A pharmacokinetic study was performed in five patients treated with the combination of amprenavir, lopinavir and nevirapine. Although the concentrations of amprenavir were within the expected range, lopinavir concentrations varied widely and tended to be lower than predicted by the manufacturer. We concluded that therapeutic drug monitoring should be performed when this combination is applied. In patients failing multiple antiretroviral regimens few options are currently available. The recently licensed protease inhibitors amprenavir and lopinavir have shown substantial virological efficacy in those individuals. When amprenavir is combined with ritonavir 100 mg twice a day, the daily dose can be reduced from 1200 to 450–600 mg twice a day, resulting in sustained or even increased minimal plasma concentrations [1]. Lopinavir is already being co-formulated with ritonavir to achieve sufficient bioavailability. Therefore, the combination of both drugs may be an interesting option for a salvage regimen from both clinical and pharmacokinetics aspects. We studied five severely immunocompromised HIV-infected individuals with virological failure after several treatment regimens including all antiretroviral classes. All patients were treated with at least one nucleoside reverse transcriptase inhibitor (NRTI) and nevirapine (200 mg twice a day) in addition to lopinavir (400/100 mg twice a day) and amprenavir (600 mg twice a day). Baseline characteristics and NRTI as well as HIV-RNA levels and CD4 cell counts after 12 weeks are given in Table 1.Table 1: Baseline and week 12 data in five patients. After 12 weeks only one subject experienced a decline in the HIV-RNA level of more than 1 log10. However, three patients showed a substantial increase in CD4 cell counts. All patients had a complete pharmacokinetic evaluation 2–4 weeks after the start of the combination. Plasma samples were drawn at time points 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, and 10 h after dosing. They were stored at −80°C until shipping to the laboratory. A method of the simultaneous determination of protease inhibitors was applied, as described previously [2]. The results of the pharmacokinetics are given in Table 2.Table 2: Pharmacokinetic data in five patients. Whereas amprenavir concentrations were within the expected range [3], lopinavir concentrations were quite variable and 40–60% lower than has been reported by the manufacturer [4]. The reason for this effect is unclear from our data. Possible explanations include the co-medication of nevirapine, which may decrease lopinavir concentrations by induction of the cytochrome P450 system, and the interaction of amprenavir with lopinavir. Decreased plasma concentrations of lopinavir when combined with efavirenz have been described in the Abbott study M98-957 [5]. This effect has not been observed with nevirapine [4]. Recently, the combination of amprenavir and lopinavir has been studied by French investigators. In contrast to our data, they found reduced minimal concentrations of amprenavir in the presence of lopinavir. However, no pharmacokinetics were performed, and data were analysed retrospectively [6]. Therefore, confounding factors cannot be excluded in this study. We concluded that the combination of amprenavir, lopinavir and nevirapine may result in unpredictable plasma concentrations of lopinavir. As in the scenario of salvage therapy with multiple underlying resistance mutations, plasma concentrations of protease inhibitors should be as high as possible, and pharmacological monitoring is advisable in patients treated with such combinations. Gerd Fätkenheuera Katja Römera Robert Kampsa Bernd Salzbergera David Burgerb
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Mar 2, 2005
Eric Dailly + 3
Open Access
