Population Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Malaria

Tarning, Joel; Rijken, Marcus J.; McGready, Rose; Phyo, Aung Pyae; Hanpithakpong, Warunee; Day, Nicholas P. J.; White, Nicholas J.; Nosten, François; Lindegardh, Niklas

doi:10.1128/aac.05756-11

Cited by 102Malaria Research and ControlPharmaceutical studies and practicesAntibiotics Pharmacokinetics and Efficacy

Population Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Malaria

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Tarning, Joel, Rijken, Marcus J., McGready, Rose, Phyo, Aung Pyae, Hanpithakpong, Warunee, Day, Nicholas P. J., White, Nicholas J., Nosten, François +1 more·2012·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.05756-11PMC PMC3318332

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Abstract

Pregnant women are particularly vulnerable to malaria. The pharmacokinetic properties of antimalarial drugs are often affected by pregnancy, resulting in lower drug concentrations and a consequently higher risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of piperaquine and dihydroartemisinin in pregnant and nonpregnant women with uncomplicated malaria. Twenty-four pregnant and 24 matched nonpregnant women on the Thai-Myanmar boarder were treated with a standard fixed oral 3-day treatment, and venous plasma concentrations of both drugs were measured frequently for pharmacokinetic evaluation. Population pharmacokinetics were evaluated with nonlinear mixed-effects modeling. The main pharmacokinetic finding was an unaltered total exposure to piperaquine but reduced exposure to dihydroartemisinin in pregnant compared to nonpregnant women with uncomplicated malaria. Piperaquine was best described by a three-compartment disposition model with a 45% higher elimination clearance and a 47% increase in relative bioavailability in pregnant women compared with nonpregnant women. The resulting net effect of pregnancy was an unaltered total exposure to piperaquine but a shorter terminal elimination half-life. Dihydroartemisinin was best described by a one-compartment disposition model with a 38% lower relative bioavailability in pregnant women than nonpregnant women. The resulting net effect of pregnancy was a decreased total exposure to dihydroartemisinin. The shorter terminal elimination half-life of piperaquine and lower exposure to dihydroartemisinin will shorten the posttreatment prophylactic effect and might affect cure rates. The clinical impact of these pharmacokinetic findings in pregnant women with uncomplicated malaria needs to be evaluated in larger series.

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Several studies have shown that the kinetics of artemisinins derivatives, most specifically of the active metabolite dihydroartemisinin, is modified during pregnancy.
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Population Pharmacokinetics of Lumefantrine in Pregnant and Nonpregnant Women With Uncomplicated Plasmodium falciparum Malaria in Uganda
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Population Pharmacokinetics of Intramuscular Artesunate in African Children With Severe Malaria: Implications for a Practical Dosing Regimen
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Antiretroviral Therapy With Efavirenz Accentuates Pregnancy‐Associated Reduction of Dihydroartemisinin‐Piperaquine Exposure During Malaria Chemoprevention
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Population Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis To Optimize Dosing
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Population pharmacokinetics of mefloquine, piperaquine and artemether-lumefantrine in Cambodian and Tanzanian malaria patients
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Optimal dosing of dihydroartemisinin-piperaquine for seasonal malaria chemoprevention in young children
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Treatment of Malaria in Pregnancy
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Randomised controlled trial of two sequential artemisinin-based combination therapy regimens to treat uncomplicated falciparum malaria in African children: a protocol to investigate safety, efficacy and adherence
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Population pharmacokinetics of quinine in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda
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Population Pharmacokinetics of Piperaquine in Young Ugandan Children Treated With Dihydroartemisinin‐Piperaquine for Uncomplicated Malaria
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Optimal designs for population pharmacokinetic studies of the partner drugs co-administered with artemisinin derivatives in patients with uncomplicated falciparum malaria
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State of Artemisinin and Partner Drug Susceptibility in Plasmodium falciparum Clinical Isolates from Colombia
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Piperaquine Exposure Is Altered by Pregnancy, HIV, and Nutritional Status in Ugandan Women
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Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Falciparum Malaria
Rijken, M. J., McGready, R., Phyo, A. P., Lindegardh, N., Tarning, J., Laochan, N., Than, H. H., Mu, O., Win, A. K., Singhasivanon, P., et al. (2011) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.05067-11 · Cited by 75 · see citing works
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Authors: Tarning, J., Rijken, M. J., McGready, R., Phyo, A. P., Hanpithakpong, W., Day, N. P. J., White, N. J., Nosten, F., & Lindegardh, N.
Affiliations: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
Shoklo Malaria Research Unit (TH)
Mahidol University (TH)
ORCID: Rijken, Marcus J.
McGready, Rose
Phyo, Aung Pyae
Hanpithakpong, Warunee
Day, Nicholas P. J.
White, Nicholas J.
Nosten, François
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2012-04
Volume: 56
Issue: 4
Pages: 1997-2007
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.05756-11
PMC: PMC3318332
OpenAlex: W2141478039
Cited by: 102
References: 63
Citations by year: 2026: 3 · 2025: 1 · 2024: 7 · 2023: 5 · 2021: 2 · 2020: 7 · 2019: 8 · 2018: 9 · 2017: 12 · 2016: 7 · 2015: 11 · 2014: 16 · 2013: 6 · 2012: 8
FWCI: 12.67
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Antimicrobial Agents and Chemotherapy (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Bill and Melinda Gates Foundation
Wellcome Trust (089275, 093956, 093956/Z/10/Z)
Topics: Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
Keywords: dihydroartemisinin, piperaquine, population pharmacokinetics, pregnancy, uncomplicated malaria, antimalarial drugs, relative bioavailability, elimination clearance, elimination half-life, one-compartment model, Thai-Myanmar border
MeSH terms: Adolescent, Adult, Antimalarials, Body Weight, Myanmar, Chromatography, High Pressure Liquid, Female, Half-Life, Humans, Malaria, Middle Aged, Piperazines, Population, Predictive Value of Tests, Pregnancy, Quinolines, Software, Thailand, Pregnancy Complications, Parasitic, Nonlinear Dynamics, Area Under Curve, Artemisinins, Tandem Mass Spectrometry, Young Adult

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Population Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Malaria

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