Influence of nevirapine and ritonavir/lopinavir based antiretroviral therapy on Lumefantrine exposure in HIV-1 infected patients.
Jose Francis (1), Tamara Kredo (1,2), Lesley Workman (1), Lubbe Wiesner (1), Karen I Barnes (1), Paolo Denti (1).
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. (2) Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa.
Objectives: Artemether-lumefantrine is the most widely recommended first-line treatment for uncomplicated falciparum malaria globally. Considering the substantial geographic overlap of HIV and malaria disease burdens, it is important to understand any potential drug interactions. Lumefantrine and many of the antiretroviral agents are metabolized by CYP3A4 isoenzyme. Nevirapine may be an inducer (and occasionally an inhibitor) whereas ritonavir is a potent inhibitor of CYP3A4, which can lead to potential drug interactions. The aim of the present study was to characterize the population pharmacokinetics of lumefantrine and to explore the impact of nevirapine- and lopinavir/ritonavir- based antiretroviral therapy (ART) on lumefantrine exposure.
Methods: The study was conducted in malaria negative but HIV positive adults in three different arms. The first arm consists of subjects on Artemether-Lumefantrine (AL) alone, the second arm consists of AL+ Nevirapine-based ART patients and the third arm comprises of patients on AL+lopinavir/ritonavir-based ART. A total of 55 patient’s data were available for analysis with 1908 lumefantrine concentration observations. The median weight and age in all arms was 59 kg and 32.3 years respectively. The pharmacokinetic data was analysed by NONMEM 7.3 with FOCE-I.
Results: A three compartment model with transit absorption described the data well. The final estimates for clearance and Vd were 11.4 l/hr and 169 litres respectively. The allometric scaling for body size was better described by fat free mass rather than total body weight. The clearance was 19.7% and 51.7% lower in patients treated with nevirapine-based ART (arm 2) and lopinavir/ritonavir-based ART (arm 3) compared to the ARV naïve group (arm 1). The bioavailability of lumefantrine was increased by 36% and 181% in Arm 2 & 3 respectively. Additionally, there was a significant difference in the bioavailability of lumefantrine with respect to morning and evening doses.
Conclusions: The concomitant administration of nevirapine and lopinavir/ritonavir based ARV’s increases lumefantrine exposure significantly. The drug interaction with lopinavir/ritonavir was as expected more pronounced than with nevirapine-based ART. Further consideration is required to understand the clinical consequences of this drug-drug interactions and subsequent dose modifications in malaria patients.
References:
[1] Kredo T, Mauff K, Workman L, Van der Walt JS, Wiesner L, Smith PJ, Maartens G, Cohen K, Barnes KI. The interaction between artemether-lumefantrine and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infected patients. BMC Infect Dis. 2016;27;16:30.
[2] Kredo T, Mauff K, Van der Walt JS, Wiesner L, Maartens G, Cohen K, Smith P, Barnes KI. Interaction between artemether-lumefantrine and nevirapine-based antiretroviral therapy in HIV-1-infected patients. Antimicrob Agents Chemother. 2011;55:5616-23.
[3] Savic RM, Jonker DM, Kerbusch T, Karlsson MO. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn. 2007;34:711-26.
