Clinical Pharmacology in Drug Development最新文献

N-acetylcysteine (NAC) is a derivative of cysteine with potent mucolytic and antioxidant properties. However, the pharmacokinetics of NAC tablets remain unclear in healthy Chinese subjects. This study aimed to assess the pharmacokinetics, bioequivalence, and safety of a domestically manufactured NAC tablet (600 mg) compared with the reference formulation in healthy Chinese volunteers under both fasting and fed conditions. A single-dose, randomized, open-label, two-formulation, crossover bioequivalence study was conducted, using a two-period, two-sequence design under fasting conditions and a four-period, fully replicated crossover design under fed conditions. Blood samples were collected at predetermined time points and analyzed using a validated liquid chromatography-tandem mass spectrometry method. The 90% confidence intervals for the geometric mean ratios (test/reference) of the maximum plasma concentration, the area under the concentration-time curve from time zero to the last measurable concentration, and from time zero to infinity were all within the accepted bioequivalence range of 80%–125%. Furthermore, both the test and reference formulations were well tolerated, and no serious adverse events were reported. These results demonstrate that the test and reference NAC tablets are bioequivalent and exhibit similar pharmacokinetic profiles and safety in healthy Chinese subjects under both fasting and fed conditions.

The oral, small molecule inhibitor of activin receptor-like kinase-2, zilurgisertib (INCB000928), is under evaluation in fibrodysplasia ossificans progressiva. Cardiac safety was assessed using electrocardiogram (ECG) parameters and a plasma concentration-heart rate-corrected QT (C-QTc) interval analysis of pooled data from single ascending dose (SAD) and multiple ascending dose (MAD) studies of zilurgisertib in healthy adult participants (SAD: 10-500 mg; INCB00928-102: 50-400 mg QD, 300 mg BID). Overall, 91 (SAD) and 79 (MAD) participants provided at least one pair of PK/ECG data. As both studies indicated a dose-dependent effect of zilurgisertib on heart rate, individualized QT correction (QTcI) was used as the primary endpoint for QTc analysis. Estimated population slope of the individualized C-ΔQTc (C-ΔQTcI) relationship was shallow (0.02 ms per µm [90% CI, −0.60, 0.65]) and not statistically significantly different from 0; treatment effect–specific intercept was small and not significant (−0.83 ms [90% CI, −2.26, 0.61]). No significant relationship between zilurgisertib plasma concentration and change in QTcI was identified; zilurgisertib did not have a clinically relevant effect on QTc prolongation. QT effect >10 ms could therefore be excluded within the dose range studied (up to 300 mg BID). No clinically meaningful effects on cardiac conduction (PR and QRS intervals) or any categorical PR or QRS outliers were observed. These data support further clinical development of zilurgisertib.

Asciminib is the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP) in patients with chronic myeloid leukemia. This phase 1, two-treatment-period, drug-drug interaction study evaluated the effect of steady-state asciminib on the pharmacokinetics of atorvastatin. A single dose of atorvastatin (20 mg) was administered on day 1 (period 1: days 1-4). On days 5-11 (period 2: days 5-12), 80 mg asciminib was administered once daily, with a single dose of atorvastatin co-administered on day 9. Pharmacokinetic sampling for atorvastatin was performed on days 1-4 in period 1 and days 9-12 in period 2. Twenty-two healthy participants were enrolled. Twenty participants completed the study, and two discontinued due to adverse events (AEs). Asciminib increased the adjusted geometric mean (G_mean) of maximum plasma concentration (C_max), the area under the curve (AUC) from zero to the last quantifiable concentration (AUC_last), and the AUC from zero to infinity (AUC_inf) of atorvastatin by 24%, 16%, and 14%, respectively, and did not affect these parameters for its active metabolites, o-hydroxy-atorvastatin and p-hydroxy-atorvastatin. Plasma concentrations of coproporphyrin-1 (CP-1), an endogenous substrate of the atorvastatin transporter OATP1B, were not affected by asciminib. Thirteen participants reported at least one AE, all being grade 1/2, except for one grade 3 AE (increased alanine aminotransferase). No serious AEs were reported. In conclusion, concomitant administration of steady-state asciminib and atorvastatin resulted in a small, clinically irrelevant increase in atorvastatin exposure and no change in CP-1 concentrations. Both drugs were well tolerated. These data support co-administration of asciminib and atorvastatin.

