The pharmacokinetics of artemether and lumefantrine in pregnant women with uncomplicated falciparum malaria

  • Rose McGready
  • Kasia Stepniewska
  • Niklas Lindegardh
  • Elizabeth A. Ashley
  • Yar La
  • Pratap Singhasivanon
  • Nicholas J. White
  • François NostenEmail author
Pharmacokinetics and Disposition



To determine the pharmacokinetic properties of artemether and lumefantrine (AL) in pregnant women with recrudescent uncomplicated multi-drug resistant falciparum malaria.


Pregnant women who had recurrence of parasitaemia following 7 days supervised quinine treatment were treated with AL. Serial blood samples were taken over a 7-day period, and pharmacokinetic parameters were estimated. For lumefantrine, these data were compared in a population pharmacokinetic model with data from non-pregnant, mainly male adults with acute malaria.


The pregnant women (five in the second trimester and eight in the third trimester) had lower concentrations of artemether, dihydroartemisinin and lumefantrine, and the elimination of lumefantrine in pregnant women was more rapid than reported previously in non-pregnant adults.


Pregnancy is associated with reduced plasma concentrations of both artemether and lumefantrine. This is likely to be of therapeutic significance as plasma concentrations of lumefantrine, after elimination of artemether, are an important determinant of cure. Further studies are needed to determine the optimum dose regimen of artemether-lumefantrine in pregnancy.


Artemether Lumefantrine Pregnancy Falciparum malaria 



We sincerely thank the pregnant women for their cooperation in completing this study. We thank also the diligent staff from SMRU. The Shoklo Malaria Research Unit is part of the Faculty of Tropical Medicine in Bangkok. This investigation was part of the Wellcome-Trust Mahidol University Oxford Tropical Medicine Research Programme, supported by the Wellcome-Trust of Great Britain. The study was supported by UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR).


