Volume 90, Issue 6
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Artesunate (AS) in combination with sulfadoxine/pyrimethamine (SP) is the first-line therapy for management of uncomplicated malaria in Sudan. The objective of this study was to assess the potential impact of SP on the pharmacokinetics of AS and its active metabolite, dihydroartemisinin (DHA), in healthy adults. A single-dose, randomized, open-label, crossover study design with a washout period of three weeks was performed with 16 volunteers. After oral administration of AS alone or in combination with SP, T values of AS and DHA were significantly prolonged in the combination group ( < 0.05). However, there was no significant effect on the other pharmacokinetic parameters ( > 0.05). The t values of AS and DHA were significantly higher in females than in males ( < 0.05). The present findings suggest that co-administration of SP with AS has no clinically relevant impact on the pharmacokinetics of AS or DHA in healthy persons.


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  1. World Health Organization, 2011. Guidelines for the Treatment of Malaria, 2011. Available at: http://www.who.int/malaria/world_malaria_report_2011/WMR2011_noprofiles_lowres.pdf.
  2. Olliaro PL, Taylor WRJ, , 2003. Review article: antimalarial compound from bench to bedside. J Exp Biol 206: 3575335759.[Crossref]
  3. Malik EM, Khalfalla OM, , 2004. Malaria in Sudan: past, present and the future. Gezira J Health Sci 1 (Suppl): 4751.
  4. Salah MT, Mohammed MM, Himeidan YE, Malik EM, Elbashir MI, Adam I, , 2005. A randomized comparison of sulphadoxinepyrimethamine and combination of sulphadoxine pyrimethamine with chloroquine in the treatment of uncomplicated falciparum malaria in eastern Sudan. Saudi Med J 26: 147148.
  5. van den Broek IV, Gatkoi T, Lowoko B, Nzila A, Ochong E, Keus K, , 2003. Chloroquine, sulfadoxine-pyrimethamine and amodiaquine efficacy for the treatment of uncomplicated Plasmodium falciparum malaria in Upper Nile, south Sudan. Trans R Soc Trop Med Hyg 97: 229235.[Crossref]
  6. World Health Organization, 2006. Global Antimalarial Drug Policies database-AFRO: 2006. Antimalarial Treatment Policies for P. falciparum and P. vivax by country in WHO Africa Region. Available Via DIALOG. Available at: http://www.who.int/malaria/amdp/amdp_afro.htm.
  7. Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W, White N, , 2004. Artesunate combinations for treatment of malaria: meta-analysis. Lancet 363: 917.[Crossref]
  8. Elamin SB, Awad AI, Eltayeb IB, Elmardi KA, Al Hassan AH, Mohamed AO, Malik EM, Mohamad TA, , 2010. Descriptive study on the efficacy of artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Sudan. Eur J Clin Pharmacol 66: 231237.[Crossref]
  9. Haynes RK, Chan HW, Lung CM, Ng NC, Wong HN, Shek LY, Williams ID, Cartwright A, Gomes MF, , 2007. Artesunate and dihydroartemisinin (DHA): unusual decomposition products formed under mild conditions and comments on the fitness of DHA as an antimalarial drug. ChemMedChem 2: 14481463.[Crossref]
  10. Davis TM, Karunajeewa HA, Ilett KF, , 2005. Artemisinin-based combination therapies for uncomplicated malaria. Med J Aust 182: 181185.
  11. Nosten F, White NJ, , 2007. Artemisinin-based combination treatment of falciparum malaria. Am J Trop Med Hyg 77 (Suppl): 181192.
  12. Morris CA, Duparc S, Borghini-Fuhrer I, Jung D, Shin CS, Fleckenstein L, , 2011. Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration. Malar J 10: 263.[Crossref]
  13. Sabchareon A, Attanath P, Chanthavanich P, Phanuaksook P, Prarinyanupharb V, Poonpanich Y, Mookmanee D, Teja-Isavadharm P, Heppner DG, Brewer TG, Chongsuphajaisiddhi T, , 1998. Comparative clinical trial of artesunate in combination with mefloquine in the treatment of children with acute falciparum malaria. Am J Trop Med Hyg 58: 1116.
