European Journal of Clinical Pharmacology

, Volume 59, Issue 7, pp 545–552 | Cite as

The pharmacokinetics of atovaquone and proguanil in pregnant women with acute falciparum malaria

  • R. McGready
  • K. Stepniewska
  • M. D. Edstein
  • T. Cho
  • G. Gilveray
  • S. Looareesuwan
  • N. J. WhiteEmail author
  • F. Nosten
Pharmacokinetics and Disposition



To determine the pharmacokinetic properties of atovaquone, proguanil, and the triazine metabolite cycloguanil in women with recrudescent multi-drug resistant falciparum malaria during the second and third trimesters of pregnancy treated by artesunate-atovaquone-proguanil.


Serial plasma concentrations of atovaquone, proguanil and cycloguanil were measured in 24 women at baseline and after the final dose of the 3-day treatment with atovaquone (20 mg/kg/day) plus proguanil (8 mg/kg/day) plus artesunate (4 mg/kg/day) daily.


The triple combination was well tolerated and highly effective. The outcomes of pregnancy were all normal. Population mean (± SEM) oral clearance (Cl/F) estimates were 313±33 ml/h/kg and 1109±43 ml/h/kg, total apparent volume of distribution (Vd/F) 13.0±1.3 l/kg and 22.9±1.4 l/kg, and terminal elimination half-life; 29.1 h and 14.3 h, for atovaquone and proguanil, respectively. Using conventional and population pharmacokinetic analyses, Cl/F and Vd/F estimates for both drugs were approximately twice, and plasma concentrations less than half those reported previously in healthy subjects and patients with acute malaria.


Artesunate-atovaquone-proguanil is a promising treatment for multi-drug resistant falciparum malaria during pregnancy, but the dose of atovaquone-proguanil may need to be increased.


P. falciparum Pregnancy Malaria 



We thank the staff of the Shoklo Malaria Research Unit antenatal clinics for their help. This investigation was part of the Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme supported by the Wellcome Trust of Great Britain.


