Pharmacogenetics of artemether‐lumefantrine influence on nevirapine disposition: clinically significant drug‐drug interaction?

Abstract

Aims

In this study the influence of first‐line antimalarial drug artemether‐lumefantrine on the pharmacokinetics of the antiretroviral drug nevirapine was investigated in the context of selected single nucleotide polymorphisms (SNPs) in a cohort of adult HIV‐infected Nigerian patients.

Methods

This was a two‐period, single sequence crossover study conducted in two stages. In stage 1, 150 HIV‐infected patients receiving nevirapine‐based antiretroviral regimens were enrolled and genotyped for 7 SNPs. Sparse pharmacokinetic sampling was conducted to identify SNPs independently associated with nevirapine plasma concentration. Patients were categorised as poor, intermediate and extensive metabolisers based on the numbers of alleles of significantly associated SNPs. Intensive sampling was conducted in selected patients from each group. In stage 2, patients received standard artemether‐lumefantrine treatment with nevirapine and intensive pharmacokinetic sampling was conducted on day 3.

Results

No clinically significant changes were observed in key nevirapine pharmacokinetic parameters, the 90% confidence interval for the measured changes falling completely within the 0.80‐1.25 no‐effect boundaries. However, the number of patients with trough plasma nevirapine concentration below the 3,400 ng ml^‐1 minimum effective concentration increased from 10% without artemether‐lumefantrine (all extensive metabolisers) to 21% with artemether‐lumefantrine (14% extensive, 4% intermediate, and 3% poor metabolisers).

Conclusions

This approach highlights additional increase in the already existing risk of suboptimal trough plasma concentration, especially in extensive metabolisers when nevirapine is co‐administered with artemether‐lumefantrine.

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