Species differences in the multiple-dose pharmacokinetics of the non-nucleoside reverse transcriptase inhibitor (NNRTI) UK-453,061 in animals and man: implications for safety considerations

Abstract

1. The requirements for safe testing of pharmaceuticals in humans places substantial emphasis on the translation of safety testing performed in animals to man.

2. The comparison of systemic exposure in animals and man has taken on increasing importance in this assessment, with the underlying assumption that plasma concentrations will elicit the same response in different species. This assumption may be flawed for a number of different reasons, one of which is differences in drug disposition between species leading to high doses required in animal species to yield equivalent systemic exposure to humans and consequent higher exposure to organs such as the intestine and liver.

3. Hepatic clearance can vary substantially, particularly between rodents and man, resulting in vast differences in the dose–exposure relationship. A specific example of a non-nucleoside reverse transcriptase inhibitor, which causes substantial auto-induction in rodents, is used to illustrate this situation and the impact this has on the interpretation of safety extrapolation from animals to man.

4. In such circumstances, it is important to recognize the impact of species differences in drug clearance and disposition and consider broader input in the assessment of clinical safety.

Keywords::

• UK-453,061
• human immunodeficiency virus (HIV)
• pharmacokinetics
• enzyme induction
• species differences

Acknowledgements

The authors would like to thank all their colleagues in the departments of Pharmacokinetics, Dynamics and Metabolism, Drug Safety Research and Development, and Clinical Pharmacology who have contributed to this work. Particular thanks go to Regis LeLain for toxicokinetic analysis, Helen Westgate, Jackie Luckwell and Daniela Fraier for clinical bioanalysis, and Gill Allan, Pat Wright, Drew Gibson and Angus Nedderman for structural elucidation of metabolites.

Declaration of interest: The authors report no conflicts of interest.