Clinical Pharmacokinetics

, Volume 37, Issue 2, pp 105–125 | Cite as

Clinical Pharmacokinetics and Pharmacodynamics of Artemether-Lumefantrine

  • Nicholas J. White
  • Michele van Vugt
  • Farka D Ezzet
Review Articles Drug Disposition

Abstract

The combination of artemether and lumefantrine (benflumetol) is a new and very well tolerated oral antimalarial drug effective even against multidrug-resistant falciparum malaria. The artemether component is absorbed rapidly and biotransformed to dihydroartemisinin, and both are eliminated with terminal half-lives of around 1 hour. These are very active antimalarials which give a rapid reduction in parasite biomass and consequent rapid resolution of symptoms. The lumefantrine component is absorbed variably in malaria, and is eliminated more slowly (half-life of 3 to 6 days). Absorption is very dependent on coadministration with fat, and so improves markedly with recovery from malaria. Thus artemether clears most of the infection, and the lumefantrine concentrations that remain at the end of the 3- to 5-day treatment course are responsible for eliminating the residual 100 to 10 000 parasites. The area under the curve of plasma lumefantrine concentrations versus time, or its correlate the plasma concentration on day 7, has proved an important determinant of therapeutic response. Characterisation of these pharmacokinetic-pharmacodynamic relationships provided the basis for dosage optimisation, an approach that could be applied to other antimalarial drugs.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Jiao XQ, Liu GY, Shan CQ, et al. Phase II trial in China of a new and rapidly-acting and effective antimalarial CGP 56697, for the treatment of Plasmodium. falciparum malaria. Southeast Asian J Trop Med Public Health 1997; 28: 476–81.Google Scholar
  2. 2.
    von Seidlein L, Jaffar S, Pinder M, et al. Treatment of African children with uncomplicated falciparum malaria with a new antimalarial drug, CGP 56697. J Infect Dis 1997; 176: 1113–6.CrossRefGoogle Scholar
  3. 3.
    van Vugt M, Brockman A, Gemperli B, et al. Randomized comparison of artemether-benflumetol and artesunate-mefloquine in treatment of multidrug-resistant falciparum malaria. Antimicrob Agents Chemother 1998; 42: 135–9.PubMedGoogle Scholar
  4. 4.
    Hatz C, Abdulla S, Mull R, et al. Efficacy and safety of CGP 56697 (artemether and benflumetol) compared with chloroquine to treat acute falciparum malaria in Tanzanian children aged 1–5 years. Trop Med Int Health 1998; 3: 495–504.CrossRefGoogle Scholar
  5. 5.
    Hien TT, Day NPJ, Phu NH, et al. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med 1996; 335: 76–83.CrossRefGoogle Scholar
  6. 6.
    Hien TT, White NJ. Qinghaosu. Lancet 1993; 341: 603–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Price RN, Nosten F, Luxemburger C, et al. Artesunate versus artemether in combination with mefloquine for the treatment of multidrug-resistant falciparum malaria. Trans R Soc Trop Med Hyg 1995; 89: 523–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Wernsdorfer WH, Landgraf B, Kilimali VAEB, et al. Activity of benflumetol and its enantiomers in fresh isolates of Plasmodium falciparum from East Africa. Acta Tropica 1998; 70: 9–15.PubMedCrossRefGoogle Scholar
  9. 9.
    Watkins WM, Mosobo M. Treatment of Plasmodium falciparum malaria with pyrimethamine-sulfadoxine: selective pressure for resistance is a function of long elimination half-life. Trans R Soc Trop Med Hyg 1993; 87: 75–8.PubMedCrossRefGoogle Scholar
  10. 10.
    White NJ. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrob Agents Chemother 1997; 41: 1413–22.PubMedGoogle Scholar
