Lopinavir/ritonavir significantly influences pharmacokinetic exposure of artemether/lumefantrine in HIV-infected Ugandan adults

Pauline Byakika-Kibwika, Mohammed Lamorde, Violet Okaba-Kayom, Harriet Mayanja-Kizza, Elly Katabira, Warunee Hanpithakpong, Nadine Pakker, Thomas P C Dorlo, Joel Tarning, Niklas Lindegardh, Peter J de Vries, David Back, Saye Khoo, Concepta Merry, Pauline Byakika-Kibwika, Mohammed Lamorde, Violet Okaba-Kayom, Harriet Mayanja-Kizza, Elly Katabira, Warunee Hanpithakpong, Nadine Pakker, Thomas P C Dorlo, Joel Tarning, Niklas Lindegardh, Peter J de Vries, David Back, Saye Khoo, Concepta Merry

Abstract

Background: Treatment of HIV/malaria-coinfected patients with antiretroviral therapy (ART) and artemisinin-based combination therapy has potential for drug interactions. We investigated the pharmacokinetics of artemether, dihydroartemisinin and lumefantrine after administration of a single dose of 80/480 mg of artemether/lumefantrine to HIV-infected adults, taken with and without lopinavir/ritonavir.

Methods: A two-arm parallel study of 13 HIV-infected ART-naive adults and 16 HIV-infected adults stable on 400/100 mg of lopinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors (ClinicalTrials.gov, NCT 00619944). Each participant received a single dose of 80/480 mg of artemether/lumefantrine under continuous cardiac function monitoring. Plasma concentrations of artemether, dihydroartemisinin and lumefantrine were measured.

Results: Co-administration of artemether/lumefantrine with lopinavir/ritonavir significantly reduced artemether maximum concentration (C(max)) and area under the concentration-time curve (AUC) [median (range): 112 (20-362) versus 56 (17-236) ng/mL, P = 0.03; and 264 (92-1129) versus 151 (38-606) ng · h/mL, P < 0.01]. Dihydroartemisinin C(max) and AUC were not affected [66 (10-111) versus 73 (31-224) ng/mL, P = 0.55; and 213 (68-343) versus 175 (118-262) ng · h/mL P = 0.27]. Lumefantrine C(max) and AUC increased during co-administration [2532 (1071-5957) versus 7097 (2396-9462) ng/mL, P < 0.01; and 41,119 (12,850-125,200) versus 199,678 (71,205-251,015) ng · h/mL, P < 0.01].

Conclusions: Co-administration of artemether/lumefantrine with lopinavir/ritonavir significantly increases lumefantrine exposure, but decreases artemether exposure. Population pharmacokinetic and pharmacodynamic trials will be highly valuable in evaluating the clinical significance of this interaction and determining whether dosage modifications are indicated.

Trial registration: ClinicalTrials.gov NCT00619944.

Figures

Figure 1.
Figure 1.
Mean (±SEM) plasma concentration versus time of (a) artemether, (b) dihydroartemisinin and (c) lumefantrine for participants taking artemether/lumefantrine alone (AL alone) and artemether/lumefantrine in combination with lopinavir/ritonavir (AL plus LPV/r).

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