Clinical Pharmacology in Drug Development最新文献

Clevidipine emulsion is an intravenous antihypertensive agent indicated for acute blood pressure control when oral therapies are contraindicated or ineffective. To address this gap in availability, a randomized, 2-period, 2-sequence crossover trial was conducted to evaluate the bioequivalence and safety of a generic clevidipine emulsion versus the reference product in 32 healthy Chinese adults. Participants received a 30-minute intravenous infusion of 3 mg of clevidipine (test or reference formulation) in each study period, with serial blood samples collected from the contralateral arm relative to the infusion site for pharmacokinetic analysis. Treatment-emergent adverse events (TEAEs) were monitored throughout the study. All participants completed both treatment phases. The generic formulation satisfied bioequivalence criteria for all primary pharmacokinetic parameters, with geometric mean ratios (90% confidence intervals) of C_max, AUC_0-t, and AUC_0-∞ fully contained within the 80%-125% equivalence range. Three participants (9.4%) experienced mild TEAEs assessed as treatment-related, including transient sinus tachycardia (n = 2) and asymptomatic alanine aminotransferase elevation (n = 1). The generic formulation met bioequivalence criteria and exhibited comparable safety profiles to the reference product.

Apalutamide, a second-generation non-steroidal androgen receptor inhibitor, is indicated for the treatment of non-metastatic castration-resistant and metastatic hormone-sensitive prostate cancer. A study was conducted to investigate the pharmacokinetic (PK) parameters of apalutamide in healthy Chinese male participants and to evaluate the bioequivalence (BE) of the test and reference formulations (Erleada) under both fed and fasted conditions. This study was a single-center, open-label, randomized, single-dose, two-period, two-sequence, crossover study. A total of 88 healthy Chinese male volunteers were enrolled in this study, with 32 assigned to the fasted study and 56 to the fed study. The subjects were administrated a single dose of either the test or the reference formulation in each treatment period. The PK parameters of apalutamide, including the time to peak (T_max), peak concentration (C_max), and the area under the concentration-time curve from time 0 to 72 h (AUC_{0–72 h}), were calculated, and the safety of apalutamide was also assessed. The C_max and AUC_{0–72 h} values were comparable between the test and reference formulations under both fasted and fed conditions. The 90% confidence intervals (CIs) for C_max and AUC_{0–72 h} fell within the BE acceptance range of 80.00% to 125.00% under both conditions. However, T_max in the fed condition was slightly different, with median values of 4.5 h for the test formulation and 3.5 h for the reference formulation. No serious adverse events occurred during the study, and both formulations were well tolerated under fasted and fed conditions. The test and reference formulations of apalutamide were demonstrated to be bioequivalent under both fasted and fed conditions, and were well tolerated with favorable safety profiles.

Glucose and lipid metabolism disorders significantly contribute to vascular damage and poor outcomes in patients with diabetes. This study aims to evaluate the combined effects of Yuquan capsules and metformin on glucose and lipid metabolism disorders and microinflammation in patients with type 2 diabetes mellitus (T2DM). In this study, 100 patients with T2DM admitted to our hospital's Endocrinology Department from June 2024 to June 2025 were randomly divided into a control group (n = 50) receiving metformin and a placebo, and an observation group (n = 50) receiving metformin and Yuquan capsules, for 12 weeks. Key blood indicators such as fasting plasma glucose, 2-hour postprandial blood glucose, glycated hemoglobin, triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, C-reactive protein, interleukin-6, and tumor necrosis factor-α were measured before and after treatment. The findings indicated that the improvement in glucose and lipid metabolism disorders, as well as the reduction in microinflammation, was significantly greater in the observation group compared to the control group (P < .05). Furthermore, interleukin-1β levels in the observation group decreased significantly from 45.6 pg/mL at baseline to 22.1 pg/mL (P < .001), with this reduction being positively correlated with a decrease in tumor necrosis factor-α levels (r = 0.62, P = .001). Subgroup analyses revealed that combined therapy led to an additional 0.9% reduction in glycated hemoglobin compared to monotherapy in patients with a body mass index of 24 kg/m² or greater (95% confidence interval, 0.6%-1.2; P < .001). The combination of Yuquan capsules and metformin effectively improves glucose and lipid metabolism disorders and reduces microinflammation in patients with type 2 diabetes, providing new insights for using traditional Chinese medicine in T2DM treatment.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit the activity of the reverse transcriptase enzyme in HIV, representing a significant advancement in antiviral therapy. The emergence of antiviral-resistant strains of HIV-1 poses a substantial challenge in the treatment of HIV. This study presents an innovative virtual screening method that integrates a drug screening approach based on molecular structure to identify potential inhibitors for drug-resistant HIV-1 strains. Wild-type reverse transcriptase and a proposed multi-mutant variant were identified as target proteins for structure-based virtual screening. For better interpretation, selected compounds were used for molecular docking and molecular dynamics simulation. Six compounds with strong binding affinities were identified from the Comprehensive Marine Natural Products Database (CMNPD) as potential NNRTI candidates. In CMNPD database six compounds were identifed that have potential activity against the multi-mutant reverse transcriptase enzyme of HIV-1. Molecular modeling studies revealed that the highest-ranking compound (CMNPD370) binds persistently and with significant affinity to the multi-mutant HIV-RT. Molecular mechanics/generalized born surface area analysis revealed CMNPD370 binds more strongly to the mutant reverse transcriptase (RT) compared to the wild-type, as indicated by a more negative total binding free energy (ΔG_bind) of –17697.64 kcal/mol versus –15503.75 kcal/mol. The results demonstrate that our proposed method is feasible, reliable, and effective. Our findings may facilitate the development of novel NNRTIs targeting drug-resistant strains and offer new insights for identifying natural therapies for HIV.

