Abstract
Pregnancy and pharmacogenetics variation alter drug disposition and treatment outcome. The objective of this study was to investigate the effect of pregnancy and pharmacogenetics variation on day 7 lumefantrine (LF) plasma concentration and therapeutic responses in malaria-infected women treated with artemether-lumefantrine (ALu) in Tanzania. A total of 277 (205 pregnant and 72 nonpregnant) women with uncomplicated Plasmodium falciparum malaria were enrolled. Patients were treated with ALu and followed up for 28 days. CYP3A4, CYP3A5, and ABCB1 genotyping were done. Day 7 plasma LF concentration and the polymerase chain reaction (PCR) - corrected adequate clinical and parasitological response (ACPR) at day 28 were determined. The mean day 7 plasma LF concentrations were significantly lower in pregnant women than nonpregnant women [geometric mean ratio = 1.40; 95% confidence interval (CI) of geometric mean ratio (1.119-1.1745), P < 0.003]. Pregnancy, low body weight, and CYP3A5*1/*1 genotype were significantly associated with low day 7 LF plasma concentration (P < 0.01). PCR-corrected ACPR was 93% (95% CI = 89.4-96.6) in pregnant women and 95.7% (95% CI = 90.7-100) in nonpregnant women. Patients with lower day 7 LF concentration had a high risk of treatment failure (mean 652 vs. 232 ng/ml, P < 0.001). In conclusion, pregnancy, low body weight, and CYP3A5*1 allele are significant predictors of low day 7 LF plasma exposure. In turn, lower day 7 LF concentration is associated with a higher risk of recrudescence. SIGNIFICANCE STATEMENT: This study reports a number of factors contributing to the lower day 7 lumefantrine (LF) concentration in women, which includes pregnancy, body weight, and CYP3A5*1/*1 genotype. It also shows that day 7 LF concentration is a main predictor of malaria treatment. These findings highlight the need to look into artemether-LF dosage adjustment in pregnant women so as to be able to maintain adequate drug concentration, which is required to reduce treatment failure rates in pregnant women.
Highlights
Artemether-lumefantrine (ALu) has been the first-line drug for the treatment of uncomplicated malaria in Tanzania since the end of 2006
The main findings include the following: 1) significantly lower day 7 LF plasma concentration in pregnant compared with nonpregnant women, 2) significant association of CYP3A5*1/*1 genotype and low body weight with low day 7 LF plasma concentration, and 3) low day 7 LF plasma concentration as a significant predictor of treatment failure
There are limited studies investigating the effect of CYP3A and ABCB1 genotype on LF concentration and malaria treatment outcome (Maganda et al, 2016; Vos et al, 2017), and only one small sample size study reported effect of genotype on LF plasma concentration in pregnant women (Mutagonda et al, 2017)
Summary
Artemether-lumefantrine (ALu) has been the first-line drug for the treatment of uncomplicated malaria in Tanzania since the end of 2006. It is the antimalarial drug of choice for the treatment of uncomplicated malaria in pregnant women in the second and third trimesters (http://www.who.int/selection_medicines/country_lists/Tanzania_STG_ 052013.pdf). Achieve adequate clinical and parasitological response (ACPR) during the course of ALu treatment, adequate LF plasma concentration after complete elimination of artemether and dihyroartemisinin needs to be achieved and maintained long enough. Sufficient LF plasma concentration is essential for the drug to be able to clear all residual malaria parasites and reduce the risk of the treatment failure and drug resistance among patients
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