No drug–drug interaction between nelfinavir or indinavir and mefloquine in HIV-1-infected patients (2000)

Indinavir and nelfinavir are potent HIV protease inhibitors (PI). Both drugs are used in highly active antiretroviral combination therapy (HAART). Indinavir and nelfinavir are metabolized by the cytochrome P450 3A4 isoenzyme (CYP3A4). Furthermore, indinavir and nelfinavir inhibit CYP3A4. Mefloquine is a quinolinemethanol antimalarial drug used in chemoprophylaxis. Mefloquine has a long elimination half-life, approximately 3 weeks [1]. The major metabolite is carboxymefloquine. In-vitro data have shown that the formation of this metabolite can be inhibited by ketoconazol, a potent inhibitor of cytochrome P450 enzymes [2]. This finding suggests that cytochrome P450 plays an important role in mefloquine elimination. In theory, the concurrent use of mefloquine and PI might cause drug–drug interactions. In healthy volunteers, ritonavir, the most potent CYP3A4 inhibitor of all currently available PI, did not appear to inhibit mefloquine metabolism [3]. However, in HIV-1-infected patients data on this interaction are not available. To evaluate the effect of mefloquine on indinavir or nelfinavir or vice versa, we measured plasma concentrations of both drugs in HIV-1-infected patients who used the drugs concurrently. Two HIV-1-infected patients using HAART for at least 6 months, containing indinavir 800 mg three times a day (patient 1) or nelfinavir 1250 mg twice a day (patient 2), took mefloquine (250 mg a week) as malaria prophylaxis when travelling to Africa. We measured the indinavir and nelfinavir plasma concentrations shortly before and indinavir, nelfinavir and mefloquine plasma concentrations during and after the use of mefloquine. In patient 1, we obtained random indinavir and trough mefloquine plasma samples (Cmin), in patient 2 we obtained trough plasma samples (Cmin) of both drugs (see Fig. 1). All PI plasma concentrations were measured as previously described [4]. To be able to compare the randomly drawn indinavir plasma concentrations, we determined so-called concentration ratios by dividing the actual indinavir concentration measured by the mean concentration found in a reference population at the same time-point after drug ingestion. Although all nelfinavir samples were trough levels, we also determined concentration ratios for these samples, comparing the concentration with a morning trough population level of 2.6 mg/l. Mefloquine elimination half-life was determined from the decay of the concentration in the mefloquine washout phase. In both patients, we found therapeutic plasma concentrations of mefloquine (> 500 μg/l). Toxic accumulation of the drug did not occur. Mefloquine elimination half-lives were approximately 15 and 27 days in the indinavir and nelfinavir patients, respectively, similar to that found in healthy individuals [1]. No side-effects were reported. We did not find a consistent increase or decrease in indinavir and nelfinavir plasma concentrations.Fig. 1.: Pharmacokinetic profiles of the protease inhibitors and mefloquine in two patients treated with a combination of these drugs. (a) Patient 1, indinavir (&◆) 800 mg three times a day plus mefloquine (○) 250 mg once a week (weeks 1–16). (b) Patient 2, nelfinavir (&◆) 1250 mg twice a day plus mefloquine (○) 250 mg once a week (weeks 1–6).We concluded that the co-administration of mefloquine to HIV-1-infected patients on HAART, containing indinavir or nelfinavir, does not result in sub-therapeutic or toxic concentrations of the drugs. Emile F. Schippersa Patricia W. H. Hugenc Jan den Hartighb David M. Burgerc Richard M. W. Hoetelmansd Leo G. Vissera Frank P. Kroona