This randomized, open-label, 2-period crossover study evaluated food effects on SPH3348 pharmacokinetics (PK) and safety in 16 healthy participants receiving a single 480-mg dose under fasting and high-fat fed conditions. PK profiling involved serial blood sampling at 15 predefined time points per period, while safety assessments included continuous monitoring of adverse events throughout the study. PK analysis revealed pronounced food-dependent alterations. Under fed conditions, the median time to peak concentration was delayed by 1 hour compared to fasting (4.00 vs. 3.00 hours), reflecting a slowdown in absorption rate (median time to peak concentration delay was statistically significant [P < .05 by Wilcoxon signed-rank test]). PK analysis demonstrated marked food-induced increases in systemic exposure. The fed-to-fasted geometric mean ratios and 90% confidence intervals were 1.9023 (1.5975-2.2653) for maximum concentration and 2.3667 (2.1140-2.6490) for AUC from time zero extrapolated to infinity, both exceeding the 1.25 threshold for bioequivalence. These exposure increases (greater than 2-fold) confirm that meal-induced enhancement of absorption is clinically significant. Safety profiles remained comparable between dosing conditions, with adverse event incidence rates of 13.3% (fasting) versus 18.8% (fed) and predominantly mild severity, primarily involving transient gastrointestinal events. These findings indicate that while food intake significantly increases SPH3348 bioavailability and slightly delays absorption kinetics, both fasting and fed administrations are well tolerated following single-dose exposure. The observed PK modifications highlight the necessity of standardizing dietary conditions in clinical use to ensure consistent drug exposure. The systematic characterization of these food effects provides critical evidence for optimizing dosing regimens and informing subsequent-phase clinical development, particularly regarding administration guidelines to manage variability between patients.

Faldaprevir (FDV) is an investigational NS3/NS4A protease inhibitor for chronic hepatitis C. This study evaluated the safety, tolerability, and pharmacokinetics (PK) of FDV after multiple rising doses in healthy male volunteers and subjects with Gilbert syndrome (GS). In this randomized, double-blind, placebo-controlled study, healthy males received once-daily oral FDV (20, 48, 120 mg [n = 6 per group], 240 mg [n = 5]), or placebo (n = 7). A single dose was given on Day 1, followed by a 72-h washout and 21 days of dosing from day 4. Separately, 9 GS subjects received open-label FDV 240 mg daily for 28 days. PK was assessed after the first and last doses; safety was evaluated throughout. FDV showed greater than dose-proportional increases in exposure (gMean C_max,ss: 99–5360 ng/mL; AUC_τ,ss: 1740–50,100 h·ng/mL) and time-dependent PK with a linearity index >1. Mean t_1/2 was 20–30 h; steady state was reached in 6–7 days with an accumulation ratio of 2.8–3.1. FDV exposure in GS subjects was similar but slightly lower. Total bilirubin increased dose-dependently, with higher indirect bilirubin in GS subjects. FDV exhibited non-linear, time-dependent PK and was generally well tolerated up to 240 mg/day in subjects with or without GS.

