A Phenotype–Genotype Approach to Predicting CYP450 and P-Glycoprotein Drug Interactions With the Mixed Inhibitor/Inducer Tipranavir/Ritonavir

Abstract

The effects of tipranavir/ritonavir (TPV/r) on hepatic and intestinal P-glycoprotein (P-gp) and cytochrome P450 (CYP) enzyme activity were evaluated in 23 volunteers. The subjects received oral (p.o.) caffeine, warfarin + vitamin K, omeprazole, dextromethorphan, and midazolam and digoxin (p.o. and intravenous (i.v.)) at baseline, during the first three doses of TPV/r (500 mg/200 mg b.i.d.), and at steady state. Plasma area under the curve (AUC) 0-∞ and urinary metabolite ratios were used for quantification of protein activities. A single dose of TPV/r had no effect on the activity of CYP1A2 and CYP2C9; it weakly inhibited CYP2C19 and P-gp; and it potently inhibited CYP2D6 and CYP3A. Multiple dosing produced weak induction of CYP1A2, moderate induction of CYP2C19, potent induction of intestinal P-gp, and potent inhibition of CYP2D6 and CYP3A, with no significant effects on CYP2C9 and hepatic P-gp. Several P450/transporter single-nucleotide polymorphisms correlated with the baseline phenotype but not with the extent of inhibition or induction. Although mixed induction and inhibition are present, this approach offers an understanding of drug interaction mechanisms and ultimately assists in optimizing the clinical use of TPV/r.Cocktail phenotyping involves simultaneous, single-dose administration of marketed drugs (also known as probes) to measure the activity (or phenotype) of multiple hepatic and intestinal drug-metabolizing enzymes and transporters for rapid and efficient assessment of the drug interaction potential of a new compound. [1][2][3][4][5] The "Cooperstown 5 + 1 cocktail" consists of caffeine, warfarin, omeprazole, dextromethorphan, intravenous (i.v.) midazolam, and vitamin K (to negate warfarin's anticoagulant effect). 6 We have modified this approach to elucidate the specific influences of drugs on hepatic and intestinal proteins by evaluating enzyme activity NIH Public Access Author ManuscriptClin Pharmacol Ther. Author manuscript; available in PMC 2011 June 1. Published in final edited form as:Clin Pharmacol Ther. 2010 June ; 87(6): 735-742. doi:10.1038/clpt.2009.253. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript under baseline conditions in addition to conditions of both acute and chronic drug exposure. Oral (p.o.) midazolam and i.v. and p.o. digoxin were also added as probe substrates in order to measure hepatic + intestinal CYP3A activity, hepatic P-glycoprotein (P-gp) activity, and hepatic + intestinal P-gp activity, respectively. 7,8 The genotyping of cytochrome P450 (CYP) genes corresponding to enzymes investigated with phenotype probes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5/7/43) and P-gp (ABCB1) also allows for investigating genotype-phenotype correlations and determining genetic influences on drug interactions.We used this modified cocktail approach to investigate the drug interaction potential of tipranavir (TPV) administered along with low-dose ritonavir (RTV). TPV is a nonpeptidic protease inhibitor (PI) with potent activity against HIV-1-res...

Tipranavir/Ritonavir Induction of Buprenorphine Glucuronide Metabolism in HIV-Negative Subjects Chronically Receiving Buprenorphine/Naloxone

“…Therefore, we cannot rule out the possibility that Pgp played some role in the effects seen. Dumond and colleagues, however, recently examined the effects of tipranvir boosted with RTV on hepatic and intestinal Pgp using digoxin as a probe for Pgp activity (34). Although TPV inhibited hepatic Pgp and induced intestinal Pgp, these effects were insufficient to statistically change digoxin levels from baseline.…”

Assessment of the Pharmacokinetic Interaction between Eltrombopag and Lopinavir-Ritonavir in Healthy Adult Subjects

“…Nelfinavir, fosamprenavir/RTV, and tipranavir/RTV are other HIV PIs that have demonstrated induction effects on CYP1A2 substrates, with potency that is relatively similar to that of RTV or LPV/RTV (5,10,18). Darunavir, saquinavir, and indinavir are not known inhibitors or inducers of CYP1A2.…”

Regulatory Considerations in Metabolism‐ and Transporter‐Based Drug Interactions

“…On the basis of these findings, the sponsor conducted a cocktail drug interaction study to evaluate tipranavir's inhibition or induction potential on cytochrome P450s and P-gp using various probe substrates for CYPs and digoxin (as a P-gp substrate) as a postmarketing commitment (APTIVUS (Tipranavir) Labeling, 2009a; Dumond et al, 2010).…”