  14. Lai CS, Nair NK, Mansor SM, Olliaro PL, Navaratnam V, , 2007. An analytical method with a single extraction procedure and two separate high performance liquid chromatographic systems for the determination of artesunate, dihydroartemisinin and mefloquine in human plasma for application in clinical pharmacological studies of the drug combination. J Chromatogr B Analyt Technol Biomed Life Sci 857: 308314.[Crossref]
  15. Awad MI, Eltayeb IB, Baraka OZ, Behrens RH, Alkadru AM, , 2004. Pharmacokinetics of artesunate following oral and rectal administration in healthy Sudanese volunteers. Trop Doct 34: 132135.[Crossref]
  16. Gordi T, Nielsen E, Yu Z, Westerlund D, Ashton M, , 2000. Direct analysis of artemisinin in plasma and saliva using coupled-column high-performance liquid chromatography with a restricted-access material pre-column. J Chromatogr B Biomed Sci Appl 742: 155162.[Crossref]
  17. Na-Bangchang K, Congpuong K, Hung LN, Molunto P, Karbwang J, , 1998. Simple high-performance liquid chromatographic method with electrochemical detection for the simultaneous determination of artesunate and dihydroartemisinin in biological fluids. J Chromatogr B Biomed Sci Appl 708: 201207.[Crossref]
  18. Benakis A, Paris M, Loutan L, Plessas CT, Plessas ST, , 1997. Pharmacokinetics of artemisinin and artesunate after oral administration in healthy volunteers. Am J Trop Med Hyg 56: 1723.
  19. Navaratnam V, Mordi MN, Mansor SM, , 1997. Simultaneous determination of artesunic acid and dihydroartemisinin in blood plasma by high-performance liquid chromatography for application in clinical pharmacological studies. J Chromatogr B Biomed Sci Appl 692: 157162.[Crossref]
  20. Batty KT, Davis TM, Thu LT, Binh TQ, Anh TK, Ilett KF, , 1996. Selective high-performance liquid chromatographic determination of artesunate and alpha- and beta-dihydroartemisinin in patients with falciparum malaria. J Chromatogr B Biomed Appl 677: 345350.[Crossref]
  21. Hanpithakpong H, Kamanikom B, Singhasivanon P, White NJ, Day NPJ, Lindegardh N, , 2009. A liquid chromatographic–tandem mass spectrometric method for determination of artemether and its metabolite dihydroartemisinin in human plasma. Bioanalysis 1: 3746.[Crossref]
  22. Lindegardh N, Tarning J, Toi PV, Hien TT, Farrar J, Singhasivanon P, White NJ, Ashton M, Day NP, , 2009. Quantification of artemisinin in human plasma using liquid chromatography coupled to tandem mass spectrometry. J Pharm Biomed Anal 49: 768773.[Crossref]
  23. Hanpithakpong W, Kamanikom B, Dondorp AM, Singhasivanon P, White NJ, Day NP, Lindegardh N, , 2008. A liquid chromatographic–tandem mass spectrometric method for determination of artesunate and its metabolite dihydroartemisinin in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 876: 6168.[Crossref]
  24. Lindegardh N, Hanpithakpong W, Kamanikom B, Singhasivanon P, Socheat D, Yi P, Dondorp AM, McGready R, Nosten F, White NJ, Day NP, , 2008. Major pitfalls in the measurement of artemisinin derivatives in plasma in clinical studies. J Chromatogr B Analyt Technol Biomed Life Sci 876: 5460.[Crossref]
  25. Xing J, Yan H, Zhang S, Ren G, Gao Y, , 2006. A high-performance liquid chromatography/ tandem mass spectrometry method for the determination of artemisinin in rat plasma. Rapid Commun Mass Spectrom 20: 14631468.[Crossref]
  26. Tekete MM, Toure S, Fredericks A, Beavogui AH, Sangare CP, Evans A, Smith P, Maiga H, Traore ZI, Doumbo OK, Barnes KI, Djimde AA, , 2011. Effects of amodiaquine and artesunate on sulphadoxine-pyrimethamine pharmacokinetic parameters in children under five in Mali. Malar J 10: 275.[Crossref]
  27. Minzi OM, Gupta A, Haule AF, Kagashe GA, Massele AY, Gustafsson LL, , 2007. Lack of impact of artesunate on the disposition kinetics of sulfadoxine/pyrimethamine when the two drugs are concomitantly administered. Eur J Clin Pharmacol 63: 457462.[Crossref]
