Mechanisms of Pharmacokinetic Enhancement Between Ritonavir and Saquinavir; Micro/Small Dosing Tests Using Midazolam (CYP3A4), Fexofenadine (p-Glycoprotein), and Pravastatin (OATP1B1) as Probe Drugs

• Published in: Journal of clinical pharmacology Vol. 53; no. 6; pp. 654 - 661
• Main Authors: Ieiri, Ichiro, Tsunemitsu, Shyohei, Maeda, Kazuya, Ando, Yukie, Izumi, Noritomo, Kimura, Miyuki, Yamane, Naoe, Okuzono, Tsuyoshi, Morishita, Mariko, Kotani, Naoki, Kanda, Eri, Deguchi, Mariko, Matsuguma, Kyoko, Matsuki, Shunji, Hirota, Takeshi, Irie, Shin, Kusuhara, Hiroyuki, Sugiyama, Yuichi
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-06-2013; American College of Clinical Pharmacology; Wiley Subscription Services, Inc
• Subjects: Adult; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; boosting; Chromatography, Liquid; Cross-Over Studies; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 CYP3A Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; fexofenadine; HIV Protease Inhibitors - administration & dosage; HIV Protease Inhibitors - pharmacokinetics; HIV Protease Inhibitors - pharmacology; Humans; Intestines - drug effects; Intestines - enzymology; Liver - drug effects; Liver - enzymology; Liver-Specific Organic Anion Transporter 1; Male; midazolam; Midazolam - pharmacokinetics; Organic Anion Transporters - drug effects; Organic Anion Transporters - metabolism; Pravastatin - pharmacokinetics; ritonavir; Ritonavir - administration & dosage; Ritonavir - pharmacology; saquinavir; Saquinavir - pharmacokinetics; Tandem Mass Spectrometry; Terfenadine - analogs & derivatives; Terfenadine - pharmacokinetics; Young Adult
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1002/jcph.62

We investigated the mechanisms of ritonavir‐mediated enhancement effect on the pharmacokinetics of saquinavir using in vivo probes for CYP3A4 (midazolam), p‐glycoprotein (fexofenadine), and OATP1B1 (pravastatin) following oral micro/small dosing. A cocktail of the drugs (2 mg of saquinavir, 100 µg of each probe) was administered to eight healthy volunteers (phase 1), and then coadministered with 20 mg (phase 2) and 100 mg (phase 3) of ritonavir. Plasma concentrations of the drugs were measured by validated LC–MS/MS methods. The mean plasma AUC0–24 (pg hour/mL) of saquinavir at phases 1, 2, and 3 was 101, 2 540, and 23 900 (P < .01), respectively. The relative area under the plasma concentration‐time curve (AUC)0–24 ratios of midazolam and fexofenadine at phases 1, 2, and 3 were 1:5.9:14.7 (P < .01), and 1:1.4:2.2 (P < .01–.05), respectively. In contrast, there was no difference in the pharmacokinetics of pravastatin. Inhibition of intestinal and hepatic CYP3A‐mediated metabolism, and intestinal p‐glycoprotein‐mediated efflux of saquinavir, but not OATP1B1, is involved in the enhancement mechanism. Micro/small dosing is useful for examining the mechanism of drug interactions without safety concern.