  11. 11.
    White NJ. Preventing antimalarial drug resistance through combinations. Drug Resistance Updates 1998; 1: 3–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Atkinson JD, Ward SA. The use of independently acting drug combinations to reduce the rate of resistance acquisition in Plasmodium falciparum malaria: studies with lumefantrine, artemether, and co-artemether [abstract]. European Congress on Tropical Medicine; 1998 Sep 14–18; Liverpool.Google Scholar
  13. 13.
    Ezzet F, Mull R, Karbwang J. Population pharmacokinetics and therapeutic response of CGP 56697 (artemether + benflumetol) in malaria patients. Br J Clin Pharmacol 1998; 46: 553–62.PubMedCrossRefGoogle Scholar
  14. 14.
    Looareesuwan S, Wilairatana P, Chokejindachai W, et al. Arandomized, double-blind, comparative trial of a new oral combination of artemether and benflumetol (CGP 56697) with mefloquine in the treatment of acute Plasmodium. falciparum malaria in Thailand. Am J Trop Med Hyg 1999; 60: 238–43.Google Scholar
  15. 15.
    van Vugt M, Wilairatana P, Gemperli B, et al. Efficacy of six doses of artemether-lumefantrine in the treatment of multidrug resistant falciparum malaria. Am J Trop Med Hyg. In press.Google Scholar
  16. 16.
    Shmuklarsky MJ, Klayman DL, Milhous WK, et al. Comparison of beta-artemether and beta-arteether against malaria parasites in vitro and in vivo. Am J Trop Med Hyg 1993; 48: 377–84.PubMedGoogle Scholar
  17. 17.
    Basco LK, Le Bras J. In vitro activity of artemisinin derivatives against African isolates and clones of Plasmodium falciparum. Am Journal Trop Med Hyg 1993; 49: 301–7.Google Scholar
  18. 18.
    Teja-Isavadharm P, Nosten F, Kyle DE, et al. Comparative bio-availability of oral, rectal and intramuscular artemether in healthy subjects — use of simultaneous measurement by high performance liquid chromatography with electrochemical detection and bioassay. Br J Clin Pharmacol 1996; 42: 599–604.PubMedGoogle Scholar
  19. 19.
    ter Kuile F, White NJ, Holloway P, et al. Plasmodium falciparum: in-vitro studies of the pharmacodynamic properties of drugs used for the treatment of severe malaria. Exp Parasitol 1993; 76: 86–95.Google Scholar
  20. 20.
    Pradines B, Tall A, Fusai T, et al. In vitro activities of benflumetol against 158 Senegalese isolates of Plasmodium falciparum in comparison with those of standard antimalarial drugs. Antimicrob Agents Chemother 1999; 43: 418–20.PubMedGoogle Scholar
  21. 21.
    Basco LK, Bickii J, Ringwald P. In vitro activity of lumefantrine (benflumetol) against clinical isolates of Plasmodium falciparum in Yaounde, Cameroon. Antimicrob Agents Chemother 1998; 42: 2347–51.PubMedGoogle Scholar
  22. 22.
    Kamchonwongpaisan S, Meshnick SR. The mode of action of the antimalarial artemisinin and its derivatives. Gen Pharmacol 1996; 27: 587–92.PubMedCrossRefGoogle Scholar
  23. 23.
    White NJ. Clinical pharmacokinetics and pharmacodynamics of artemisinin and derivatives. Trans R Soc Trop Med Hyg 1994; 88 Suppl. 1: 41–3.CrossRefGoogle Scholar
  24. 24.
    Melendez V, Peggins JO, Brewer TG, et al. Determination of the antimalarial arteether and its dethylated metabolite dihydroartemisinin in plasma by high performance liquid chromatography with reductive electrochemical detection. J Pharm Sci 1991; 80: 132–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Navaratnam V, Mansor SM, Chin LK, et al. Determination of artemether and dihydroartemisinin in blood plasma by high-performance liquid chromatography for application in clinical pharmacological studies. J Chromatogr (B) Biomed Appl 1995; 669: 289–94.CrossRefGoogle Scholar
