Clinical Pharmacology in Drug Development最新文献

Ticagrelor is a key antiplatelet agent used to prevent thrombotic events in patients with acute coronary syndrome. This open-label, 2-period, crossover Phase I study assessed the pharmacokinetics and bioequivalence of a generic ticagrelor 90-mg formulation compared to the innovator product under fasting conditions. Twenty-eight healthy White adults participated in the study. Each participant received a single dose of either the test or reference formulation, followed by a 7-day washout period before switching to the alternate formulation. Plasma concentrations of ticagrelor were measured using a validated high-performance liquid chromatography-tandem mass spectrometry method. Statistical analysis of primary pharmacokinetic parameters, including maximum concentration and area under the plasma concentration-time curve from time 0 to the last quantifiable concentration, showed bioequivalence with test/reference ratios of 110.9% and 107.1%, respectively, and 90% confidence intervals within the 80%-125% regulatory range. Treatment-emergent adverse events, such as headache, dysphagia, and dizziness, were moderate and transient and resolved promptly, with no significant difference in incidence between the formulations. These results confirm that the generic ticagrelor formulation is bioequivalent to the innovator product, supporting its use as an interchangeable option in clinical practice.

The aim of this study was to evaluate the comparative effectiveness and safety profiles of generic lenvatinib mesylate capsules and the reference product in a cohort of healthy Chinese individuals. The research design consisted of a randomized, open-label trial with a single-dose regimen, 2 crossover periods, and 2 distinct phases involving participants from the Chinese population. A total of 24 individuals were enrolled in the fasting study, with an additional 27 participants included in the postmeal study. Each participant received a single dose of either 4 mg of the reference product or the study product per cycle. The washout period was 14 days between each period. Bioequivalence was assessed through the analysis of geometric mean and ratio of pharmacokinetic parameters, while the safety of both drugs was evaluated by monitoring adverse events (AEs). Following a single oral administration of lenvatinib (4 mg), linear pharmacokinetics were observed. The rate of absorption was found to be significantly faster under fasting conditions (median time to maximum concentration, 2.3-2.5 hours), while the presence of a high-fat diet resulted in delayed absorption (median t_max, 5.3-6.1 hours). Furthermore, the 90% confidence intervals for the reference and test pharmacokinetic parameters under both fasting and postprandial conditions fell within the bioequivalence standard range of 80%-125%. AEs were reported in 34.78% of cases during fasting and in 48.15% of cases after eating. There was no significant difference in AE rates between the reference and study products. The study determined that both the study product and the reference product were bioequivalent and well tolerated by healthy Chinese participants in both fasting and postprandial conditions.

This single-center, randomized, open, two-preparation, single-dose, two-period, self-crossover trial aimed to assess the bioequivalence and safety of the test (T) preparation compared to the reference (R) preparation following intravenous injection in healthy subjects under fasting conditions. Twenty-four healthy subjects were enrolled in the study and subjects were randomly divided into two groups at a 1:1 ratio and were administered once per period, with an 8-day washout period. During each period, serum drug concentrations were detected for pharmacokinetic analysis and adverse events were recorded for safety analysis. The 90% confidence intervals for the geometric mean ratios (T:R) of maximum serum concentration, area under the serum concentration-time curve from time zero to the last measurable concentration, and area under the serum concentration-time curve from time zero to infinite time fell within the predefined bioequivalence range of 80%-125%, indicating bioequivalence between the T and R preparation under fasting conditions. Additionally, four subjects (16.7%) experienced five instances of adverse events in the T group, while five subjects (21.7%) experienced five instances of adverse events in the R group. This trial indicated the potential bioequivalence between the T and R products under fasting conditions, based on pharmacokinetic and safety profile.

Sotorasib is approved to be taken as 960 mg orally once daily (8 × 120-mg tablets) for the treatment of KRAS G12C-mutated nonsmall cell lung cancer. Dispersion of tablets in water could be an alternative method for patients who require a liquid formulation due to dysphagia and enteral administration. A clinical study was conducted to assess the pharmacokinetics of 960 mg of sotorasib administered as tablets and as tablets dispersed in water in healthy volunteers. Each subject received 960 mg of sotorasib by mouth, as tablets and as tablets dispersed in water on Days 1 and 4. Sotorasib median time to maximum observed plasma concentration was similar when administered as tablets and as tablets predispersed in water. The geometric least squares mean ratios (water dispersion/tablets) for area under the concentration-time curve from time 0 extrapolated to infinity and maximum observed plasma concentration were 1.049 and 1.080, respectively. Sotorasib 960 mg was well tolerated. Administration of 960 mg of sotorasib as tablets predispersed in water achieved similar systemic exposures to that of sotorasib administered as oral tablets. In vitro evaluations were performed to assess the feasibility of administering sotorasib through an enteral feeding tube. Approximately 98% of sotorasib was recovered, with no new impurities, from enteral feeding tubes. Collectively, these results support that sotorasib can be administered by mouth and via enteral feeding tubes as tablets predispersed in water.

