title: Pharmacokinetics of the TRPV1 antagonist ABT-102 in healthy human volunteers: population analysis of data from 3 phase 1 trials.
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, placebo-controlled designs. ABT-102 exhibited dose- and time-linear 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 (F(rel)) 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 F(rel), 40% (35%-45%). Evaluation of ABT-102 pharmacokinetic model indicated its robustness and adequacy.
authors.affiliation: Abbott Laboratories, Abbott Park, IL, USA. ahmed.othman@abbott.com
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Othman
authors.forename: Wolfram
authors.initials: W
authors.lastname: Nothaft
authors.forename: Walid M
authors.initials: WM
authors.lastname: Awni
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dutta
mesh_terms: D000284:Administration, Oral; D000328:Adult; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D016032:Randomized Controlled Trials as Topic; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014018:Tissue Distribution; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: C528492:ABT 102; D007191:Indazoles; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D014508:Urea