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Effects of the TRPV 1 antagonist ABT ‐102 on body temperature in healthy volunteers: pharmacokinetic/ pharmacodynamic analysis of three phase 1 trials
Author(s) -
Othman Ahmed A.,
Nothaft Wolfram,
Awni Walid M.,
Dutta Sandeep
Publication year - 2013
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2012.04405.x
Subject(s) - circadian rhythm , pharmacodynamics , pharmacokinetics , population , nonmem , pharmacology , chemistry , medicine , environmental health
Aim To characterize quantitatively the relationship between ABT ‐102, a potent and selective TRPV 1 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 ( E max function of plasma concentration) with tolerance development (decrease in ABT ‐102 E max 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 E max , 2.2 (1.9, 2.7)° C ; ABT ‐102 E C 50 , 20 (15, 28) ng ml −1 ; tolerance T 50 , 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.