Population pharmacokinetics and clinical response for artemether-lumefantrine in pregnant and nonpregnant women with uncomplicated Plasmodium falciparum malaria in Tanzania.
- Mosha D Ifakara Health Institute, Rufiji Health Demographic Surveillance System (HDSS), Rufiji, Tanzania Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland dfmosha@hotmail.com.
- Guidi M School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Lausanne, Switzerland Division of Clinical Pharmacology and Toxicology, Department of Laboratories, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
- Mwingira F Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland.
- Abdulla S Ifakara Health Institute, Rufiji Health Demographic Surveillance System (HDSS), Rufiji, Tanzania.
- Mercier T Division of Clinical Pharmacology and Toxicology, Department of Laboratories, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
- Decosterd LA Division of Clinical Pharmacology and Toxicology, Department of Laboratories, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
- Csajka C School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Lausanne, Switzerland Division of Clinical Pharmacology and Toxicology, Department of Laboratories, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
- Genton B Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland Department of Ambulatory Care and Community Medicine and Division of Infectious Diseases, University Hospital, Lausanne, Switzerland.
- 2014-05-29
Published in:
- Antimicrobial agents and chemotherapy. - 2014
Adolescent
Adult
Antimalarials
Artemether, Lumefantrine Drug Combination
Artemisinins
Biological Availability
Biotransformation
Case-Control Studies
Drug Administration Schedule
Drug Combinations
Ethanolamines
Female
Fluorenes
Humans
Malaria, Falciparum
Models, Statistical
Plasmodium falciparum
Pregnancy
Pregnancy Trimester, Second
Pregnancy Trimester, Third
Severity of Illness Index
Treatment Failure
English
Artemether-lumefantrine (AL) is the first-line treatment for uncomplicated malaria in the second and third trimesters of pregnancy. Its efficacy during pregnancy has recently been challenged due to altered pharmacokinetic (PK) properties in this vulnerable group. The aim of this study was to determine the PK profile of AL in pregnant and nonpregnant women and assess their therapeutic outcome. Thirty-three pregnant women and 22 nonpregnant women with malaria were treated with AL (80/480 mg) twice daily for 3 days. All patients provided five venous plasma samples for drug quantification at random times over 7 days. Inter- and intraindividual variability was assessed, and the effects of covariates were quantified using a nonlinear mixed-effects modeling approach (NONMEM). A one-compartment model with first-order absorption and elimination with linear metabolism from drug to metabolite fitted the data best for both arthemether (AM) and lumefantrine (LF) and their metabolites. Pregnancy status and diarrhea showed a significant influence on LF PK. The relative bioavailability of lumefantrine and its metabolism rate into desmethyl-lumefantrine were, respectively, 34% lower and 78% higher in pregnant women than in nonpregnant patients. The overall PCR-uncorrected treatment failure rates were 18% in pregnant women and 5% in nonpregnant women (odds ratio [OR] = 4.04; P value of 0.22). A high median day 7 lumefantrine concentration was significantly associated with adequate clinical and parasitological response (P = 0.03). The observed reduction in the relative bioavailability of lumefantrine in pregnant women may explain the higher treatment failure in this group, mostly due to lower posttreatment prophylaxis. Hence, a modified treatment regimen of malaria in pregnancy should be considered.
- Language
-
- English
- Open access status
- bronze
- Identifiers
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- DOI 10.1128/AAC.02595-14
- PMID 24867986
- Persistent URL
- https://susi.usi.ch/global/documents/62345
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