed studies, both involving 24 subjects, were conducted. A single dosage of either the reference or the test preparation was given to each eligible subject in a 1:1 ratio, followed by a 7-day rest interval before the administration of the alternative formulation. After taking the capsules, plasma samples were taken for 48 hours, and using liquid chromatography-tandem mass spectrometry, the calcium dobesilate level was determined. The PK parameters evaluated in the study included the maximum serum concentration (C_max), area under the plasma concentration-time curve (AUC) from time 0 to the last quantifiable concentration, AUC from time 0 to infinity, half-life, time to C_max, and terminal elimination rate constant. In addition, the safety evaluation encompassed monitoring fluctuations in vitals (temperature, pulse, and blood pressure) and laboratory tests (urinalysis, hepatic function, blood biochemistry, and hematology), as well as recording the emergence of adverse events (AEs). The geometric mean ratio (GMR) of the test/reference medications was used to assess bioequivalence by determining if the 90% confidence intervals of the GMR fell within the predefined range of 80%-125%. AEs were assessed as safety end points. The study included 48 healthy Chinese volunteers (with n = 24 each for the fasting and the fed conditions), and no subjects dropped out for any reason. The differences in the PK metrics for the test and reference drugs for both conditions were insignificant (P > .05). For bioequivalence, irrespective of whether the food was consumed or not, the range of the 90% confidence intervals of the GMR for C_max, AUC from time 0 to the last quantifiable concentration, and AUC from time 0 to infinity was between 80% and 125%. In the experiment, no serious AEs were recorded. Our findings revealed that the calcium dobesilate capsules used as the reference and the test drugs were both bioequivalent. Irrespective of whether the healthy Chinese volunteers consumed food or not, the PK and safety profiles were comparable.

Inhibition of activated factor XI reduces thrombogenesis while maintaining physiological hemostasis, with the expectation of reduced bleeding risk compared with standard of care in the clinical setting. Asundexian (BAY 2433334), an activated factor XI inhibitor, is in clinical development for the prevention of thromboembolic events. The effect of asundexian and its plasma metabolite M10 on cardiac repolarization and potential interactions with the hNav1.5 sodium, hCav1.2 calcium, and human ether-à-go-go-related gene (hERG) potassium channels was investigated in vitro. Additionally, asundexian effects on cardiac parameters and electrocardiogram were examined in telemetered beagle dogs. A randomized, placebo-controlled, 4-way crossover, thorough QT study in healthy adults evaluated the influence of 50 and 150 mg of asundexian on the corrected QT interval, including 400 mg of moxifloxacin as positive control. Across all studies, asundexian and M10 were not associated with any effects on cardiac repolarization. The largest in vitro effects of asundexian (approximately 20% inhibition) were seen for hCav1.2 and hERG. Throughout the thorough QT study, the upper limits of the one-sided 95% confidence interval of placebo-corrected mean changes from baseline in Fridericia corrected QT for 50 and 150 mg of asundexian were below Δ = 10 milliseconds. Asundexian demonstrated favorable safety and tolerability profiles.

Deutetrabenazine is approved for the treatment of tardive dyskinesia and chorea associated with Huntington's disease. This study compared the exposure between the once-daily (test) and twice-daily (reference) formulations of deutetrabenazine under fed conditions. Using a randomized crossover design, healthy adults (n = 262) received the 24 mg of the test formulation once daily and 12 mg of the reference formulation twice daily, each for 7 days. Plasma concentrations were collected on Days 4-6 before dose intake, and frequently for pharmacokinetic evaluation on Days 6 and 7 for determination of deutetrabenazine and active metabolites, deuterated α-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (β-HTBZ). Geometric mean ratios (GMRs, test/reference) were computed for all analytes, and bioequivalence was tested for area under the plasma concentration-time curve over 24 hours at steady state (AUC_0-24 h,ss) and for maximum plasma concentrations at steady state (C_max,ss). The GMRs for AUC_0-24 h,ss were 115% for deutetrabenazine and 95% for deuterated total (α+β)-HTBZ; and the GMR for C_max,ss for deutetrabenazine was 95%. Relative bioavailability was assessed for C_max,ss of the active metabolites; the GMR was 78% for total (α+β)-HTBZ. At steady state, deutetrabenazine administered as the once-daily formulation was bioequivalent to the twice-daily formulation for both AUC and C_max, and the active metabolites were bioequivalent with regard to AUC_0-24 h,ss.

