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

Article date: April 2013

By: Ahmed A. Othman, Wolfram Nothaft, Walid M. Awni, Sandeep Dutta, in Volume 75, Issue 4, pages 1029-1040

Aim

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.

Methods

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.

Results

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.

Conclusions

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.

DOI: 10.1111/j.1365-2125.2012.04405.x

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