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, it is important to understand any potential drug-drug interactions. Artemether is rapidly converted to active metabolite dihydroartemisinin (DHA) by CYP3A4 isoenzymes, of which it is also an inducer, and it undergoes significant first-pass hepatic metabolism. DHA is further metabolised by UGT isoenzymes. Nevirapine (NVP) is an inducer whereas ritonavir is a potent inhibitor of CYP3A4, which can lead to potential drug-drug interactions. The aim of the present analysis was to explore the impact of nevirapine- and lopinavir/ritonavir (LPV/r) -based antiretroviral therapy (ART) on artemether and DHA exposure with a semi- mechanistic parent to metabolite population pharmacokinetic model.
Methods: Malaria-negative but HIV positive adults were recruited in three different arms; (a) Artemether-Lumefantrine (AL) alone, (b) AL+ NVP-based ART and (3) AL + LPV/r-based ART. All patients received the standard recommended dose of the fixed AL combination, i.e. 80 mg artemether plus 480 mg lumefantrine twice daily for three days. Intensive sampling after the first and the last dose was performed for the drug concentration measurements. The pharmacokinetic data was analysed using NONMEM 7.4 with FOCE-I. The parent drug and the metabolite were initially analysed separately and then a semi-mechanistic parent-to-metabolite model was developed aiming to quantify drug-drug interactions.
Results: : Data were available from a total of 55 patients with 1217 concentration observations for both artemether and DHA. The median weight and age overall were 59 kg (45.5-88) and 32.3 years (19.6-60.9) respectively. A semi-mechanistic model was developed accounting for artemether conversion to DHA both in the GI tract and the liver. A transit compartment absorption model characterised the delayed appearance of the artemether into the GI tract compartment, where a (logit transformed) GI-extraction parameter was applied to capture the metabolism of artemether into DHA. Both artemether and DHA are then absorbed into the bloodstream, but first undergo hepatic-first pass, which was described with a well-stirred model as explained in Gordi et al. The effect of concomitant ART was tested on the pre-hepatic bioavailability and hepatic drug clearance parameters. The pre-hepatic bioavailability of artemether was estimated to be 6.41% for the first dose in the control arm but was reduced to 1.39% for the consecutive doses due to auto-induction of CYP3A4. The estimates for this pre-hepatic bioavailability were lowered to 0.79% and 0.47% with respect to the first dose and the consecutive doses in the NVP-based ART arm compared to the first dose in the control arm and this was due to the induction effect of NVP on CYP3A4 for the first dose and additional auto-induction effect for the consecutive doses. There was no significant influence of LPV/r-based ART on artemether exposure except for the similar decrease as in the control arm from the second dose which corresponds to the auto-induction effect. LPV/r-based ART was found to increase DHA exposure, which was instead not affected by NVP-based ART.
Conclusions: Our model reveals that, after oral administration, a significant proportion of CYP3A4-mediated metabolism of artemether into DHA happens pre-hepatically, at the GI tract level. The exposure of artemether was reduced significantly after the first dose due to the auto-induction on CYP3A4 isoenzymes. NVP-based ART reduced the systemic exposure of artemether significantly but had no influence on DHA exposure. The concomitant administration of LPV/r-based ART increased the systemic exposure of DHA. This could be due to ritonavir’s inhibitory effect on UGT isoenzymes, or because of the inhibition of an alternative metabolic pathway clearing artemether without the formation of DHA. An individual patient data meta-analysis on these drug-drug interactions and subsequent dose modifications is recommended to inform better treatment of malaria-HIV co-infected 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] Gordi T, Xie R, Huong NV, Huong DX, Karlsson MO, Ashton M. A semi-physiological pharmacokinetic model for artemisinin in healthy subjects incorporating autoinduction of metabolism and saturable first-pass hepatic extraction. Br J Clin Pharmacol. 2005;59:189-98.
Reference: PAGE 28 (2019) Abstr 9051 [www.page-meeting.org/?abstract=9051]
Poster: Drug/Disease Modelling - Infection