Fezolinetant is a non-hormonal, selective neurokinin-3 receptor antagonist that blocks neurokinin B activation of kisspeptin/neurokinin B/dynorphin neurons to thereby modulate neuronal activity in the thermoregulatory center. Fezolinetant has been approved in many regions, including North America, Europe, Asia, and Australia for the treatment of vasomotor symptoms associated with menopause at a dose of 45 mg once daily (QD). The risk of potential QT prolongation for fezolinetant was assessed prior to the initiation of the phase 3 trials. A concentration–QTc (C–QTc) analysis was performed in accordance with recommendations from ICH E14 Guideline and utilized data from a phase 1 single and multiple ascending dose study, which tested single doses up to 900 mg and multiple daily doses up to 720 mg in healthy male and female participants. The fezolinetant C–QTc relationship indicated no clinically relevant QT prolongation at therapeutic or supra-therapeutic doses of fezolinetant. Based on these modeling results as well as data from other clinical and non-clinical studies, no thorough QT/QTc (TQT) study was required for fezolinetant.

Multidrug–resistant Enterobacteriaceae are a primary cause of complicated urinary tract infections (cUTIs) worldwide. This study compared pharmacokinetic (PK) parameters of plazomicin among Indian versus non–India participants. This was a post hoc analysis of PK data from the Phase 2 study (ACHN–490-002), a multicenter, double–blind, randomized, comparator–controlled study. Eligible participants (aged 18-85 years, body weight ≤100 kg) with documented/suspected cUTI or acute pyelonephritis received either 10 or 15 mg/kg plazomicin. Among 91 participants, 70 were non–Indian and 21 were Indian. For the 15 mg/kg dose, plazomicin demonstrated a higher area under the plasma time–concentration curve from time 0 to 24 h (AUC_0-24) and maximum concentration (C_max) compared to the 10 mg/kg dose, which showed greater variability. At the 10 mg/kg dose, Indian participants had a mean AUC_0-24 of 163.0 mg•h/L, while non–Indian participants had a mean AUC_0-24 of 185.0 mg•h/L. The estimated mean plazomicin AUC_0-24 values were comparable between Indian and non–Indian participants. The mean C_max for Indian participants was 17.2 mg•h/L, and for non–Indian participants it was 15.7 mg•h/L. Dose–normalized AUC_0-24 and C_max point estimates were 110% and 103%, respectively. This showed comparable plazomicin exposure in Indian and non–Indian patients.

Zavegepant is the only calcitonin gene-related peptide antagonist approved as a nasal spray in the United States for acute treatment of migraine in adults with or without aura. This Phase 1, open-label study evaluated the pharmacokinetics, safety, and tolerability of a single intranasal dose of zavegepant 10 mg in 12 healthy Chinese adults. Blood samples were collected for pharmacokinetic assessment prior to dosing and from 5 min to 24 h post dose. Geometric mean values for the primary pharmacokinetic parameters were 53.53 ng h/mL for area under the plasma concentration–time curve (AUC) from time zero to infinity, 44.25 ng h/mL for AUC from time zero to time of last quantifiable concentration, and 20.32 ng/mL for maximum plasma concentration (C_max). Secondary parameters included time to C_max (median, 0.58 h), apparent clearance (geometric mean, 186.8 L/h), apparent volume of distribution (geometric mean, 2943 L), and terminal half-life (arithmetic mean, 11.0 h). Results were comparable to exposures observed previously in non-Asian healthy participants following a single intranasal dose of zavegepant 10 mg. Zavegepant demonstrated a favorable safety profile, with no serious or severe adverse events and no clinically relevant findings regarding laboratory tests, vital signs, or electrocardiograms observed.

