Effect of pharmacogenetics on plasma lumefantrine pharmacokinetics and malaria treatment outcome in pregnant women
Abstract Background Pregnancy 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...
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| Format: | Article |
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BMC
2017-07-01
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| Series: | Malaria Journal |
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| Online Access: | http://link.springer.com/article/10.1186/s12936-017-1914-9 |
| _version_ | 1828518674473943040 |
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| author | Ritah F. Mutagonda Appolinary A. R. Kamuhabwa Omary M. S. Minzi Siriel N. Massawe Muhammad Asghar Manijeh V. Homann Anna Färnert Eleni Aklillu |
| author_facet | Ritah F. Mutagonda Appolinary A. R. Kamuhabwa Omary M. S. Minzi Siriel N. Massawe Muhammad Asghar Manijeh V. Homann Anna Färnert Eleni Aklillu |
| author_sort | Ritah F. Mutagonda |
| collection | DOAJ |
| description | Abstract Background Pregnancy 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. Methods Pregnant 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. Results In 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). Conclusions Genetic variations in CYP3A4 and CYP3A5may influence LF pharmacokinetics and treatment outcome in pregnant women. |
| first_indexed | 2024-12-11T18:58:38Z |
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| issn | 1475-2875 |
| language | English |
| last_indexed | 2024-12-11T18:58:38Z |
| publishDate | 2017-07-01 |
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| spelling | doaj.art-6d52330c190f4dc681bbef9713f527c32022-12-22T00:54:03ZengBMCMalaria Journal1475-28752017-07-0116111010.1186/s12936-017-1914-9Effect of pharmacogenetics on plasma lumefantrine pharmacokinetics and malaria treatment outcome in pregnant womenRitah F. Mutagonda0Appolinary A. R. Kamuhabwa1Omary M. S. Minzi2Siriel N. Massawe3Muhammad Asghar4Manijeh V. Homann5Anna Färnert6Eleni Aklillu7Department of Clinical Pharmacy and Pharmacology, School of Pharmacy, Muhimbili University of Health and Allied SciencesDepartment of Clinical Pharmacy and Pharmacology, School of Pharmacy, Muhimbili University of Health and Allied SciencesDepartment of Clinical Pharmacy and Pharmacology, School of Pharmacy, Muhimbili University of Health and Allied SciencesDepartment of Obstetrics and Gynaecology, School of Medicine, Muhimbili University of Allied SciencesUnit of Infectious Diseases, Department of Medicine, Karolinska InstitutetUnit of Infectious Diseases, Department of Medicine, Karolinska InstitutetUnit of Infectious Diseases, Department of Medicine, Karolinska InstitutetSection of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska InstitutetAbstract Background Pregnancy 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. Methods Pregnant 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. Results In 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). Conclusions Genetic variations in CYP3A4 and CYP3A5may influence LF pharmacokinetics and treatment outcome in pregnant women.http://link.springer.com/article/10.1186/s12936-017-1914-9Malaria in pregnancyDay 7 lumefantrine concentrationRecrudescencePharmacogenetics |
| spellingShingle | Ritah F. Mutagonda Appolinary A. R. Kamuhabwa Omary M. S. Minzi Siriel N. Massawe Muhammad Asghar Manijeh V. Homann Anna Färnert Eleni Aklillu Effect of pharmacogenetics on plasma lumefantrine pharmacokinetics and malaria treatment outcome in pregnant women Malaria Journal Malaria in pregnancy Day 7 lumefantrine concentration Recrudescence Pharmacogenetics |
| title | Effect of pharmacogenetics on plasma lumefantrine pharmacokinetics and malaria treatment outcome in pregnant women |
| title_full | Effect of pharmacogenetics on plasma lumefantrine pharmacokinetics and malaria treatment outcome in pregnant women |
| title_fullStr | Effect of pharmacogenetics on plasma lumefantrine pharmacokinetics and malaria treatment outcome in pregnant women |
| title_full_unstemmed | Effect of pharmacogenetics on plasma lumefantrine pharmacokinetics and malaria treatment outcome in pregnant women |
| title_short | Effect of pharmacogenetics on plasma lumefantrine pharmacokinetics and malaria treatment outcome in pregnant women |
| title_sort | effect of pharmacogenetics on plasma lumefantrine pharmacokinetics and malaria treatment outcome in pregnant women |
| topic | Malaria in pregnancy Day 7 lumefantrine concentration Recrudescence Pharmacogenetics |
| url | http://link.springer.com/article/10.1186/s12936-017-1914-9 |
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