  1. 1.
    McGready R, Stepniewska K, Edstein MD, Cho T, Gilveray G, Looareesuwan S, White NJ, Nosten F (2003a) The pharmacokinetics of atovaquone and proguanil in pregnant women with acute falciparum malaria. Eur J Clin Pharmacol 59: 545CrossRefPubMedGoogle Scholar
  2. 2.
    McGready R, Stepniewska K, Seaton E, Cho T, Cho D, Ginsberg A, Edstein MD, Ashley E, Looareesuwan S, White NJ, Nosten F (2003b) Pregnancy and use of oral contraceptives reduces the biotransformation of proguanil to cycloguanil. Eur J Clin Pharmacol 59:553CrossRefPubMedGoogle Scholar
  3. 3.
    McGready R, Stepniewska K, Ward SA, Cho T, Gilvary G, Looareesuwan S, White NJ, Nosten F (2006) Pharmacokinetics of dihydroartemisinin following oral artesunate treatment of pregnant women with acute uncomplicated falciparum malaria. Eur J Clin Pharmacol 62:367–371Google Scholar
  4. 4.
    Nosten F, van Vugt M, Price R, Luxemburger C, Thway KL, Brockman A, McGready R, ter Kuile F, Looareesuwan S, White NJ (2000) Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: a prospective study. Lancet 356:297CrossRefPubMedGoogle Scholar
  5. 5.
    Nosten F, Vincenti M, Simpson J, Yei P, Thwai KL, de Vries A, Chongsuphajaisiddhi T, White NJ (1999) The effects of mefloquine treatment in pregnancy. Clin Infect Dis 28:808CrossRefPubMedGoogle Scholar
  6. 6.
    McGready R, Cho T, Samuel, Villegas L, Brockman A, van Vugt M, Looareesuwan S, White NJ, Nosten F (2001) Randomized comparison of quinine-clindamycin versus artesunate in the treatment of falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg 95:651CrossRefPubMedGoogle Scholar
  7. 7.
    WHO (2003) Assessment of the safety of artemisinin compounds in pregnancy. World Health Organization, GenevaGoogle Scholar
  8. 8.
    McGready R, Cho T, Keo NK, Thwai KL, Villegas L, Looareesuwan S, White NJ, Nosten F (2001) Artemisinin antimalarials in pregnancy: a prospective treatment study of 539 episodes of multidrug-resistant Plasmodium falciparum. Clin Infect Dis 33:2009CrossRefPubMedGoogle Scholar
  9. 9.
    Vugt M van, Looareesuwan S, Wilairatana P, McGready R, Villegas L, Gathmann I, Mull R, Brockman A, White NJ, Nosten F (2000) Artemether-lumefantrine for the treatment of multidrug-resistant falciparum malaria. Trans R Soc Trop Med Hyg 94:545CrossRefPubMedGoogle Scholar
  10. 10.
    Longo M, Zanoncelli S, Manera D, Brughera M, Colombo P, Lansen J, Mazue G, Gomes M, Taylor WR, Olliaro P (2006) Effects of the antimalarial drug dihydroartemisinin (DHA) on rat embryos in vitro. Reprod Toxicol 21:83CrossRefPubMedGoogle Scholar
  11. 11.
    Wang TY (1989) Follow-up observation on the therapeutic effects and remote reactions of artemisinin (Qinghaosu) and artemether in treating malaria in pregnant woman. J Tradit Chin Med 9:28PubMedGoogle Scholar
  12. 12.
    Adam I, Elwasila E, Mohammed Ali DA, Elansari E, Elbashir MI (2004) Artemether in the treatment of falciparum malaria during pregnancy in eastern Sudan. Trans R Soc Trop Med Hyg 98:509CrossRefPubMedGoogle Scholar
  13. 13.
    Sowunmi A, Oduola AMJ, Ogundahunsi O, Fehintola FA, Ilesanmi OA, Akinyinka OO, Arowojolu AO (1998) Randomised trial of artemether versus artemether and mefloquine for the treatment of chloroquine/sufadoxine-pyrimethamine-resistant falciparum malaria during pregnancy. J Obstet Gynaecol 18: 322CrossRefPubMedGoogle Scholar
  14. 14.
    White NJ, van Vugt M, Ezzet F (1999) Clinical pharmacokinetics and pharmacodynamics and pharmacodynamics of artemether-lumefantrine. Clin Pharmacokinet 37:105CrossRefPubMedGoogle Scholar
  15. 15.
    Dubowitz LM, Dubowitz V, Goldberg C (1970) Clinical assessment of gestational age in the newborn infant. J Pediatr 77:1CrossRefPubMedGoogle Scholar
  16. 16.
    McGready R, Simpson J, Panyavudhikrai S, Loo S, Mercuri E, Haataja L, Kolatat T, Nosten F, Dubowitz L (2000) Neonatal neurological testing in resource-poor settings. Ann Trop Paediatr 20:323PubMedGoogle Scholar
  17. 17.
    Haataja L, McGready R, Arunjerdja R, Simpson JA, Mercuri E, Nosten F, Dubowitz L (2002) A new approach for neurological evaluation of infants in resource-poor settings. Ann Trop Paediatr 22:355CrossRefPubMedGoogle Scholar
