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Clinical Pharmacokinetics

, Volume 19, Issue 4, pp 264–279 | Cite as

Clinical Pharmacokinetics of Mefloquine

  • Jantra Karbwang
  • Nicholas J. White
Drug Disposition

Summary

Mefloquine, a quinolinemethanol antimalarial, is effective single dose therapy for all species of malaria infecting humans, including multi-drug—resistant Plasmodium falciparum. It is used both in prophylaxis and treatment. Mefloquine is available either as the hydrochloride salt alone, or in a combined preparation with sulfadoxine and pyrimethamine. There is no parenteral formulation. Several assay methodologies have been developed, but high performance liquid chromatography has been the most used in recent pharmacokinetic studies. These have shown in healthy volunteers that mefloquine is absorbed with a half-life of 1 to 4 hours and a time to peak concentration of 7 to 24 hours (median 16.7 hours). Mean peak blood concentrations have ranged between 50 and 110 (median 83) ng/ml/mg/kg. Estimates of total apparent volume of distribution (Vd/f) have ranged from 13.3 to 40.9 (median 19.2) L/kg, systemic clearance (CL/f) from 0.022 to 0.073 L/h/kg (median 0.026 L/h/kg), and terminal elimination half-life from 13.8 to 40.9 days (median 20 days). Systemic clearance appears to be increased in late pregnancy. In uncomplicated falciparum malaria, peak blood concentrations are 2 to 3 times higher than those in healthy subjects ranging from 112 to 209 (median 144) ng/ml/mg/kg because of contraction in the total apparent volume of distribution. Systemic clearance is usually reduced but elimination rates are increased (possibly because of reduced enterohepatic recycling). Mefloquine absorption appears to be reduced in severe falciparum malaria; plasma protein binding exceeds 98% in both healthy subjects and patients. No important drug interactions have been identified as yet, but the potential for serious interactions with quinine has not been adequately investigated. More studies are needed on the disposition of mefloquine in children.

