Orforglipron is a non-peptide, oral glucagon-like peptide 1 receptor agonist under development for glycemic control in adults with type 2 diabetes and weight management in people with obesity. Two phase 1, open-label studies evaluated the disposition and absolute bioavailability of orforglipron in healthy adults. Study A participants (N = 10) received a 1-mg orforglipron oral capsule while fasting and an intravenous dose of ∼21 µg of [14C]-orforglipron. Study B participants (N = 6) received an oral solution of 3 mg of orforglipron with ∼200 µCi of [14C]-orforglipron while fasting. In study A, total plasma radioactivity and [14C]-orforglipron were measured by accelerator mass spectrometry (AMS) and high-performance liquid chromatography (HPLC)/AMS, while orforglipron was measured by HPLC/MS. The mean absolute oral bioavailability of orforglipron was 79.1% ± 16.8%. In study B, urine and feces were analyzed for total radioactivity. Metabolic radioprofiling was performed on selected plasma and fecal samples by HPLC/high-resolution MS. The primary route of elimination for [14C]-orforglipron-related radioactivity was via the feces (87% ± 2.8%) with minimal urinary excretion (0.2% ± 0.02%). Total recovery of administered radioactivity was 88% over 384 hours after the dose. Metabolite profiling from study B showed that orforglipron underwent extensive oxidative metabolism, followed by microbial metabolism of the oxadiazolone ring. Orforglipron was the most abundant plasma component (93.3%) with minor oxidative metabolites M7 (3.3%) and M23 (1.6%).
Bexicaserin (LP352) is a selective 5-hydroxytryptamine 2C (5-HT2C) superagonist in development for the treatment of seizures in developmental and epileptic encephalopathies (DEEs). This double-blind, placebo-controlled, single ascending dose (SAD) Phase 1 study aimed to assess the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles of single oral doses of bexicaserin and determine any relevant food effects. Forty healthy adult females were randomized to six treatment groups (1, 3, 6, 12, and 24 mg fasted; 6 mg fed) or placebo. Bexicaserin was generally safe and well tolerated: treatment-related adverse events were mild to moderate. Bexicaserin was rapidly absorbed into circulation (median Tmax 1.02–1.54 h), with a mean terminal elimination half-life ranging from 4.67–6.66 h. Mean Cmax and AUClast of bexicaserin increased by at least >55-fold for a 24-fold dose increase. Three pharmacologically inactive circulatory metabolites (M9, M12, and M20) were further characterized. M20 was the major metabolite, with levels ranging from 3.47 to 10.8 times higher than bexicaserin. In comparison, M12 ranged from 0.35 to 0.98 times, and M9 from 0.037 to 0.53 times, relative to bexicaserin. Metabolism was the major route of clearance, as <5% of parent bexicaserin was eliminated in the urine. A high-fat meal did not alter the exposure of bexicaserin, supporting administration without regard to food. Increases in prolactin concentrations, a potential PD marker, were dose-dependent, suggesting central 5-HT2C receptor engagement. In summary, this Phase 1 SAD study demonstrated safety, tolerability, and adequate characterization of PK/PD of bexicaserin, which is currently in Phase 3 clinical development.
Bexicaserin (LP352) is a selective superagonist of the 5-hydroxytryptamine 2C (5-HT2C) receptor currently in development for the treatment of seizures that arise from developmental and epileptic encephalopathies. This phase 1, double-blind, placebo-controlled multiple ascending dose (MAD) study assessed the safety, tolerability, and pharmacokinetic profile of bexicaserin in healthy participants. Doses ranging from 3 to 24 mg three times daily (TID) were administered for up to 14 days. Serial blood and urine samples were collected to assess pharmacokinetics, and prolactin was assessed as a pharmacodynamic biomarker. Bexicaserin was generally safe and well-tolerated, rapidly absorbed, metabolized to three circulatory pharmacologically inactive metabolites, and had a median Tmax of about 1–2 h. Cmax accumulation ranged from 1.5 to 5.1-fold for all analytes after multiple doses. M20 was the major metabolite, with exposures ranging from 9 to 33-fold versus bexicaserin. Overall clearance of bexicaserin ranged from 45.9 to 125 L/h, with renal clearance between 5.04 to 6.58 L/h, suggesting that hepatic metabolism and/or excretion is the main elimination pathway. There was a weak dose-dependent positive correlation between bexicaserin Cmax and prolactin mean percentage change from baseline, suggesting successful engagement of central 5-HT2C receptors. Overall, this Phase 1 MAD study demonstrated bexicaserin to be safe and well-tolerated, with rapid absorption, presence of one major metabolite, accumulation upon multiple dosing TID, and a greater than dose-proportional increase in exposures. These findings support the continued development of bexicaserin, which is currently in Phase 3 clinical trials.
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 Cmax, AUC0-t, and AUC0-∞ 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 (Tmax), peak concentration (Cmax), and the area under the concentration-time curve from time 0 to 72 h (AUC0–72 h), were calculated, and the safety of apalutamide was also assessed. The Cmax and AUC0–72 h values were comparable between the test and reference formulations under both fasted and fed conditions. The 90% confidence intervals (CIs) for Cmax and AUC0–72 h fell within the BE acceptance range of 80.00% to 125.00% under both conditions. However, Tmax 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 Cmax,ss: 99–5360 ng/mL; AUCτ,ss: 1740–50,100 h·ng/mL) and time-dependent PK with a linearity index >1. Mean t1/2 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.
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