The objective of this phase 1 single-dose study was to evaluate the safety, tolerability, and pharmacokinetics of mirikizumab in Chinese healthy adults. Sixty participants were randomized within 5 planned dose cohorts: intravenous (IV) 300 mg, IV 600 mg, IV 1200 mg, subcutaneous (SC) 200 mg, and SC 400 mg to receive mirikizumab (10 participants in each cohort) or placebo (2 participants in each cohort). No death or serious adverse events occurred. Twenty-eight (56.0%) participants who received mirikizumab reported 49 treatment-emergent adverse events (TEAEs) and 8 (80.0%) participants who received placebo reported 18 TEAEs. The majority of TEAEs were mild in severity. Following IV 300-1200 mg mirikizumab, the arithmetic mean of both area under the concentration versus time curve from time 0 to infinity (AUC_0-∞) and maximum observed drug concentration (C_max) increased by approximately 3.5-fold, and the arithmetic mean half-life (t_1/2) ranged from 9.64 to 12.0 days. Following SC 200 and 400 mg mirikizumab, the arithmetic mean of both AUC_0-∞ and C_max increased by approximately 1.6-fold, the median time to C_max (t_max) was 2.98 days for both, and the arithmetic mean t_1/2 was 10.6 and 10.5 days, respectively. Absolute bioavailability based on pooled SC and IV dose data was 38.2%. In this study, the safety and pharmacokinetic profile of mirikizumab were consistent with what has been reported in other studies.

DATE: 9/8/2024

TIME: 5:00 PM – 7:00 PM

DATE: 9/9/2024

TIME: 5:00 PM – 7:00 PM

Abrocitinib is a selective Janus kinase 1 inhibitor approved for the treatment of atopic dermatitis. It is metabolized primarily by cytochrome P450 (CYP) 2C19 (approximately 53%) and CYP2C9 (approximately 30%), which form 2 active metabolites. The pharmacologic activity of abrocitinib is attributable to the unbound exposures of abrocitinib and those metabolites with active moiety area under the plasma concentration–time curve (AUC) considered the best measure of the total pharmacological effect. The effect of CYP2C19 and/or CYP2C9 genotypes on abrocitinib and active moiety exposures were evaluated using a meta-analysis of the noncompartmental estimates of exposure pooled from 10 clinical studies. A linear mixed-effects model was developed on the basis of the power model to evaluate the effect of CYP2C19 and/or CYP2C9 genotypes on exposure (i.e., abrocitinib AUC and peak plasma concentration, active moiety AUC and peak plasma concentration). The genotypes were evaluated individually and as a combined phenotype effect. When evaluating the poor metabolizers of CYP2C19 or CYP2C9 individually, the estimated increases were 44.9% and 42.0% in active moiety AUC, respectively. The combined phenotype models showed a 0.6% decrease, and 25.1% and 10.5% increases in the active moiety AUC for “elevated,” “mixed,” and “reduced” metabolizers, respectively. Overall, the active moiety exposures did not appear to be affected to a clinically meaningful extent by different genotypes of CYP2C19 and/or CYP2C9.

This study aimed to evaluate the pharmacokinetics (PKs) and safety of a generic drug, linezolid, compared to those of a reference drug in healthy Chinese subjects under both fasting and fed conditions. This was a randomized, open-label, 2-period, 2-sequence crossover study. The subjects received a single dose of the test or reference drug, linezolid (600 mg), in each period. The PK parameters were calculated using a non-compartmental method and compared between the 2 drugs. Bioequivalence was analyzed using geometric mean ratios (GMRs) of the 2 formulations and their corresponding 90% confidence intervals (CIs). The safety of the 2 formulations was assessed under both fasting and fed conditions. Forty-eight subjects completed the study, 24 each in the fasting and feeding groups. The average plasma concentration-time patterns of linezolid were similar for both medications under both conditions. The GMR and 90% CIs of the maximum plasma concentration and the area under the plasma concentration-time curve of linezolid were ranged from 0.80 to 1.25. Both drugs were well tolerated with a similar incidence of adverse drug reactions. In conclusion, the PK and safety profiles of the 2 formulations were comparable. Food intake did not influence the PK profiles of linezolid. These results suggest that the test drug can be used as an alternative to reference drugs.

This was an open-label, randomized, single-dose, 2-period, crossover clinical trial with an adaptive design to evaluate the bioequivalence and comparative pharmacokinetics of generic glecaprevir/pibrentasvir versus the brand name product in healthy White male and female volunteers under fed conditions. Safety profiles were also assessed. A total of 56 healthy adult volunteers were enrolled and randomly assigned in a 1:1 ratio to receive a single dose of either the generic or reference formulation. After a 7-day washout period, subjects received the alternate product. Blood samples were collected at pre-specified time points up to 48 hours post-dosing. Plasma concentrations of glecaprevir and pibrentasvir were determined using a validated high-performance liquid chromatography-tandem mass spectrometry method. The geometric mean ratios of the test to the reference formulation for maximum plasma concentration (C_max) and area under the concentration-time curve from drug administration to the last measurable concentration (AUC_0-t) fell within the predefined bioequivalence range of 80%-125%. Both formulations demonstrated comparable pharmacokinetic profiles for glecaprevir and pibrentasvir, and can be considered bioequivalent. No adverse events were reported, and both formulations were well tolerated by all participants.