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The Pharmacokinetics of Nucleoside Reverse Transcriptase Inhibitors when Coadministered with the HIV Protease Inhibitor Tipranavir in HIV-1 Infected Patients L. PHILLIPS1, M. T. BORIN*2, N. K. HOPKINS2, C. L. DAENZER2, and Y. WANG2.
1Pharmaceutical Outcomes Res., Inc., Williamsville, NY and 2Pharmacia & Upjohn Co., Kalamazoo, MI Background: Tipranavir (TPV), a non-peptidic HIV protease inhibitor, demonstrates potent antiretroviral activity in vitro against HIV-1 laboratory strains and clinical isolates resistant to many antiretroviral agents. TPV is a substrate and inducer of cytochrome P450 3A (CYP3A) in animals and humans. In rats, glucuronidation of TPV is the major clearance mechanism, and there is evidence for induction of CYP3A and/or glucuronidation enzymes. The effect of TPV on the pharmacokinetics of nucleoside reverse transcriptase inhibitors (NRTIs) was investigated in a Phase I/II study in HIV-1 infected patients.
Methods: Patients on stable dual NRTIs for >2 months were randomized to one of 3 TPV dose groups: 900, 1200, or 1500 mg three times daily, administered as 150-mg hard-filled capsules. NRTI pharmacokinetic profiles were obtained on study day -1, prior to receiving TPV, and study day 10, after 10 days of coadministration with TPV. Plasma NRTI concentrations were quantified using a specific, validated LC-MS-MS method.
Results: For didanosine (ddI) 200mg BID (n=4), mean (SD) AUC0-12 was 1280 (1000) ng h/mL and 692 (321) ng h/mL, respectively, on study days -1 and 10 (p=.22). AUC0-12 for the 15 patients receiving stavudine (d4T) 40mg BID averaged 1230 (326) and 1050 (276) ng h/mL, respectively, on study days -1 and 10 (p<.02). In patients taking lamivudine (3TC) 150mg BID (n=30), mean (SD) AUC0-12 was 6090 (1590) and 4420 (1160) ng h/mL, respectively, on study days -1 and 10 (p<.01). AUC0-12 for patients on zidovudine (ZDV) 300mg BID (n=16) averaged 1990 (807) and 1070 (435) ng h/mL, respectively, on study days -1 and 10 (p<.01); the mean ratio of ZDV glucuronide to ZDV AUC increased from 4.7 to 9.7.
Conclusions: These findings show that TPV decreases the steady-state plasma concentrations of ddI, d4T, 3TC, and ZDV. The observed differences (15% to 46% decrease) in NRTI concentrations are not of clinical importance, and therefore, TPV can be combined with these agents.
Key Words: drug interaction, nucleoside RTI, tipranavir
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