  28. Chow SC, Wang H, , 2001. On sample size calculation in bioequivalence trials. J Pharmacokinet Pharmacodyn 28: 155169.[Crossref]
  29. Peters F, Drummer O, Musshoff F, , 2007. Validation of new methods. Forensic Sci Int 165: 216224.[Crossref]
  30. Matuszewski B, Constanzer M, Chavez-Eng C, , 2003. Strategies for the assessment of matrix effect in quantitative bioanalytical methods based on HPLC-MS/MS. Anal Chem 75: 30193030.[Crossref]
  31. Lee IS, Hufford CD, , 1990. Metabolism of antimalarial sesquiterpene lactones. Pharmacol Ther 48: 345355.[Crossref]
  32. Simpson JA, Agbenyega T, Barnes KI, Di Perri G, Folb P, Gomes M, Krishna S, Krudsood S, Looareesuwan S, Mansor S, McIlleron H, Miller R, Molyneux M, Mwenechanya J, Navaratnam V, Nosten F, Olliaro P, Pang L, Ribeiro I, Tembo M, van Vugt M, Ward S, Weerasuriya K, Win K, White NJ, , 2006. Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients. PLoS Med 3: e444.[Crossref]
  33. Bethell DB, Teja-Isavadharm P, Cao XT, Pham TT, Ta TT, Tran TN, Nguyen TT, Pham TP, Kyle D, Day NP, White NJ, , 1997. Pharmacokinetics of oral artesunate in children with moderately severe Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg 91: 195198.[Crossref]
  34. Olliaro PL, Nair NK, Sathasivam K, Mansor SM, Navaratnam V, , 2001. Pharmacokinetics of artesunate after single oral administration to rats. BMC Pharmacol 1: 14.[Crossref]
  35. Teja-Isavadharm P, Watt G, Eamsila C, Jongsakul K, Li Q, Keeratithakul G, Sirisopana N, Luesutthiviboon L, Brewer TG, Kyle DE, , 2001. Comparative pharmacokinetics and effect kinetics of orally administered artesunate in healthy volunteers and patients with uncomplicated falciparum malaria. Am J Trop Med Hyg 65: 717721.
  36. Navaratnam V, Ramanathan S, Wahab MS, Siew Hua G, Mansor SM, Kiechel JR, Vaillant M, Taylor WR, Olliaro P, , 2009. Tolerability and pharmacokinetics of non-fixed and fixed combinations of artesunate and amodiaquine in Malaysian healthy normal volunteers. Eur J Clin Pharmacol 65: 809821.[Crossref]
  37. Zhang SQ, Hai TN, Ilett KF, Huong DX, Davis TM, Ashton M, , 2001. Multiple dose study of interactions between artesunate and artemisinin in healthy volunteers. Br J Clin Pharmacol 52: 377385.[Crossref]
  38. Gautam A, Ahmed T, Batra V, Paliwal J, , 2009. Pharmacokinetics and pharmacodynamics of endoperoxide antimalarials. Curr Drug Metab 10: 289306.[Crossref]
  39. Ilett KF, Ethell BT, Maggs JL, Davis TM, Batty KT, Burchell B, Binh TQ, Thu le TA, Hung NC, Pirmohamed M, Park BK, Edwards G, , 2002. Glucuronidation of dihydroartimisinin in vivo and by human liver microsomes and expressed UDP-glucuronidation-syltransferases. Drug Metab Dispos 30: 10051012.[Crossref]
  40. Li XQ, Björkman A, Andersson TB, Gustafsson LL, Masimirembwa CM, , 2003. Identification of human cytochrome P(450)s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data. Eur J Clin Pharmacol 59: 429442.[Crossref]
  41. Gutman J, Kachur S, Slutsker L, Nzila A, Mutabingwa T, , 2012. Combination of probenecid-sulphadoxine-pyrimethamine for intermittent preventive treatment in pregnancy. Malar J 11: 39.[Crossref]
  42. Li Q, Xie LH, Haeberle A, Zhang J, Weina P, , 2006. The evaluation of radiolabeled artesunate on tissue distribution in rats and protein binding in humans. Am J Trop Med Hyg 75: 817826.
  43. Batty KT, Iletr KE, Powell SM, Martin J, Davis TM, , 2002. Relative bioavailability of artesunate and dihydroartemisinin: investigations in the isolated perfused rat liver and in healthy Caucasian volunteers. Am J Trop Med Hyg 66: 130136.

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  • Received : 23 May 2013
  • Accepted : 06 Feb 2014

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