Interaction with indinavir to enhance systemic exposure of an investigational HIV protease inhibitor in rats, dogs and monkeys


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Abstract

The use of a beneficial interaction between indinavir and compound A, a potent investigational HIV protease inhibitor to enhance systemic exposure of compound A, was investigated.When administrated alone, compound A underwent extensive hepatic first-pass metabolism in rats and monkeys, resulting in low oral bioavailability.In vitro studies with liver microsomes revealed that compound A metabolism was mediated exclusively by CYP3A enzymes in rats, dogs and monkeys. Indinavir, which also was metabolized predominantly by CYP3A enzymes, extensively inhibited compound A metabolism in microsomes, whereas compound A showed weak inhibitory potency on indinavir metabolism.Consistent with in vitro observations, co-administration of the two compounds resulted in a 17-fold increase in oral AUC of compound A in rats owing to the inhibition of metabolism of compound A by indinavir, whereas compound A did not affect indinavir metabolism as indicated by the unchanged indinavir AUC. Similarly, the systemic exposure of compound A in dogs and monkeys was increased substantially following oral co-administration with indinavir by 7- and > 50-fold, respectively.Enhancement in compound A systemic exposure by indinavir in humans, as predicted based on the in vivo animal and in vitro human liver microsomal data, was confirmed in subsequent clinical studies.

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