Pharmacokinetics of the TRPV1 Antagonist ABT-102 in Healthy Human Volunteers: Population Analysis of Data From 3 Phase 1 Trials


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Abstract

ABT-102 is a selective TRPV1 antagonist with robust efficacy in several preclinical models of pain. Three phase 1 studies evaluated ABT-102 pharmacokinetics upon oral administration to healthy human volunteers: a single-dose study (2, 6, 18, 30, and 40 mg) and a multiple-dose study (2, 4, and 8 mg twice daily for 7 days) using a solution formulation and a multiple-dose study (1, 2, and 4 mg twice daily for 7 days) using a solid-dispersion formulation. These studies followed double-blind, randomized, placebocontrolled designs. ABT-102 exhibited dose- and timelinear pharmacokinetics. ABT-102 half-life ranged from 7 to 11 hours, and steady state was achieved by day 5 of dosing. Population analysis of the pharmacokinetic data from the 3 studies was conducted. A 1-compartment model with a transit compartment for absorption and first-order elimination provided best fit to the data. The model included formulation-dependent lag times and a bioavailability factor (Frel) for solution relative to solid dispersion. The population parameter estimates (95% bootstrap confidence intervals) were oral clearance, 16 (14–18) L/h; oral volume of distribution, 215 (192–237) L; transit rate constant, 1.4 (1.3–1.6) h-1; solid-dispersion lag, 0.6 (0.5–0.8) h; solution lag, 0.3 (0.2–0.4) h; and solution Frel, 40% (35%- 45%). Evaluation of ABT-102 pharmacokinetic model indicated its robustness and adequacy.

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