Clinical Pharmacology in Drug Development最新文献

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.

In this study, we assessed the pharmacokinetics, safety, and bioequivalence of trimetazidine tablets from 2 different manufacturers in healthy Chinese individuals under both fasting and fed conditions. Twenty-eight healthy Chinese volunteers were included in each fasting and fed group. They were randomly assigned to fasting and fed arms in a single-center, randomized, open-label, crossover trial with a 2-period, 2-sequence design. Plasma trimetazidine levels were determined using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were determined using a nonatrioventricular model. The pharmacokinetic parameters were obtained by the concentration-time profiles, including the area under the plasma concentration-time curve from time 0 to 24 hours, area under the concentration-time curve from time 0 to infinity, maximum concentration, time to achieve maximum concentration, and elimination half-life. Both trimetazidine preparations were bioequivalent under fasting and fed states, with all parameters within the acceptable limits. All recorded adverse events were mild. Overall, the test trimetazidine formulation was bioequivalent to the reference formulation and safe for use in healthy Chinese subjects in both the fasting and fed states.

This prospective study compared the therapeutic efficacy of Ginaton alone, Ginaton combined with glucocorticoids, or Ginaton with mouse nerve growth factor (mNGF) in patients with sudden sensorineural hearing loss (SSNHL). Between January 2014 and June 2015, 101 SSNHL patients, with treatment initiated 3-10 days post onset, were randomly assigned to receive 1 of 3 2-week regimens: Ginaton alone (n = 33), Ginaton + glucocorticoid (n = 34), or Ginaton + mNGF (n = 34). Primary outcome was overall hearing improvement. Effectiveness rates were 78.79% (95% confidence interval [CI] 61.8%-89.9%) for Ginaton, 79.41% (95% CI 62.9%-90.1%) for Ginaton + glucocorticoid, and 88.24% (95% CI 72.5%-95.8%) for Ginaton + mNGF; these differences were not statistically significant (P > .05). All 3 groups showed significant post-treatment reductions in whole blood viscosity (high, medium, low shear rates; all P < .01), low-density lipoprotein cholesterol (all P < .01), and triglycerides (all P < .01). The neutrophil-to-lymphocyte ratio, an inflammatory marker, significantly decreased in the Ginaton + glucocorticoid (P < .05) and Ginaton + mNGF groups (P < .01). While all regimens demonstrated positive effects on hearing and surrogate markers, and Ginaton + mNGF showed a numerically higher hearing improvement rate, no statistically superior regimen for overall hearing was identified. This study suggests these approaches improve inner ear blood rheology and inflammation. However, larger, placebo-controlled trials are crucial to confirm efficacy and elucidate the distinct pharmacological contributions of each component, considering the study's sample size and open-label design.

Recently, a local pharmaceutical company produced levothyroxine sodium tablets, an endogenous drug that helps improve water-salt metabolism and reduce myxedema. However, the bioequivalence of these tablets is not well known. The present study aimed to investigate the bioequivalence, pharmacokinetics, and safety of a single oral dose of 2 levothyroxine sodium tablets in healthy adult Chinese subjects under fasting conditions. The study used a single-center randomized, single-dose, 2-sequence, 4-period replicate crossover design. Forty-eight subjects fasted for at least 10 hours before taking the medication. According to the literature, levothyroxine sodium is an endogenous narrow therapeutic index drug; therefore, baseline samples were collected before administration in healthy adult subjects. Blood specimens from all subjects were collected against the light within 48 hours to detect levothyroxine concentration in serum. A noncompartmental model was used for the analysis of pre- and post-baseline correction pharmacokinetic parameters. The geometric mean ratio of the post-baseline correction maximum plasma concentration and area under the concentration-time curve from time 0 to 48 hours with a 90% confidence interval was calculated. The final data met the bioequivalence criteria. No serious adverse reactions were found, suggesting that the test and reference preparations of levothyroxine sodium tablets have a similar safety profile.