Indinavir-ritonavir combination: pharmacokinetics and tolerance in patients with HIV infection

OBJECTIVES: Ritonavir (RTV) is a powerful inhibitor of P450 3A4 cytochorme. When given in combination with indinavir (IDV) it increases the IDV trough concentrations (C-min) allowing a lower IDV dosage in a twice a day regime n, independently of meals. We report tolerance data and IDV C-min levels ob served in plasma and cerebrospinal fluid (CSF) in a cohort of HIV-infected patients treated with the IDV-RTV combination at different dosages of IDV a nd RTV. PATIENTS AND METHODS: IDV C-min was assayed 56 times in 40 patients (few pa tients had received different dosages of the IDV-RTV combination). Toleranc e was recorded. RESULTS: For patients given the IDV-RTV combination at the doses of 800/100 mg b.i.d., 800/200 mg b.i.d. or 400/400 mg b.i.d., the IDV C-min was 12 ti mes the median IDV IC95. If the C-min/IC95 ratio was greater than 10 with t he 800/100 mg b.i.d. regimen and virological success was achieved, the IDV dosage was reduced to 400 mg b.i.d. For these patients, the 400/ 100 mg b.i .d. IDV-RTV regimen always gave a Cmin above the IDV IC95 Median C-min for IDV in CSF was 146 ng/ml (range 71 - 881 ng/ml), above the IDV IC95,. It wa s possible to control most of the adverse effects by reducing dosage after obtaining the IDV pharmacological levels. Definitive interruption of treatm ent was required in only 2 cases at mean follow-up of 7.9 months. DISCUSSION: The IDV-RTV combination should be used to improve observance of antiretroviral treatments and reduce the risk of virological failure relat ed to low plasma levels. The IDV-RTV combination at 800/100 mg b.i.d. is a useful protocol when IDV efficacy alone is the goal. The 400/400 mg b.i.d. IDV-RTV regimen is an interesting alternative when efficacy of both inhibit ors is the goal. Drug assays should be systematic to adapt individual dosag es and limit the risk of adverse effects.