Effect of Oral Ketoconazole on Oral and Intravenous Pharmacokinetics of Simvastatin and Its Acid in Cynomolgus Monkeys

Abstract

ABSTRACT:Drugs with potential drug-drug interactions (DDIs) may have a limited scope of use and, at worst, may have to be withdrawn from the market. Therefore, during the drug discovery process it is important to select drug candidates with reduced potential for DDIs. In the present study, we evaluated the pharmacokinetics of simvastatin (SV), a typical substrate for cytochrome P450 (P450) 3A, and examined the DDI between SV and ketoconazole (KTZ), a P450 3A inhibitor, in monkeys. SV metabolism in monkey liver and intestinal microsomes was almost completely inhibited by addition of anti-P450 3A4 antiserum. A similar effect was seen in human microsomes, and the IC 50 values of KTZ for inhibition of SV metabolism were similar in monkey and human samples. In vivo, there were no significant differences in the pharmacokinetic parameters of SV and SVA after i.v. administration of SV in the presence of KTZ compared with those in controls, probably because of the limited systemic exposure to KTZ. In contrast, the pharmacokinetics of SV and SVA after p.o. administration of SV were significantly influenced by the presence of KTZ, and C max and area under the plasma concentration-time curve were approximately 5 to 10 times higher than those after p.o. dosing with SV alone. The increases in systemic SV exposure caused by a concomitant p.o. dose of KTZ in monkeys were similar to those observed in clinical studies, which suggests that monkeys might be a suitable animal model in which to predict DDIs involving P450 3A inhibition.

Pitavastatin as an In Vivo Probe for Studying Hepatic Organic Anion Transporting Polypeptide-Mediated Drug–Drug Interactions in Cynomolgus Monkeys

“…Hence, monkeys may be useful as a preclinical in vivo DDI model involving OATP inhibition. Previously, we reported that clinical DDIs related to P-glycoprotein (P-gp)-mediated transport and cytochrome P450 3A (CYP3A)-mediated metabolism were reproduced in cynomolgus monkeys (Ogasawara et al, 2007(Ogasawara et al, , 2009aOhtsuka et al, 2010). Tahara et al (2006) reported that monkeys (rather than rats) were useful for predicting the DDI risks involving renal tubular transport in humans.…”

Prediction of the Intestinal First-Pass Metabolism of CYP3A Substrates in Humans Using Cynomolgus Monkeys

“…Because the plasma protein binding ratio of ketoconazole is high (99%), it is an appropriate compound to selectively inhibit intestinal metabolism of CYP3A substrates before entering the blood flow (Heel et al, 1982). Ogasawara et al (2007Ogasawara et al ( , 2009) have already reported inhibitory effects on CYP3A in cynomolgus monkeys using midazolam and simvastatin, and ketoconazole interaction studies focusing only on intestinal metabolism may be a particularly useful tool for studies of CYP3A4 substrates.…”

Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys

“…However, the study failed to detect any increase in total clearance of MDZ after intravenous administration, because its hepatic clearance was close to the hepatic blood flow rate in monkeys. Monkeys also show poor oral bioavailability for other CYP3A substrates such as verapamil (ϳ1%), nifedipine (ϳ1%), methotrexate (8%), and simvastatin (0.8%), which are therefore not well suited for in vivo enzyme induction study (Ogasawara et al, 2009b;Takahashi et al, 2009). In addition, CYP3A is known to be induced in the small intestine as well as in the liver, and clinical studies have shown that repeated oral administration of representative CYP3A inducers, such as RIF and St. John's wort, resulted in the up-regulation of CYP3A expression in the small intestine (Tannergren et al, 2004;Glaeser et al, 2005) and increased intestinal first-pass metabolism of verapamil, another CYP3A substrate (Fromm et al, 1996).…”