Clinical Pharmacology in Drug Development最新文献

To investigate the pharmacokinetic characteristics of bromocriptine mesylate tablets in healthy Chinese subjects and to assess their bioequivalence and safety. A randomized, open-label, single-dose, four-period, two-sequence, complete crossover study was conducted. Forty healthy volunteers were enrolled and administered a single oral dose of 2.5 mg of either the test formulation (T) or the reference formulation (R) of bromocriptine mesylate tablets under fed conditions, with a 7-day washout period between treatments. Plasma concentrations of bromocriptine mesylate were measured using ultra-performance liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were calculated using Phoenix WinNonlin software for bioequivalence evaluation. Geometric mean ratios of maximum concentration, the area under the concentration–time curve from time zero to the last measurable concentration, and the area under the concentration–time curve from time zero to infinity were calculated: maximum concentration by reference-scaled average bioequivalence using a 95% upper confidence bound, and the area under the concentration-time curve from time zero to the last measurable concentration and the area under the concentration-time curve from time zero to infinity by average bioequivalence with 90% confidence intervals. Data from the fed trial met the bioequivalence criteria. No serious adverse reactions were observed, indicating that the test and reference bromocriptine mesylate tablets have similar safety profiles under fed conditions.

BNC210 is an investigational small molecule selective negative allosteric modulator of the alpha-7 nicotinic acetylcholine receptor (α7 nAChR). It is an anxiolytic compound with a novel mechanism of action. In a series of Phase 1 clinical trials in healthy volunteers, psychometric test batteries showed that BNC210 did not cause attention, cognition, or memory impairment, negative effects on mood or emotional stability, sedation, or addiction, ruling out undesirable side effects of known anxiolytic compounds. In healthy volunteers, target engagement at the α7 nAChR was demonstrated in a nicotine shift assay using quantitative electroencephalography, and BNC210 demonstrated improvement in panic-like symptoms in a cholecystokinin tetrapeptide panic model. Initial clinical trials used an aqueous suspension formulation of BNC210 to cover a wide dosage range; however, its pharmacokinetic parameters were consistent with solubility-limited absorption and a significant food effect. A dispersible tablet formulation was then developed with improved bioavailability and is being used in Phases 2 and 3 clinical trials. Collectively, the Phase 1 data demonstrated desired properties of BNC210 supporting proof-of-concept clinical trials. BNC210 is currently being developed for acute, as-needed treatment of social anxiety disorder and chronic treatment of post-traumatic stress disorder.

ALG–055009 is an oral thyroid hormone receptor beta (THR-β) agonist being evaluated for treating metabolic dysfunction–associated steatohepatitis (MASH). This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of ALG-055009 and bioavailability/food effect. Part 1 was a single–ascending dose study in healthy participants randomized to ALG-055009 (0.1 to 4.0 mg) or placebo. Part 2 was a multiple–ascending dose study in participants with mild hyperlipidemia randomized to ALG-055009 (0.3 to 1.0 mg) or placebo once daily for 14 days. Part 3 was an open–label study to determine relative bioavailability and food effect of 0.6 mg ALG-055009 solution versus soft gelatin (softgel) capsule formulation. Among 78 participants, ALG-055009 was well tolerated, and most adverse events were mild or moderate with no clinically meaningful safety issues. Transient reductions in thyroid hormone levels were observed with no clinical manifestation of hypo/hyperthyroidism. Plasma ALG-055009 exposure increased in a dose–proportional manner with rapid absorption, low variability, accumulation ranging from 1.6-2.6-fold, and t_1/2 of 20 h. Relative bioavailability of the softgel capsule was 86% versus solution, with no food effect. Dose–dependent decreases in atherogenic lipids and increases in sex hormone binding globulin were observed. These results support further development of ALG-055009 for patients with MASH.

This study aimed to evaluate the pharmacokinetics, bioequivalence, and safety for two formulations of acetylcysteine granules in healthy Chinese subjects under fasting and postprandial conditions. A single-center, randomized, open-label, single-dose, two-period, two-sequence crossover study was performed. 34 and 38 healthy Chinese volunteers were enrolled in the fasting and postprandial groups, respectively. Each subject received a single oral dose (0.2 g) of acetylcysteine granules per period either as the test (T) or reference (R) formulation, followed by a 5-day washout interval. Serial blood samples were collected for up to 24 h post-dose in each period, and plasma concentration of acetylcysteine was detected using high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Whether under fasting or postprandial conditions, all the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) for maximum concentration (C_max), area under the curve from time 0 to the time of the last measurable concentration (AUC_0-t), and area under the curve from time 0 to infinity (AUC_0-∞) were all found to fall within the bioequivalence range of 80.00-125.00%. Only mild adverse events (AEs) were observed. In the study, the two formulations of acetylcysteine granules were bioequivalent and safe.

This 2-part, randomized, placebo-controlled, double-blind, Phase 1 study analyzed the pharmacokinetics, safety, and biomarker profile of fezolinetant in healthy Japanese individuals. Part 1: male participants received single doses of placebo or fezolinetant 15 or 60 mg. Part 2: male and premenopausal and postmenopausal female participants received a single dose of placebo or fezolinetant 180 mg, followed by a 2-day washout, and multiple dosing once daily for 10 days. Fezolinetant was rapidly absorbed with peak concentrations 1-2 hours after single-dose administration; plasma levels subsequently declined (half-life range, 3.29-7.24 hours). Only slight accumulation (area under the concentration–time curve accumulation ratio, 1.46-1.57) was observed after once-daily multiple-dose administration. No serious/severe treatment-emergent adverse events were observed; the only fezolinetant-related treatment-emergent adverse event was mild uterine bleeding in 1 premenopausal woman and 1 postmenopausal woman. Concentration-QT analysis showed that fezolinetant does not have a clinically significant effect on QT interval. Fezolinetant produced dose-dependent reductions in luteinizing hormone and slight reductions in follicle-stimulating hormone; levels subsequently returned to baseline 48 hours or fewer after dosing. This analysis shows that fezolinetant doses up to 180 mg had an acceptable safety, pharmacokinetic, and biomarker profile. This study clarifies the safety, pharmacokinetic, and biomarker profiles of fezolinetant in Japanese individuals.

