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Abstract Article References

HIV¹ protease is a constitutive enzyme of HIV that processes viral proteins essential for the maturation of infectious virions. HIV protease is necessary for the completion of the viral life cycle, and represents a key target for intervention in the development of novel therapeutic agents for treatment of HIV infection (1).

Ritonavir is a potent HIV protease inhibitor (K_i = 15 pM) that has been tested extensively for its ability to inhibit the HIV protease enzyme and HIV viral replication in cell culture (2). Ritonavir has a broad spectrum of activity against HIV types 1 and 2 (including zidovudine-resistant HIV) in a variety of transformed and primary human cell lines, yet seems to be selective with limited inhibition of other aspartic acid proteases (2). Administration of ritonavir is associated with exponential decreases in plasma viral RNA within a few days (3-5), and ritonavir was approved by the Food and Drug Administration for mono- and combination therapy for individuals with HIV infection.

Fluconazole is used to treat fungal infections that occur frequently in patients with AIDS, including cryptococcal meningitis and candidal infections (6). Therefore, it is likely that ritonavir and fluconazole may be administered concurrently. Fluconazole inhibits fungal CYP (7), but seems to have less of an effect on mammalian CYP metabolism, as indicated by the results of in vitro studies using human hepatocytes and the lack of effect on antipyrine pharmacokinetics in vivo (8, 9). Nonetheless, potentially clinically significant effects of fluconazole have been documented on the metabolism of cyclosporin A, tolbutamide, warfarin, phenytoin, and terfenadine (9-14). Fluconazole is a moderately potent inhibitor of CYP3A4 in vitro (K_i = 15-18 µM, ~5 µg/ml), and fluconazole plasma concentrations during steady-state dosing typically range from 15 to 60 µM (15).

Because ritonavir is metabolized principally by the CYP3A and, to a lesser extent, the CYP2D6 subfamilies (16), the possibility that fluconazole could affect the metabolism of ritonavir was investigated in this study. Moreover, because 80% of fluconazole is excreted unchanged in the urine (17), whereas ritonavir is excreted primarily via the hepatobiliary route (18), it is unlikely that ritonavir would have a significant effect on fluconazole pharmacokinetics. Therefore, the purpose of this study was to evaluate the effect of fluconazole on ritonavir pharmacokinetics.

Subjects and Methods. Healthy subjects of either gender between the ages of 18 and 45 years old and weighing within 10% of the ideal weight for the subject's height were eligible to participate in the study. Subjects were to have no recent history of drug or alcohol abuse, were not to be users of tobacco products, and were to be negative for the hepatitis B virus. Appropriate contraceptive measures were required for women. All subjects gave written, informed consent in compliance with the Food and Drug Administration's regulations, and Institutional Review Board approval was obtained. Subjects were excluded from study participation if they had received any investigational drug, terfenadine, astemizole, loratadine, erythromycin, or clarithromycin within 6 weeks before the initial study drug administration, or had used any other drug (with the exception of oral contraceptives), including over-the-counter medications within 2 weeks before the initial study dosing.

Study Design. This was a single-center, multiple-dose, open-label, two-period, randomized, crossover study with a 2-week washout interval between periods. Subjects received ritonavir (200 mg every 6 hr for 4 days) during regimen A and a combination of ritonavir at the same dosage plus fluconazole (400 mg every day on day 1 and 200 mg every day on days 2-5) during regimen B. All fluconazole doses were administered at the same time as the morning dose of ritonavir (~7:00 a.m.). Both drugs were administered orally: fluconazole as 200 mg tablets and ritonavir as a liquid (80 mg/ml) by oral syringe. All doses were administered with ~200 ml of water and within 10 min after a meal or a snack.

Statistical Analysis. An analysis of variance with effects for sequence, subjects nested within sequence, period, and regimen was performed on C_max, C_min, AUC_0-24, average t_max, and  for the 24-hr period and those parameters calculated for each of the 6-hr dose intervals of this 24 hr. For each of 24-hr C_min, C_max, and AUC_0-24, an exact 95% confidence interval for the ratio of the mean with concurrent fluconazole administration to the mean for ritonavir administered alone was calculated. Because 3 of 5 women finished the regimen of ritonavir administered alone, an analysis of covariance with effects for gender and weight was performed on the ritonavir 24-hr parameters for ritonavir administered alone, followed by an analysis with effects for gender only.

Results and Discussion. Thirteen subjects were enrolled (5 women, 8 men), and five of these subjects (4 women, 1 man) were unable to complete the study. The eight subjects who completed the study were (mean ± SD) 29.6 ± 9.7 years old (range: 19-43 years), weighed 81.9 ± 10.6 kg (70.3-100.7 kg), and were 179 ± 9.1 cm tall (161-189 cm). Of the subjects that did not complete the study, only one subject withdrew from the study during concurrent administration of ritonavir and fluconazole after completing the regimen of ritonavir alone, and that subject was experiencing adverse events similar to those during treatment with ritonavir alone (nausea and vomiting). Thus, compared with the subjects completing the study, there was no indication that the subjects who were unable to complete the study were more sensitive to an interaction between ritonavir and fluconazole.

View larger version (15K): [in this window] [in a new window]   Fig. 1.   Mean (N = 8) ritonavir plasma concentrations after administration of ritonavir concurrently with fluconazole () or alone ().