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Antimicrobial Agents and Chemotherapy, September 2009, p. 3837-3846, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00195-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Population Pharmacokinetics of Lumefantrine in Pregnant Women Treated with Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria{triangledown}

Joel Tarning,1,2* Rose McGready,1,2,3 Niklas Lindegardh,1,2 Elizabeth A. Ashley,3 Mupawjay Pimanpanarak,3 Benjamas Kamanikom,1 Anna Annerberg,1 Nicholas P. J. Day,1,2 Kasia Stepniewska,1,2 Pratap Singhasivanon,4 Nicholas J. White,1,2 and François Nosten1,2,3

Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand,1 Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, United Kingdom,2 Shoklo Malaria Research Unit, Mae Sot, Thailand,3 Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand4

Received 12 February 2009/ Returned for modification 11 May 2009/ Accepted 20 June 2009

Artemether-lumefantrine has become one of the most widely used antimalarial drugs in the world. The objective of this study was to determine the population pharmacokinetic properties of lumefantrine in pregnant women with uncomplicated multidrug-resistant Plasmodium falciparum malaria on the northwestern border of Thailand. Burmese and Karen women (n = 103) with P. falciparum malaria and in the second and third trimesters of pregnancy were treated with artemether-lumefantrine (80/480 mg) twice daily for 3 days. All patients provided five capillary plasma samples for drug quantification, and the collection times were randomly distributed over 14 days. The concentration-time profiles of lumefantrine were assessed by nonlinear mixed-effects modeling. The treatment failure rate (PCR-confirmed recrudescent infections at delivery) was high; 16.5% (95% confidence interval, 9.9 to 25.1). The population pharmacokinetics of lumefantrine were described well by a two-compartment open model with first-order absorption and elimination. The final model included interindividual variability in all pharmacokinetic parameters and a linear covariate relationship between the estimated gestational age and the central volume of distribution. A high proportion of all women (40%, 41/103) had day 7 capillary plasma concentrations of <355 ng/ml (which corresponds to approximately <280 ng/ml in venous plasma), a threshold previously associated with an increased risk of therapeutic failure in nonpregnant patients in this area. Predictive modeling suggests that a twice-daily regimen given for 5 days would be preferable in later pregnancy. In conclusion, altered pharmacokinetic properties of lumefantrine contribute to the high rates of failure of artemether-lumefantrine treatment in later pregnancy. Dose optimization is urgently needed.

* Corresponding author. Mailing address: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Rd., Bangkok 10400, Thailand. Phone: 66 22 036 369. Fax: 66 2354 6018. E-mail: joel{at}tropmedres.ac

{triangledown} Published ahead of print on 29 June 2009.

Antimicrobial Agents and Chemotherapy, September 2009, p. 3837-3846, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00195-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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