Effect of pharmacogenetics on plasma lumefantrine pharmacokinetics and malaria treatment outcome in pregnant women

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.

Pregnancy andCYP3A5Genotype Affect Day 7 Plasma Lumefantrine Concentrations

“…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. To date, there are limited studies investigating the effect of CYP3A and ABCB1 genotype on LF concentration and malaria treatment outcome 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). Therefore, the present study described the effect of pregnancy and CYP3A genotype on day 7 LF plasma concentration and malaria treatment outcome.…”

“…In the pharmacogenetics analysis, genomic DNA was isolated in whole-blood samples using QIAamp DNA Midi Kit (Qiagen GmbH, Hilden, Germany), according to the manufacturer's instructions. Genotyping for the common functional variant alleles for ABCB1 c.3435C.T and ABCB1 c.4036A.G (rs3842), CYP3A4*1B, CYP3A5*3, CYP3A5*6, and CYP3A5*7, which have been reported to be relevant for LF disposition (German and Aweeka, 2008;Djimdé and Lefèvre, 2009), was carried out at the Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Sweden, as previously described (Mutagonda et al, 2017). The Quant Studio 12 K Flex Real-Time PCR system (Life Technologies Holding, Singapore) was used for genotyping.…”

“…Dried blood spots on filter papers were punched, and three punched-out circles 3 mm in diameter were used for DNA extraction using QIAamp DNA blood micro kit (Qiagen GmbH) following the manufacturer's recommendations. Screening of Plasmodium parasites was performed using a species-specific PCR targeting the ssRNA gene, as previously described (Shokoples et al, 2009;Mutagonda et al, 2017). P. falciparum genotyping was performed by nested PCR using fluorescent primers in the nested allelic specific reaction, followed by capillary electrophoresis in a DNA sequencer for fragment sizing, as previously described (Liljander et al, 2009;Mutagonda et al, 2017).…”

“…Recently, few studies highlighted relevance of pharmacogenetics variations in determining patient variability in plasma LF exposure Mutagonda et al, 2017;Vos et al, 2017). In a small sample size study, it was reported that pregnant women who were carriers of functional CYP3A5 and CYP3A4*1B allele had lower day 7 LF concentrations and recrudescence, respectively, compared with the carriers of defective alleles (Mutagonda et al, 2017). However, a study in nonpregnant population did not yield significant associations between LF pharmacokinetic parameters with CYP3A and ABCB1 single-nucleotide polymorphisms (Staehli-Hodel et al, 2013).…”

Conference report: pharmacogenomics in special populations at WCP2018

“…Few recent studies have investigated the pharmacogenetics of antimalarial drugs and its relevance for antiretroviral and antimalarial drug interaction in HIV–malaria coinfected patients receiving dual therapy in Africa . Lumefantrine, a long‐acting antimalarial drug, is metabolized by CYP3A4, an enzyme inducible by efavirenz .…”