Galcanezumab is used in several regions, including the United States, Europe, and China, as a preventive treatment for migraine. This study aimed to evaluate the safety, tolerability, and pharmacokinetics (PK) of galcanezumab in healthy Chinese participants. In this phase I single-dose study, 30 healthy adults were assigned to one of the two cohorts (120 or 240 mg) and randomized in a 4:1 ratio to receive a single subcutaneous (SC) dose of galcanezumab or placebo. Overall, 29 (96.7%) participants reported 93 treatment-emergent adverse events (TEAEs), with 21 participants reporting 44 TEAEs related to the study treatment. Most study-related TEAEs (95%) were mild in severity. The most commonly reported TEAE was upper respiratory tract infection. The PK data demonstrated that maximum observed drug concentration (C_max) and area under the serum concentration curve from time zero to infinity increased proportionally to dose, with an apparent clearance of 0.009 L/h and a terminal elimination half-life (t_1/2) of 27 days. Galcanezumab was safe and well tolerated and demonstrated a PK profile consistent with that of non-Chinese populations, supporting its use for the preventive treatment of migraine in Chinese patients.

HR19042 is a novel, orally administered, targeted-release formulation of the topically active corticosteroid budesonide, developed to release active drug within the terminal ileum and indicated to reduced estimated glomerular filtration rate loss in adults with primary immunoglobulin A nephropathy. This randomized, single-dose, open-label, six-sequence, three-treatment crossover trial aimed to explore the pharmacokinetic (PK) of HR19042 in comparison with two other budesonide targeted-release formulations among healthy Chinese subjects. Plasma budesonide concentrations were measured via liquid chromatography with tandem mass spectrometry, and PK parameters were analyzed using non-compartmental methods. Eighteen subjects successfully completed the trial. The median T_lag and T_max of HR19042 were 1.25 and 3.50 h shorter than those of Nefecon, respectively. The C_max of HR19042 was approximately 1.9-fold higher than that of Nefecon and 1.4-fold higher than that of Budenofalk. Based on the AUC_0-t determination, the relative bioavailability (F) of HR19042 was approximately 136.93% relative to Nefecon and 129.68% relative to Budenofalk. In vitro, the dissolution of HR19042 occurred 30 min earlier than that of Nefecon in the intestinal buffer medium. In conclusion, both in vivo and in vitro findings suggest that HR19042 exhibits a faster absorption rate and higher oral bioavailability.

This study assessed the pharmacokinetics (PK) and bioequivalence (BE) of valsartan and amlodipine (80/5 mg) tablets in healthy Chinese subjects under fasting and fed conditions. A randomized, open-label, four-period crossover trial was conducted, with participants receiving test (T) or reference (R) formulations in cycles separated by a 14-day washout. Plasma concentrations of valsartan and amlodipine were measured using high-performance liquid chromatography-tandem mass spectrometry. PK parameters were analyzed noncompartmentally, and BE was evaluated using reference-scaled average bioequivalence (RSABE) for high-variability parameters (CV_W ≥ 30%) and average bioequivalence (ABE) for low-variability parameters (CV_W < 30%). Under fasting conditions, the maximum concentration of drug in blood plasma (C_max) of valsartan was assessed using RSABE methodology and demonstrated bioequivalence. For amlodipine, bioequivalence was established through conventional ABE analysis, with the 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) of C_max, AUC_0-t, and AUC_0-∞ all residing within the predefined equivalence boundaries. Under postprandial conditions, both drugs met BE criteria using ABE, with 90% CIs of GMRs within the acceptable range. Importantly, postprandial administration resulted in a significant reduction of approximately 30% in systemic exposure of valsartan for both test and reference formulations. All adverse events were mild and transient. The T and R formulations demonstrated bioequivalence and were well tolerated, supporting their interchangeability.

Tamsulosin is a highly selective α1A adrenergic receptor antagonist that can relax smooth muscles in the urethra, bladder neck, and prostate and improve urinary disorders. It is therefore widely used to treat lower urinary tract symptoms caused by benign prostatic hyperplasia. The aim of this study is to evaluate the pharmacokinetic (PK) characteristics and bioequivalence of 2 different formulations (tamsulosin sustained-release tablets and tamsulosin sustained-release capsules) in healthy Chinese subjects. This study was a single-center, randomized, open label, 2-formulation, single-administration, 2-cycle, double-crossover fasting/postprandial bioequivalence trial that included 56 healthy volunteers (28 fasting and 28 postprandial). Blood samples were collected from volunteers after oral administration, plasma concentrations of tamsulosin were determined by liquid chromatography-tandem mass spectrometry for PK analysis, and the safety and tolerability of the drug were monitored. Under fasting and postprandial conditions, the 90% confidence intervals for maximum observed concentration (C_max) and area under the plasma concentration-time curve from time 0 to the last sampling time (AUC_0-t) of the test and reference formulations were within an acceptable range (80%-125%). All adverse events (AEs) were mild and no serious AEs were observed in the study. The subject formulation of tamsulosin extended-release tablets was safe and well tolerated in healthy Chinese Volunteers.