  18. 18.
    Brockman A, Paul RE, Anderson TJ, Hackford I, Phaiphun L, Looareesuwan S, Nosten F, Day KP (1999) Application of genetic markers to the identification of recrudescent Plasmodium falciparum infections on the northwestern border of Thailand. Am J Trop Med Hyg 60:14PubMedGoogle Scholar
  19. 19.
    Lindegardh N, Annerberg A, Blessborn D, Bergqvist Y, Day N, White NJ (2005) Development and validation of a bioanalytical method using automated solid-phase extraction and LC-UV for the simultaneous determination of lumefantrine and its desbutyl metabolite in plasma. J Pharm Biomed Anal 37:081CrossRefGoogle Scholar
  20. 20.
    Souppart C, Gauducheau N, Sandrenan N, Richard F (2002) Development and validation of a high-performance liquid chromatography-mass spectrometry assay for the determination of artemether and its metabolite dihydroartemisinin in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 774:195CrossRefPubMedGoogle Scholar
  21. 21.
    Ezzet F, van Vugt M, Nosten F, Looareesuwan S, White NJ (2000) Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria. Antimicrob Agents Chemother 44:697CrossRefPubMedGoogle Scholar
  22. 22.
    Ashley E, Stepniewska K, Lindergardh N, McGready R, Annerberg A, Hutagalung R, Singtoroj T, Hla G, Brockman A, Proux S, Wilahphaingern J, Singhasivanon P, White N, Nosten F (2006) A pharmacokinetic study of artemether-lumefantrine given once daily for the treatment of uncomplicated multidrug resistant falciparum malaria. Trop Med Int Health (in press)Google Scholar
  23. 23.
    Lefevre G, Looareesuwan S, Treeprasertsuk S, Krudsood S, Silachamroon U, Gathmann I, Mull R, Bakshi R (2001) A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg 64:247PubMedGoogle Scholar
  24. 24.
    Brockman A, Price RN, van Vugt M, Heppner DG, Walsh D, Sookto P, Wimonwattrawatee T, Looareesuwan S, White NJ, Nosten F (2000) Plasmodium falciparum antimalarial drug susceptibility on the north-western border of Thailand during five years of extensive use of artesunate-mefloquine. Trans R Soc Trop Med Hyg 94:537CrossRefPubMedGoogle Scholar
  25. 25.
    Teja-Isavadharm P, Nosten F, Kyle DE, Luxemburger C, ter Kuile F, Peggins JO, Brewer TG, White NJ (1996) Comparative bio-availability of oral, rectal and intramuscular artemether in healthy subjects-use of simultaneous measurement by high performance liquid chromatography with electro-chemical detection and bioassay. Brit J Clin Pharmacol 42:599–604Google Scholar
  26. 26.
    Teja-Isavadharm P, Peggins JO, Brewer TG, White NJ, Webster HK, Kyle DE (2004) Plasmodium falciparum-based bioassay for measurement of artemisinin derivatives in plasma or serum. Antimicrob Agents Chemother 48:954CrossRefPubMedGoogle Scholar
  27. 27.
    Ezzet F, Mull R, Karbwang J (1998) Population pharmacokinetics and therapeutic response of CGP 56697 (artemether + benflumetol) in malaria patients. Br J Clin Pharmacol 46:553CrossRefPubMedGoogle Scholar
  28. 28.
    Herrera E, Amusquivar E, Lopez-Soldado I, Ortega H (2006) Maternal lipid metabolism and placental lipid transfer. Horm Res 65:59CrossRefPubMedGoogle Scholar
  29. 29.
    Price R, Uhlemann AC, van Vugt M, Brockman A, Hutagalung R, Nair S, Nash D, Singhasivanon P, Anderson T, Krishna S, White NJ, Nosten F (2006) Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multi-drug resistant falciparum malaria. Clin Infect Dis 42:1570–1577Google Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Rose McGready
    • 1
    • 2
    • 3
  • Kasia Stepniewska
    • 2
    • 3
  • Niklas Lindegardh
    • 2
    • 3
  • Elizabeth A. Ashley
    • 1
    • 2
    • 3
  • Yar La
    • 1
  • Pratap Singhasivanon
    • 2
  • Nicholas J. White
    • 2
    • 3
  • François Nosten
    • 2
    • 3
    • 1
    Email author
  1. 1.Shoklo Malaria Research UnitTakThailand
  2. 2.Faculty of Tropical MedicineMahidol UniversityBangkokThailand
  3. 3.Centre for Vaccinology and Tropical MedicineChurchill HospitalOxfordUK

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