  1. 1.
    Brockman A, Price RN, van Vugt M, Heppner DG, Walsh DS, 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 artesunate-mefloquine use. Trans R Soc Trop Med Hyg 94:537–544PubMedGoogle Scholar
  2. 2.
    McGready R, Brockman A, Cho T, Cho D, van Vugt M, Luxemburger C, Chongsuphajaisiddhi T, White NJ, Nosten F (2000) Randomized comparison of mefloquine-artesunate combination versus quinine in treatment of multi-drug resistant falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg 94:689–693PubMedGoogle Scholar
  3. 3.
    McGready R, Cho T, Khan Keo N, Thwai KL, S L, White NJ, Nosten F (2001) Artemisinin antimalarials in pregnancy: a prospective treatment study of 539 episodes of multidrug-resistant P. falciparum. Clin Infec Dis 33:2009–2016Google Scholar
  4. 4.
    Looareesuwan S, Viravan C, Webster HK, Kyle DE, Hutchinson DB, Canfield CJ (1996) Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand. Am J Trop Med Hyg 54:62–66PubMedGoogle Scholar
  5. 5.
    Product information, Malarone (atovaquone and proguanil hydrochloride). Physician's Desk Reference 2001; Medical Economics Company, Inc. Montvale (NJ), USAGoogle Scholar
  6. 6.
    van Vugt M, Edstein MD, Proux S, Lay K, Ooh M, Loorareesuwan S, White NJ, Nosten F (1999) Absence of an interaction between artesunate and atovaquone–proguanil. Eur J Clin Pharmacol 55:469–474PubMedGoogle Scholar
  7. 7.
    van Vugt M, Leonardi E, Phaipun L, Slight T, Thway KL, McGready R, Brockman A, Villegas L, Looareesuwan S, White NJ, Nosten F (2002) Treatment of uncomplicated multidrug-resistant falciparum malaria with artesunate-atovaquone-proguanil. Clin Infect Dis 35:1498–1504PubMedGoogle Scholar
  8. 8.
    McGready R, Khan Keo N, Villegas L, White NJ, Looareesuwan S, Nosten F (2003) Artesunate–atovaquone–proguanil rescue treatment of multidrug resistant falciparum malaria in pregnancy: a preliminary report. Trans R Soc Trop Med Hyg (in press)Google Scholar
  9. 9.
    Nosten F, ter Kuile F, Maelankirri L, Decludt B, White NJ (1991) Malaria during pregnancy in an area of unstable endemicity. Trans R Soc Trop Med Hyg 85:424–429PubMedGoogle Scholar
  10. 10.
    Price RN, Nosten F, Luxemburger C, van Vugt M, Phaipun L, Chongsuphajaisiddhi T, White NJ (1997) Artesunate/mefloquine treatment of multi-drug resistant falciparum malaria. Trans R Soc Trop Med Hyg 91:574–577PubMedGoogle Scholar
  11. 11.
    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 60:14–21PubMedGoogle Scholar
  12. 12.
    Nosten F, McGready R, Simpson JA, Thwai KL, Balkan S, Cho T, Hkirijaroen L, Looareesuwan S, White NJ (1999) Effects of Plasmodium vivax malaria in pregnancy. Lancet 354:546–549PubMedGoogle Scholar
  13. 13.
    Rolan PE, Mercer AJ, Weatherley BC, Holdich T, Meire H, Peck RW, Ridout G, Posner J (1994) Examination of some factors responsible for a food-induced increase in absorption of atovaquone. Br J Clin Pharmacol 37:13–20PubMedGoogle Scholar
  14. 14.
    Shanks GD, Edstein MD, Chedester AL, Smith CD, Corcoran KD, Ngampochjana M, Hansukjariya P, Sattabongkot J, Webster HK (1994) Proguanil plus sulfamethoxazole is not causally prophylactic in the Macaca mulatta-Plasmodium cynomolgi model. Am J Trop Med Hyg 50:641–645PubMedGoogle Scholar
  15. 15.
    Taylor RB, Moody RR, Ochekpe NA (1987) Determination of proguanil and its metabolites cycloguanil and 4-chlorophenylbiguanide in plasma, whole blood and urine by HPLC. J Chromatogr 416:394–399Google Scholar
  16. 16.
    Lindstrom ML, Bates DM (1990) Nonlinear mixed effects models for repeated measures data. Biometrics 46:673–687PubMedGoogle Scholar
  17. 17.
    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 95:651–656PubMedGoogle Scholar
  18. 18.
    Hussein Z, Eaves J, Hutchinson D, Canfield C (1997) Population pharmacokinetics of atovaquone in patients with acute malaria caused by Plasmodium falciparum. Clin Pharm Therapeut 61:518–530Google Scholar
  19. 19.
    Hussein Z, Eaves CJ, Hutchinson DB, Canfield CJ (1996) Population pharmacokinetics of proguanil in patients with acute P. falciparum malaria after combined therapy with atovaquone. Br J Clin Pharmacol 42:589–597PubMedGoogle Scholar
  20. 20.
    Sabcharoen A, Attanath P, Phanuaksook P, Chanthavanich P, Poonpanich Y,Mookmanee D, Chongsuphajaisiddhi T, Sadler BM, Hussein Z, Canfield CJ, Hutchinson DB (1998) Efficacy and pharmacokinetics of atovaquone and proguanil in children with multidrug-resistant Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg 92:201–206PubMedGoogle Scholar
  21. 21.
    Ward SA, Helsby NA, Skjelbo E, Brosen K, Gram LF, Breckenridge AM (1991) The activation of the biguanide antimalarial proguanil co-segregates with the mephenytoin oxidation polymorphism—a panel study. Br J Clin Pharmacol 31:689–692PubMedGoogle Scholar
  22. 22.
    Edstein MD, Shanks GD, Teja-Isavadharm P, Rieckmann KH, Webster HK (1994) Oxidative activation of proguanil and dapsone acetylation in Thai soldiers. Br J Clin Pharmacol 37:67–70PubMedGoogle Scholar
  23. 23.
    Wangboonskul J, White NJ, Nosten F, ter Kuile F, Moody RR, Taylor RB (1993) Single dose pharmacokinetics of proguanil and its metabolites in pregnancy. Eur J Clin Pharmacol 44:247–251PubMedGoogle Scholar
  24. 24.
    Wattanagoon Y, Taylor RB, Moody RR, Ochekpe NA, Looareesuwan S, White NJ (1987) Single dose pharmacokinetics of proguanil and its metabolites in healthy subjects. Br J Clin Pharmacol 24:775–780PubMedGoogle Scholar
  25. 25.
    Karbwang J, White NJ (1990) Clinical pharmacokinetics of mefloquine. Clin Pharmacokinet 19:264–279PubMedGoogle Scholar
  26. 26.
    McGready R, Stepniewska K, Seaton E, Cho T, Cho D, Ginsburg A, Edstein MD, Ashley E, Looareesuwan S, White NJ, Nosten F. (2003) Pregnancy and use of oral contraceptives reduces the biotransformation of proguanil to cycloguanil. Eur J Clin Pharm (this issue)Google Scholar
  27. 27.
    Jones K, Ward SA (2002) Biguanide-atovaquone synergy against Plasmodium falciparum in vitro. Antimicrob Agents Chemother 46:2700–2703PubMedGoogle Scholar
  28. 28.
    White NJ, van Vugt M, Ezzet F (1999) Clinical pharmacokinetics and pharmacodynamics of artemether-lumefantrine. Clin Pharmacokinet 37:105–125PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • R. McGready
    • 1
    • 2
    • 3
  • K. Stepniewska
    • 2
    • 3
  • M. D. Edstein
    • 4
  • T. Cho
    • 1
  • G. Gilveray
    • 1
  • S. Looareesuwan
    • 2
  • N. J. White
    • 2
    • 3
    Email author
  • F. Nosten
    • 1
    • 2
    • 3
  1. 1.Shoklo Malaria Research UnitMae SotThailand
  2. 2.Faculty of Tropical MedicineMahidol UniversityBangkokThailand
  3. 3.Centre for Tropical Medicine, Nuffield Department of MedicineJohn Radcliffe HospitalOxford UK
  4. 4.Australian Army Malaria InstituteBrisbaneAustralia

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