Introduction: GSK3640254 is a next-generation maturation inhibitor that would likely be combined with standard antiretroviral agents to form a regimen of ≥2 fully active classes.
Methods: This phase I, open-label, 2-period, 1-way study assessed potential pharmacokinetic (PK) interactions between GSK3640254 and tenofovir alafenamide/emtricitabine (TAF/FTC; including the metabolite tenofovir [TFV]) in healthy volunteers. Eligible participants received TAF/FTC 25/200 mg once daily (QD) on Days 1 through 21 with a moderate-fat meal; GSK3640254 200 mg QD was added on Days 15 through 21. Geometric least squares mean ratios (GMRs) and 90% CIs were derived using linear mixed-effect models. Adverse events (AEs) and laboratory, electrocardiogram, and vital sign parameters were monitored.
Results: Sixteen participants, all male, received treatment; one withdrew because of treatment-related grade 1 urticaria. After TAF/FTC + GSK3640254 coadministration, TAF steady-state area under the plasma concentration-time curve from time 0 to the end of the dosing interval and maximum observed concentration were 11% and 13% lower than when TAF/FTC was administered alone, with GMR (90% CI) of 0.886 (0.75-1.04) and 0.874 (0.68-1.12), respectively. Steady-state PK of TFV and FTC was similar when TAF/FTC was administered alone or with GSK3640254. No clinically significant trends in tolerability or safety were observed.
Conclusions: GSK3640254 200 mg QD did not meaningfully affect the steady-state PK of TAF, TFV, or FTC in healthy participants under fed conditions and was not associated with major tolerability or safety findings. These data support the further investigation of GSK3640254 for coadministration with TAF/FTC for the treatment of HIV (ClinicalTrials.gov, NCT03836729).
The study findings suggest that in the presence of rifampin, a strong CYP3A4/moderate CYP2C9 inducer, siponimod showed significant decrease in C (45%) and AUC (57%) in healthy subjects.
CVN424 is a novel small molecule and first-in-class candidate therapeutic to selectively modulate GPR6, an orphan G-protein coupled receptor. Expression of GPR6 is largely confined to the subset of striatal projection neurons that give rise to the indirect (striatopallidal) pathway, important in the control of movement. CVN424 improves motor function in preclinical animal models of Parkinson's disease. Here we report results of a phase 1, first-inhuman study investigating the safety, tolerability, and pharmacokinetics of CVN424 in healthy volunteers. The study (NCT03657030) was randomized, double-blind, and placebo controlled.CVN424 was orally administered in ascending doses to successive cohorts as inpatients in a clinical research unit. Single doses ranged from 1 mg to 225 mg, and repeated (7 day) daily doses were 25 mg, 75 mg, or 150 mg. CVN424 peak plasma concentrations were reached within 2h post-dose in the fasted state and increased with increasing dose. Dosing after a standardized high-fat meal reduced and delayed the peak plasma concentration but total plasma exposure was similar. Mean terminal half-life ranged from 30h to 41h. CVN424 was generally well tolerated: no serious or severe adverse effects were observed, and there were no clinically significant changes in vital signs or laboratory parameters. We conclude that CVN424, a nondopaminergic compound that modulates a novel therapeutic target, was safe and well tolerated. A phase 2 study in patients with Parkinson's disease is underway.
area under the concentration-time curve from time zero to infinity (AUC 0-inf ); area under the concentration-time curve from time zero to the last quantifiable concentration (AUC 0-last ); maximum serum concentration (C max ). Equivalence was determined if the 90% confidence interval for the geometric least-squares mean ratio was within the 80-125% equivalence margin. Additional pharmacokinetic endpoints, safety and immunogenicity were evaluated.Results: Of 193 subjects who were randomised (98 CT-P17 AI; 95 CT-P17 PFS), 180 received study drug. Pharmacokinetic equivalence was demonstrated: 90% confidence intervals were within the 80-125% equivalence margin (AUC 0-inf : 93.98-114.29; AUC 0-last : 91.09-121.86; C max : 94.08-111.90). Mean serum CT-P17 concentrations, secondary pharmacokinetic parameters and numbers of subjects with antidrug antibodies (ADAs) or neutralising ADAs were comparable between groups. AUC 0-inf , AUC 0-last and C max were numerically lower for ADA-positive than for ADAnegative subjects (both groups); pharmacokinetic equivalence was also demonstrated among ADA-positive subjects. CT-P17 AI and CT-P17 PFS were well tolerated, with comparable overall safety profiles.Conclusions: CT-P17 AI and CT-P17 PFS were pharmacokinetically equivalent.Overall safety and immunogenicity were comparable between the 2 delivery devices.
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