Aripiprazole once-monthly (AOM) is approved for the maintenance monotherapy treatment of bipolar I disorder (BP-I) in adults. A previously developed population pharmacokinetic model was validated by applying it to data from patients diagnosed with BP-I. The model was then used to generate aripiprazole exposures for an exposure-response model intended to describe the relationship between aripiprazole exposure and time to recurrence of any mood episode in patients with BP-I. The BP-I data were best described by a continuous model in which higher aripiprazole exposure was associated with a lower risk of recurrence. For each 1 ng/mL increase in aripiprazole plasma concentration, the predicted hazard for recurrence decreased by 0.34%. An aripiprazole plasma concentration of 95 ng/mL (clinically relevant in schizophrenia) was tested in a separate categorical model and was a significant predictor of time to recurrence (P = .0270), with a 36% (1.55-fold) decrease in the predicted risk of recurrence with an aripiprazole concentration of ≥95 versus <95 ng/mL. Plasma aripiprazole concentration was identified as an important predictor of recurrence in patients diagnosed with BP-I treated with AOM, highlighting the importance of maintenance therapy. A 95 ng/mL threshold is relevant in BP-I, but with a smaller effect size compared with that in schizophrenia.

Extended-release (ER) formulations of the stimulant methylphenidate are commonly used to treat attention-deficit/hyperactivity disorder in both children and adults. Previous studies have shown that the clinical effectiveness of long-acting methylphenidate formulations is closely tied to the drug's pharmacokinetic (PK) profile, highlighting the need for consistency in drug exposure. ODX-methylphenidate ER uses an osmotic pump design to provide controlled release of drug over the course of the day. In these similarly designed 4-period replicate crossover studies, the PK profile of ODX-methylphenidate ER was compared to the reference product, osmotic release oral system (OROS)-methylphenidate ER, in healthy subjects in the fasted state. In the first trial (N = 60), a single 72-mg tablet of ODX-methylphenidate ER was compared to two 36-mg tablets of OROS-methylphenidate ER, while in the second trial (N = 36), a single 54-mg tablet of ODX-methylphenidate ER was compared to a 54-mg tablet of OROS-methylphenidate ER. The 2 studies had very comparable results, demonstrating similar PK parameters for the 2 products, including during the critical 7-12-hour postdose window. Statistical bioequivalence between the 2 formulations was confirmed for maximum drug concentration, area under the concentration-time curve from time 0 to 3 hours after dosing (AUC_{0-3 h}), AUC from 3 to 7 hours after dosing, AUC from 7 to 12 hours after dosing, and AUC from time 0 extrapolated to infinity in both trials. Safety and tolerability were similar for both products and in both trials, with no serious adverse events reported.

Endogenous oxytocin plays an important role in lactation, but its effectiveness as an exogenous galactagogue has been modest due to dose-limiting side effects related to off-target effects at the vasopressin V2 receptor. Merotocin (FE 202767) is a short-acting peptidic oxytocin receptor agonist with the potential to aid mothers experiencing preterm delivery and inadequate milk production by increasing their milk volume. A first-in-human, single-center, randomized, placebo-controlled study investigated single and repeated intranasal administrations (every 3 hours) at doses from 5 to 400 µg and intravenous administration at 20 µg in healthy, nonpuerperal women. Pharmacokinetic parameters were determined after all doses. Bioavailability was determined after crossover intranasal and intravenous administrations. Merotocin was rapidly absorbed and eliminated after intranasal administration, median time to maximum plasma concentration was approximately 15 minutes, and the terminal half-life was approximately 30 minutes. No accumulation was seen. Merotocin was not detected in urine, and metabolites were not detected in either plasma or urine, indicating elimination independent of the kidneys. Systemic bioavailability of merotocin after intranasal administration is low. All doses were tolerated, with few adverse events (mostly headache), all mild intensity. A maximum tolerated intranasal dose was not identified in this study. Intranasal administration of merotocin at doses up to 400 µg was tolerated by healthy women, and the pharmacokinetic and safety profiles support frequent repeated administration expected in lactation clinical practice.