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Unfavourable interaction of amprenavir and lopinavir in combination with ritonavir?

2002; Lippincott Williams & Wilkins; Volume: 16; Issue: 2 Linguagem: Inglês

10.1097/00002030-200201250-00023

1473-5571

Stefan Mauss, Guenther Schmutz, Dieter Kuschak,

Hepatitis C virus research

Ritonavir-boosted HIV protease inhibitor combinations are used to reduce pill burden and improve the pharmacokinetic profile of some of the HIV protease inhibitors. A suitable candidate for this strategy is amprenavir. Recent data [1,2] suggested that a combination of amprenavir 600 mg twice a day plus ritonavir 100 mg twice a day is appropriate, giving an approximately fivefold increase in amprenavir trough concentrations without an increase in its peak concentration compared with the standard amprenavir regimen (1200 mg twice a day). As part of a double HIV protease inhibitor strategy, particularly in heavily pretreated patients, the combined use of the fixed combination of lopinavir/ritonavir (kaletra) and amprenavir may be an option. However, pharmacokinetic data on this combination are not available from the manufacturers of these drugs. In this pilot study, we assessed the influence of lopinavir as part of a fixed combination with ritonavir on the plasma concentrations of amprenavir and vice versa. Plasma steady-state concentrations of amprenavir, lopinavir and ritonavir were assessed using high performance liquid chromatography over 8 h in 10 patients. The methods have been published elsewhere [3]. All patients were men who had been heavily pretreated (four or more nucleoside reverse transcriptase inhibitors, three or more protease inhibitors, and one or more non-nucleoside reverse transcriptase inhibitor), and antiretroviral therapy was chosen according to the results of the HIV genotype analysis. Initially, lopinavir/ritonavir (400 mg/100 mg twice a day) was available through the early access programme of the manufacturer. The patients took their medication according to their established routine. All patients were treated for at least 6 months with the current antiretroviral combination at the time of the pharmacokinetic analysis. No concomittant use of non-nucleoside reverse transcriptase inhibitors or any other drugs, except nucleoside reverse transcriptase inhibitors and low-dose cotrimoxazole for Pneumocystis carinii prophylaxis, was permitted to exclude confounding by additional drug–drug interactions. Amprenavir trough plasma concentrations showed a median of 625 ng/ml (131–2600 ng/ml). The median amprenavir peak plasma concentration was 2175 ng/ml (912–7100 ng/ml) (Fig. 1). Compared with historical data, amprenavir plasma trough concentrations were found to be substantially lower as reported by Lamotte and coworkers [1], with a median trough concentration of 1663 ng/ml (553–5356 ng/ml), or Wood and coworkers [2], with 1320 ng/ml (1000–1740 ng/ml), for a combination of amprenavir 600 mg twice a day plus ritonavir 100 mg twice a day. However, plasma trough concentrations generally remained higher than for amprenavir 1200 mg twice a day without ritonavir (260 ng/ml; 170–400 ng/ml) [2].Fig. 1.: Steady-state pharmacokinetic profile of amprenavir (600 mg twice a day) in combination with lopinavir/ritonavir (400 mg/100 mg twice a day). The solid line represents the median concentration. The two broken lines represent the median trough concentrations of amprenavir (600 mg twice a day) and ritonavir (100 mg twice a day) according to Lamotte et al. [1] (upper line), and Wood et al. [2] (lower line).Median lopinavir trough concentrations were 2190 ng/ml (983–7000 ng/ml) and median peak plasma concentrations reached 8335 ng/ml (2980–10 900 ng/ml). As a result, the observations made regarding amprenavir may also be true for lopinavir, in that the median trough concentrations without amprenavir reported by Lamotte et al. [1] were approximately twice as high (4800 ng/ml; 2100–6500 ng/ml). From these preliminary findings we concluded that amprenavir and lopinavir in combination may act to lower the concentrations of each. A possible explanation for this may be a synergistic inducing effect on the metabolism of ritonavir by amprenavir and lopinavir, which can be postulated from data recently presented by Poirier and coworkers [4], demonstrating a negative drug–drug interaction of lopinavir or amprenavir with ritonavir. In addition, a high inter-patient variability, particularly of the plasma trough concentrations of amprenavir and lopinavir, was observed. Therapeutic drug monitoring in patients on a combination of amprenavir and lopinavir/ritonavir would seem to be useful to prevent treatment failure as a result of low exposure. In addition, a controlled study to assess the pharmacokinetics and safety of the combination of lopinavir and amprenavir is needed to confirm these findings and to establish proper dosing recommendations. Stefan Maussa Guenther Schmutza Dieter Kuschakb