  26. 26.
    Edwards G. Measurement of artemisinin and its derivatives in biological fluids. Trans R Soc Trop Med Hyg 1994; 88 Suppl. 1: 37–9.CrossRefGoogle Scholar
  27. 27.
    Zeng MY, Lu ZL, Yang SC, et al. Determination of benflumetol in human plasma by reversed-phase high-performance liquid chromatography with ultraviolet detection. J Chromatogr B Biomed Appl 1996; 681: 299–306.PubMedCrossRefGoogle Scholar
  28. 28.
    Mansor SM, Navaratnam V, Yahaya N, et al. Determination of a new antimalarial drug, benflumetol, in blood plasma by high-performance liquid chromatography. J Chromatogr B Biomed Appl 1996; 682: 321–5.PubMedCrossRefGoogle Scholar
  29. 29.
    van Vugt M, Ezzet F, Phaipun L, et al. The relationship between capillary and venous concentrations of lumefantrine (benflumetol). Trans R Soc Trop Med Hyg 1998; 92: 564–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Grace JM, Aguilar AJ, Trotman KM, et al. Metabolism of β-arteether to dihydroqinghaosu by human liver microsomes and recombinant cytochrome P-450. Drug Metab Dispos 1998; 26: 313–17.PubMedGoogle Scholar
  31. 31.
    van Agtmael MA, Van Der Graaf CA, Dien TK, et al. The contribution of the enzymes CYP2D6 and CYP2C19 in the demethylation of artemether in healthy subjects. Br J Pharmacol 1998; 125: 159–67.CrossRefGoogle Scholar
  32. 32.
    Leo KU, Grace JM, Li Q, et al. Effects of Plasmodium berghei infection on arteether metabolism and disposition. Pharmacology 1997; 54: 276–84.PubMedCrossRefGoogle Scholar
  33. 33.
    Batty KT, Ilett KF, Edwards G, et al. Assessment of the effect of malaria infection on hepatic clearance of dihydroartemisinin using rat liver perfusions and microsomes. Br J Pharmacol 1998; 125: 159–67.PubMedCrossRefGoogle Scholar
  34. 34.
    Murdoch RT, Ghabrial H, Mihaly GW, et al. Malaria infection impairs glucuronidation and biliary excretion by the isolated perfused rat liver. Xenobiotica 1991; 15: 71–82.Google Scholar
  35. 35.
    van Agtmael MA, Gupta V, van Boxtel CJ. Aglass of grapefruit juice makes new malaria treatment more effective [abstract A-081]. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1998 Sep 24–27; San Diego (CA).Google Scholar
  36. 36.
    Li Q-G, Peggins JO, Fleckenstein L, et al. Binding characteristics of 14C-arteether, 14C-artemether, and 14C-dihydroartemisinin to plasma proteins and red blood cells of human and animal species in-vivo and in-vitro [abstract PpA 144]. 21st Annual Meeting Experimental Biology; 1998; San Francisco.Google Scholar
  37. 37.
    Lee IS, Hufford CD. Metabolism of antimalarial sesquiterpene lactones. Pharmacol Ther 1990; 48: 345–55.PubMedCrossRefGoogle Scholar
  38. 38.
    Chi HT, Ramu K, Baker JK, et al. Identification of the in-vivo metabolites of the antimalarial arteether by thermospray high performance liquid chromatography/mass spectrometry. Biol Mass Spectrom 1991; 20: 609–28.PubMedCrossRefGoogle Scholar
  39. 39.
    Novartis AG. Data on file.Google Scholar
  40. 40.
    Na Bangchang K, Karbwang J, Thomas CG, et al. Pharmacokinetics of artemether after oral administration to healthy Thai males and patients with acute, uncomplicated falciparum malaria. Br J Clin Pharmacol 1994; 37: 249–53.PubMedCrossRefGoogle Scholar
  41. 41.
    Mordi MN, Mansor SM, Navaratnam V, et al. Single dose pharmacokinetics of oral artemether in healthy Malaysian volunteers. Br J Clin Pharmacol 1998; 43: 363–5.CrossRefGoogle Scholar
  42. 42.
