Prediction of Maximum Exposure in Poor Metabolizers Following Inhibition of Nonpolymorphic Pathways

C.      Collins; R.      Levy; I.      Ragueneau-Majlessi; H.      Hachad

Abstract

Marked increases in exposure of some substrates have been noted in poor metabolizers given inhibitors of nonpolymorphic enzymes. Among the small number of clinical trials conducted to investigate this problem, a wide variation in the degree of maximum exposure ratios (area under the curve in poor metabolizers in the presence of inhibitor/area under the curve in extensive metabolizers) among the different substrates has been reported, with some trials reporting profound increases ( > tenfold), and others demonstrating less remarkable changes ( < twofold). The conduct of such trials raises safety concerns for the trial participants, in addition to other ethical and logistic concerns; therefore, the possibility was investigated that maximum exposure (area under the curve in poor metabolizers in the presence of an inhibitor) could be predicted, and that substrates susceptible to large increases in exposure could be identified. Existing clinical trials were identified by data mining the literature. A theoretical approach was developed to predict maximum exposure in poor metabolizers from studies in extensive metabolizers treated with an inhibitor of the nonpolymorphic pathway. Maximum exposure was predicted in eleven instances and the mean percentage difference between predicted and observed was 11.9%. Substrates with a fraction of substrate dose metabolized by the polymorphic enzyme (fmPOLY) higher than 75% are at greater risk of exhibiting maximum exposure ratios of more than tenfold.

Keywords: Inhibition, prediction, cytochrome P450, drug metabolizing enzymes, polymorphisms

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