Referenced in: none

Automatically associated channels: TRP , TRPV , TRPV1

Title: Effects of the TRPV1 antagonist ABT-102 on body temperature in healthy volunteers: pharmacokinetic/ pharmacodynamic analysis of three phase 1 trials.

Authors: Ahmed A Othman, Wolfram Nothaft, Walid M Awni, Sandeep Dutta

Journal, date & volume: Br J Clin Pharmacol, 2013 Apr , 75, 1029-40

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22966986

Abstract
To characterize quantitatively the relationship between ABT-102, a potent and selective TRPV1 antagonist, exposure and its effects on body temperature in humans using a population pharmacokinetic/pharmacodynamic modelling approach.Serial pharmacokinetic and body temperature (oral or core) measurements from three double-blind, randomized, placebo-controlled studies [single dose (2, 6, 18, 30 and 40 mg, solution formulation), multiple dose (2, 4 and 8 mg twice daily for 7 days, solution formulation) and multiple-dose (1, 2 and 4 mg twice daily for 7 days, solid dispersion formulation)] were analyzed. NONMEM was used for model development and the model building steps were guided by pre-specified diagnostic and statistical criteria. The final model was qualified using non-parametric bootstrap and visual predictive check.The developed body temperature model included additive components of baseline, circadian rhythm (cosine function of time) and ABT-102 effect (Emax function of plasma concentration) with tolerance development (decrease in ABT-102 Emax over time). Type of body temperature measurement (oral vs. core) was included as a fixed effect on baseline, amplitude of circadian rhythm and residual error. The model estimates (95% bootstrap confidence interval) were: baseline oral body temperature, 36.3 (36.3, 36.4)°C; baseline core body temperature, 37.0 (37.0, 37.1)°C; oral circadian amplitude, 0.25 (0.22, 0.28)°C; core circadian amplitude, 0.31 (0.28, 0.34)°C; circadian phase shift, 7.6 (7.3, 7.9) h; ABT-102 Emax , 2.2 (1.9, 2.7)°C; ABT-102 EC50 , 20 (15, 28) ng ml(-1) ; tolerance T50 , 28 (20, 43) h.At exposures predicted to exert analgesic activity in humans, the effect of ABT-102 on body temperature is estimated to be 0.6 to 0.8°C. This effect attenuates within 2 to 3 days of dosing.