Interaction with indinavir to enhance systemic exposure of an investigational HIV protease inhibitor in rats, dogs and monkeys.
1. 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. 2. When administrated alone, compound A underwent extensive hepatic first-pass metabolism in rats and monkeys, resulting in low oral bioavailability. 3. 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. 4. 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. 5. 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.
Jin
L
L
Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA. lixia_jin@merck.com
Chen
I-W
IW
Chiba
M
M
Lin
J H
JH
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D019540:Area Under Curve; D001572:Benzofurans / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D004285:Dogs; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019469:Indinavir / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D007275:Injections, Intravenous; D008253:Macaca mulatta; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013056:Spectrophotometry, Ultraviolet
D019138:Antibodies, Blocking; D001572:Benzofurans; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D017320:HIV Protease Inhibitors; C481503:N-tertiary-butyl-4-(benzofuran-2-ylmethyl)-1-(2(S)-hydroxy-4)(R)-(2(R)-hydroxy-indan-1 (S)-ylcarbomoyl)-5-phenyhl-pentyl-piperazine-2-(S)-crboxamide; D010879:Piperazines; C400322:cytochrome P-450 CYP2C subfamily; D019469:Indinavir; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A