Abstract
BackgroundPregnancy has considerable effects on the pharmacokinetic properties of drugs used to treat uncomplicated Plasmodium falciparum malaria. The role of pharmacogenetic variation on anti-malarial drug disposition and efficacy during pregnancy is not well investigated. The study aimed to examine the effect of pharmacogenetics on lumefantrine (LF) pharmacokinetics and treatment outcome in pregnant women.MethodsPregnant women with uncomplicated falciparum malaria were enrolled and treated with artemether-lumefantrine (ALu) at Mkuranga and Kisarawe district hospitals in Coast Region of Tanzania. Day-7 LF plasma concentration and genotyping forCYP2B6 (c.516G>T, c.983T>C), CYP3A4*1B, CYP3A5 (*3, *6, *7) and ABCB1 c.4036A4G were determined. Blood smear for parasite quantification by microscopy, and dried blood spot for parasite screening and genotyping using qPCR and nested PCR were collected at enrolment up to day 28 to differentiate between reinfection from recrudescence. Treatment response was recorded following the WHO protocol.ResultsIn total, 92 pregnant women in their second and third trimester were included in the study and 424 samples were screened for presence of P. falciparum. Parasites were detected during the follow up period in 11 (12%) women between day 7 and 28 after treatment and PCR genotyping confirmed recrudescent infection in 7 (63.3%) women. The remaining four (36.4%) pregnant women had reinfection: one on day 14 and three on day 28. The overall PCR-corrected treatment failure rate was 9.0% (95% CI 4.4–17.4). Day 7 LF concentration was not significantly influenced by CYP2B6, CYP3A4*1B and ABCB1 c.4036A>G genotypes. Significant associations between CYP3A5 genotype and day 7 plasma LF concentrations was found, being higher in carriers of CYP3A5 defective variant alleles than CYP3A5*1/*1 genotype. No significant influence of CYP2B6, CYP3A5 and ABCB1 c.4036A>Genotypes on malaria treatment outcome were observed. However, CYP3A4*1B did affect malaria treatment outcome in pregnant women followed up for 28 days (P = 0.018).ConclusionsGenetic variations in CYP3A4 and CYP3A5may influence LF pharmacokinetics and treatment outcome in pregnant women.
Highlights
Pregnancy has considerable effects on the pharmacokinetic properties of drugs used to treat uncomplicated Plasmodium falciparum malaria
The aim of this study is to investigate the effects of pharmacogenetics on day 7 LF plasma concentrations and treatment outcome in pregnant patients treated with ALu in Tanzania
Day 28 malaria treatment outcome in pregnant women In total, 424 samples were screened for presence of parasites and P. falciparum was present in 11 (12%) patients during the follow up period
Summary
Pregnancy has considerable effects on the pharmacokinetic properties of drugs used to treat uncomplicated Plasmodium falciparum malaria. Catalytic activity of CYP3A4, CYP2C9 and CYP2A6 enzymes increases during pregnancy, while CYP2C19 and CYP1A2 enzyme activity decreases [6, 7] These enzymes are involved in metabolism of several anti-malarial drugs including LF and artemether [8,9,10], and are genetically polymorphic displaying wide interindividual variations in enzyme activity [11,12,13,14,15,16]. A higher treatment failure rate has been observed in pregnant women compared to non-pregnant ones living in the same area [1, 19, 20] In this case, treatment failure may not be caused by intrinsic parasite resistance but is instead the result of inadequate drug levels due to pregnancy, pharmacogenetic profile of the host or other nongenetic modifiers of the pharmacokinetic parameters
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