SAQUINAVIR PHARMACOKINETICS ALONE AND IN COMBINATION WITH RITONAVIR IN HIV-INFECTED PATIENTS

Objective: The most important hepatic enzyme involved in the metabolis m of protease inhibitors is cytochrome P450 3A4 (CYP3A4). Ritonavir (R IT) is a potent inhibitor of CYP3A4 and inhibits saquinavir (SQV) meta bolism in healthy volunteers. In this study we investigated the kineti cs of SQV when administered alone and in combination with RIT in HIV-i nfected patients. Design: SQV pharmacokinetics were determined in seve n patients who had advanced HIV disease. Steady-state SQV profiles wer e obtained on two occasions following treatment with SQV 600 mg three times daily alone and when administered with RIT 300 mg twice daily. M ethods: Blood samples were obtained al limes 0, 1, 2, 4, 6 and 8 h pos t-dosing. Following centrifugation, separated plasma was heated at 58 degrees C for at least 30 min to inactivate HIV and stored al -80 degr ees C until analysis using high performance liquid chromatography. Res ults: For patients treated with SQV alone there was a 12-fold variabil ity in the area under the SQV concentration-time curve (AUC(0.8h)) ran ging from 293 to 3446 ng . h/ml. When combined with RIT there was a ma rked increase in the maximum plasma concentration of SQV [median (rang e), 146 (57-702) versus 4795 (1420-15810) ng/ml; similar to 95% confid ence interval (CI), 2988-6819; P = 0.0006, Mann-Whitney U test]. The A UC(0.8h) for SQV was also significantly increased in the presence of R IT [median (range), 470 (293-3446) versus 27 458 (7357-108 001) ng . h /ml; similar to 95% CI, 16 628-35 111; P = 0.0006]. Conclusions: For s ome patients, administration of SQV 600 mg three times daily results i n very low SQV plasma levels and possibly little antiviral effect. Com bination of SQV with RIT results in a significant drug interaction med iated by enzyme inhibition which exposes patients to very high SQV con centrations and potential toxicity. If combination therapy with SQV pl us RIT is considered then the dose of SQV should be greatly reduced.