Bepirovirsen, an antisense oligonucleotide in development for the treatment of chronic hepatitis B virus (HBV) infection, is administered from glass vials as a subcutaneous (SC) injection by healthcare professionals (HCPs). A ready-to-use prefilled syringe (PFS) assembled with a safety syringe device (SSD) has been developed to make administration more convenient and facilitate patient self-administration. This Phase 1, open-label, randomized, parallel-group study evaluated the relative bioavailability of bepirovirsen delivered from a vial or PFS SSD, assessed the viability of PFS SSD self-administration, and evaluated the safety and tolerability of SC bepirovirsen in healthy participants. Participants (N = 159) received a single 300 mg SC dose of bepirovirsen administered by a HCP (vial [n = 46] or PFS SSD [n = 49]), or self-administered (PFS SSD, with [n = 32] or without [n = 32] training from a HCP). Relative bioavailability (primary endpoint) of HCP-administered bepirovirsen delivered by vial versus PFS SSD was assessed using maximum observed plasma concentration (C_max) and area under the concentration–time curve from time zero extrapolated to infinity (AUC_(0-inf)). Participants were monitored for adverse events. Bepirovirsen exposure was bioequivalent when HCP-administered either by vial or PFS SSD; the 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) were within the standard bioequivalence reference range, 0.80-1.25, for both C_max (1.02 [0.91-1.14]) and AUC_(0-inf) (1.05 [0.96-1.15]). Self-administration using PFS SSD achieved bioequivalence for bepirovirsen exposure compared with HCP administration. No new safety concerns were identified. These findings confirm that PFS SSD is a viable alternative to vials for bepirovirsen administration, when HCP- or self-administered, for the treatment of chronic HBV.

Clinical trial identifier: NCT06058390

This study aimed to assess the bioequivalence of a newly developed generic formulation of empagliflozin in comparison with the reference product. A total of 32 healthy adult volunteers participated in an open-label, randomized, balanced, two-treatment, two-sequence, two-period crossover study. Following an overnight fast, each participant received a 25 mg single oral dose of either the test or the reference empagliflozin with a 1-week washout period between treatments. Safety was monitored throughout the study, and 21 blood samples were collected at pre-dose and at multiple time points from 0.5 to 48 h post-dose. Plasma concentrations of empagliflozin were quantified using a validated LCMS/MS method following liquid–liquid extraction. Pharmacokinetic parameters were calculated using non-compartmental analysis and statistically compared between formulations using multivariate analysis of variance. The test formulation was well tolerated under fasting conditions, with no serious adverse events reported. The pharmacokinetic parameters, including C_max and AUC_0–t, were not significantly different between the test and reference products. The 90% confidence intervals of the Ln-transformed pharmacokinetic parameters fell within the bioequivalence acceptance range of 80.00% to 125.00%. In conclusion, the test and reference formulations of empagliflozin 25 mg are bioequivalent under fasting conditions in healthy individuals.

This randomized, open-label, single-dose crossover study evaluated the bioequivalence of a Chinese-manufactured oseltamivir phosphate oral suspension (7.5 mg/12.5 mL) against Tamiflu under fasting and fed conditions. A total of 42 healthy Chinese adults were enrolled in each group, with 39 completing the fasting group (3 withdrew) and 40 completing the fed group (1 withdrew in washout, 1 lost to follow-up). Plasma concentrations of oseltamivir and its active metabolite oseltamivir carboxylate were measured via LC-MS/MS, and pharmacokinetic parameters were calculated using non-compartmental models. The 90% confidence intervals of key parameters fell within the 80.00-125.00% range, confirming bioequivalence. No serious adverse events occurred, indicating similar safety profiles. The test formulation is bioequivalent to Tamiflu under both fasting and fed conditions.