    Bindschedler M, Degen P, Lu ZL, et al. Comparative bioavailability of benflumetol after administration of single oral doses of co-artemether under fed and fasted conditions to healthy subjects [abstract]. XIVth International Congress for Tropical Medicine and Malaria; 1996 Nov 17–22; Nagasaki.Google Scholar
  43. 43.
    White NJ. Antimalarial pharmacokinetics. Br J Clin Pharmacol 1992; 34: 1–10.PubMedCrossRefGoogle Scholar
  44. 44.
    Lindstrom MJ, Bates DM. Nonlinear mixed effects models for repeated measures data. Biometrics 1990; 46: 673–87.PubMedCrossRefGoogle Scholar
  45. 45.
    Davidian M, Giltinan AR. Nonlinear models for repeated measurements data. London: Chapman and Hall, 1995.Google Scholar
  46. 46.
    Field JW. Blood examination and prognosis in acute falciparum malaria. Trans R Soc Trop Med Hyg 1949; 43: 33–48.PubMedCrossRefGoogle Scholar
  47. 47.
    Brewer TG, Peggins JO, Grate SJ, et al. Neurotoxicity in animals due to arteether and artemether. Trans R Soc Trop Med Hyg 1994; 88 Suppl. 1: 33–6.CrossRefGoogle Scholar
  48. 48.
    Brewer TG, Grate SJ, Peggins JO, et al. Fatal neurotoxicity of arteether and artemether. Am J Trop Med Hyg 1994; 51: 251–9.PubMedGoogle Scholar
  49. 49.
    Price RN, van Vugt M, Phaipun L, et al. Adverse effects in patients with acute uncomplicated falciparum malaria treated with artemisinin derivatives. Am J Trop Med Hyg 1999; 60: 547–55.PubMedGoogle Scholar
  50. 50.
    Nosten F, ter Kuile FO, Luxemburger C, et al. Cardiac effects of antimalarial treatment with halofantrine. Lancet 1993; 341: 1054–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Price R, Nosten F, White NJ. Prolongation of the QTc interval in African children treated for Falciparum malaria. Am J Trop Med Hyg 1998; 59: 503.PubMedGoogle Scholar
  52. 52.
    Wilkinson GR. Cytochrome P4503A (CYP3A) metabolism: prediction of in vivo activity in humans. J Pharmacokinet Biopharm 1996; 24: 474–90.Google Scholar
  53. 53.
    Molyneux ME, Looareesuwan S, Menzies IS, et al. Reduced hepatic blood flow and intestinal malabsorption in severe falciparum malaria. Am J Trop Med Hyg 1989; 40: 470–76.PubMedGoogle Scholar
  54. 54.
    White NJ, Nosten F, Looareesuwan S, et al. Averting a malaria disaster. Lancet 1999; 353: 1965–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Nosten F, Luxemburger C, ter Kuile FO, et al. Treatment of multi-drug resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combination. J Infect Dis 1994; 170: 971–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Milton KA, Edwards G, Ward SA, et al. Pharmacokinetics of halofantrine in man: effects of food and dose size. Br J Clin Pharmacol 1989; 28: 71–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Hussein Z, Eaves J, Hutchinson DB, et al. Population pharmacokinetics of atovaquone in patients with acute malaria caused by Plasmodium falciparum. Clin Pharmacol Ther 1997; 61: 518–30.PubMedCrossRefGoogle Scholar
  58. 58.
    Yorke W, Macfie JWS. Observations on malaria made during treatment of general paralysis. Trans R Soc Trop Med Hyg 1924; 18: 33.CrossRefGoogle Scholar

Copyright information

© Adis International Limited 1999

Authors and Affiliations

  • Nicholas J. White
    • 1
    • 2
    • 3
  • Michele van Vugt
    • 1
    • 2
    • 4
  • Farka D Ezzet
    • 5
  1. 1.Faculty of Tropical MedicineMahidol UniversityBangkokThailand
  2. 2.Department of Infectious DiseasesTropical Medicine and AIDS, Academic Medical CentreAmsterdamThe Netherlands
  3. 3.Centre for Tropical Medicine, Nuffield Department of MedicineUniversity of OxfordOxfordEngland
  4. 4.Shoklo Malaria Research UnitMae Sot, Tak ProvinceThailand
  5. 5.Novartis Pharma AGBaselSwitzerland

Personalised recommendations