Vonoprazan holds significant research promise for Helicobacter pylori eradication, with the goal of determining the most effective drug regimen. In this study, H. pylori patients (426) were enrolled and randomized into 3 groups: an EA14 group (20 mg of esomeprazole qid and 1000 mg of amoxicillin tid for 14 days), a VA14 group (20 mg of vonoprazan bid and 750 mg of amoxicillin qid for 14 days), and a VA10 group (20 mg of vonoprazan bid and 1000 mg of amoxicillin tid for 10 days). Key outcomes encompassed the H. pylori eradication rate, patient adverse effects, and compliance. In the EA14, VA14, and VA10 groups, H. pylori eradication rates were 89.4%, 90.1%, and 88.7% in intention-to-treat analysis, and 94.2%, 94.4%, and 94.6% in per-protocol analysis, respectively. Adverse events incidences were 14.8%, 12.7%, and 5.6%, while compliance rates were 88.7%, 90.9%, and 95.8%, respectively. Notably, the VA10 regimen demonstrated comparable H. pylori eradication rates, adverse effect incidences, and compliance levels to the EA14 and VA14 regimens.

Acarbose is a widely used α-glucosidase inhibitor for the management of postprandial hyperglycemia in patients with type 2 diabetes mellitus. Recent pilot studies on acarbose bioequivalence (BE) have successfully identified additional pharmacodynamic (PD) parameters as valid end points. Nevertheless, there was a scarcity of published pivotal studies using novel PD parameters. The purpose of the study is to investigate the acarbose BE using the new PD parameters. The study was conducted with an open, randomized, 2-period crossover design. A total of 64 healthy Chinese volunteers received either the reference (R) or test (T) acarbose at a dose of 2×50 mg orally, followed by a 1-week washout period. After sucrose treatment (baseline) and sucrose/acarbose co-administration, serum glucose, and insulin concentrations were assessed. The rectifying approach yielded geometric mean ratios of 102.9% for maximum serum glucose concentration with deduction of glucose concentration at 0 hour and 105.3% for the area under the serum glucose concentration-time curve profile 0-2 hours after coadministration of sucrose and acarbose with deduction of baseline (AUC_0-2 h,r). The 90% confidence intervals of maximum serum glucose concentration with deduction of glucose concentration at 0 hour and the area under the serum glucose concentration-time curve profile 0-2 hours after coadministration of sucrose and acarbose with deduction of baseline all fell within the acceptance limits. The incidence of adverse events after the T or R drug was comparable, and healthy subjects were well tolerated. The findings of our investigation clearly show that the PD parameters of the rectifying method exhibit enhanced suitability and sensitivity when assessing acarbose BE in healthy participants. The T and R drugs were bioequivalent using the novel PD parameters, and both drugs demonstrated good safety and tolerability.

Pritelivir is a helicase-primase inhibitor active against HSV. Two human mass balance trials (a multiple-dose trial and a single-dose trial) were performed to characterize the absorption, distribution, metabolism, and excretion of 100 mg oral pritelivir combined with a single microdose of ¹⁴C-pritelivir. Blood, urine, and feces samples were collected up to 26 days postdose. The plasma half-life of pritelivir was 63-67 hours. Overall, 92% and 66% of the administered dose was recovered in the multiple and single dose trials, respectively. The low recovery after the single dose (66%) was most likely related to the formulation used. The major metabolic pathway was amide hydrolysis leading to amino thiazole sulfonamide (ATS) and pyridinyl phenyl acetic acid (PPA). In plasma, pritelivir, ATS, PPA, and PPA-acyl glucuronide accounted for 40.6%, 9.4%, 5.1%, and 0.2% of total radioactivity. More than 90% of drug-related material was eliminated 624 hours postdose. The majority was excreted in urine (75% and 77%), followed by feces (16% and 23%). The main components in urine were PPA-acyl glucuronide (and its isomers), ATS, and its N-demethylated isomers. Only minor metabolites were observed in feces. In conclusion, the major metabolic pathways of pritelivir have been identified with the primary excretion route being renal.