Keywords

High Performance Liquid Chromatography Malaria Quinine Mefloquine Falciparum Malaria 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Arnold PJ, Stetten OV. High performance liquid Chromatographic analysis of mefloquine and its metabolites by direct plasma injection with pre-column enrichment and column switching techniques. Journal of Chromatography 353: 193–200, 1986PubMedCrossRefGoogle Scholar
  2. Bergqvist Y, Churchill FC, Mount DL. Determination of mefloquine by electron capture gas chromatography after phosgene derivatisation in biological samples and in capillary blood collected on filter paper. Journal of Chromatography 428: 281–290, 1988aPubMedCrossRefGoogle Scholar
  3. Bergqvist Y, Hellgren U, Churchill FC. High performance liquid Chromatographic assay for the simultaneous monitoring of mefloquine and its acid metabolite in biological samples using protein precipitation and ion-pair extraction. Journal of Chromatography 432: 253–263, 1988bPubMedCrossRefGoogle Scholar
  4. Chanthavanich P, Looareesuwan S, White NJ, Warrell DA, Warrell MJ, et al. Intragastric mefloquine is absorbed rapidly in patients with cerebral malaria. American Journal of Tropical Medicine and Hygiene 34: 1028–1036, 1985PubMedGoogle Scholar
  5. Chongsuphajaisiddhi T, Sabcharoen A, Chantavanich P, Singhasivanon P, Attanath P, et al. A phase-III clinical trial of mefloquine in children with chloroquine-resistant falciparum malaria in Thailand. Bulletin of the World Health Organization 65: 223–226, 1987PubMedGoogle Scholar
  6. Dadgar D, Climax J, Lambe R, Darragh A. Gas Chromatographie determination of mefloquine in human and dog plasma using electron-capture detection. Journal of Chromatography 37: 47–54, 1985Google Scholar
  7. Desjardins RE, Pamplin CL, Von Bredow J, Barry KG, Canfield CJ Kinetics of a new antimalanal mefloquine. Clinical Pharmacology and Therapeutics 26: 372–379, 1979PubMedGoogle Scholar
  8. De Souza JM. A phase I clinical trial of mefloquine in Brazilian male subjects. Bulletin of the World Health Organization 61: 809–814, 1983aPubMedGoogle Scholar
  9. De Souza JM. A phase II clinical trial of mefloquine in Brazilian male subjects. Bulletin of the World Health Organization 61: 815–820, 1983bPubMedGoogle Scholar
  10. De Souza JM, Heizmann P, Schwartz DE. Single dose kinetics of mefloquine in Brazilian male subjects. Bulletin of the World Health Organization 65: 353–356, 1987PubMedGoogle Scholar
  11. De Souza JM, Sheth UK, De Oliveira RMG, Roulet H, De Souza SD. An open randomized, phase III clinical trial of mefloquine and of quinine plus sulfadoxine-pyrimethamine in the treatment of symptomatic falciparum malaria in Brazil. Bulletin of the World Health Organization 63: 603–609, 1985PubMedGoogle Scholar
  12. Doberstyn EB, Phintuyothin P, Noeypatimanondh S, Teerakiarkamjorn C. Single dose therapy of falciparum malaria with mefloquine or pyrimethamine-sulfadoxine. Bulletin of the World Health Organization 57: 275–279, 1979PubMedGoogle Scholar
  13. Ekue KMK, Ulrich AM, Rwawogo J, Sheth UK. A double blind comparative clinical trial of mefloquine and chloroquine in symptomatic falciparum malaria. Bulletin of the World Health Organization 61: 713–718, 1983Google Scholar
  14. Fitch CD, Chan RL, Chevli R. Chloroquine resistance in malaria: accessibility of drug receptors to mefloquine. Antimicrobial Agents and Chemotherapy 15: 258–262, 1979PubMedCrossRefGoogle Scholar
  15. Franssen G, Rouveix B, Lebras J, Bauchet J, Verdier F, et al. Divided-dose kinetics of mefloquine in man. British Journal of Clinical Pharmacology 28: 179–184, 1989PubMedCrossRefGoogle Scholar
  16. Grindel JM, Tilton PF, Shaffer. Quantitation of the antimalarial agent mefloquine in blood, plasma and urine using high pressure liquid chromatography. Journal of Pharmaceutical Science 66: 834–836, 1979CrossRefGoogle Scholar
  17. Harinasuta T, Bunnag D, Lasserre R, Leimer R, Vanijanond S. Trials of mefloquine in vivax and of mefloquine plus ‘Fansidar’ in falciparum malaria. Lancet 1: 885–888, 1985PubMedCrossRefGoogle Scholar
  18. Harinasuta T, Bunnag D, Vanijanond S, Charoenlarp P, Sujntarasamai P, et al. Mefloquine, sulfadoxine and pyrimethamine in the treatment of symptomatic falciparum malaria: a double-blind trial for determining the most effective dose. Bulletin of the World Health Organization 3: 363–367, 1987Google Scholar
  19. Harinasuta T, Bunnag D, Werndorfer WH. A phase II clinical trial of mefloquine in patients with chloroquine-resistant falciparum malaria in Thailand. Bulletin of the World Health Organization 61(2): 299–305, 1983PubMedGoogle Scholar
  20. Heizman P, Geschke R. Determination of the antimalarial mefloquine in human plasma by gas chromatography with electron-capture detection. Journal of Chromatography 311: 411–417, 1984CrossRefGoogle Scholar
  21. von Jauch R, Greisser E, Oesterhelt G. Metabolismus von Ro 21–5998 (mefloquine) bei der Ratte. Arzneimittel-Forschung 30: 60–66, 1980PubMedGoogle Scholar
  22. Jiang JB, Li GQ, Guo XB, Kong YC, Arnold K. Antimalarial activity of mefloquine and qinghaosu. Lancet 1: 285–288, 1982CrossRefGoogle Scholar
  23. Juma FD, Ogeto JO. Mefloquine disposition in normals and in patients with severe Plasmodium falciparum malaria. European Journal of Drug Metabolism and Pharmacokinetics 14: 15–18, 1989PubMedCrossRefGoogle Scholar
  24. Kapetanovic IM, Digiovanni JD, Bartosevich J, Melendez V, von Bredow J, et al. Analysis of the antimalarial mefloquine in blood and plasma using high performance liquid chromatography. Journal of Chromatography 277: 209–215, 1983PubMedCrossRefGoogle Scholar
  25. Karbwang J, Back DJ, Bunnag D, Breckenridge AM, A comparison of the pharmacokinetics of mefloquine in healthy Thai volunteers and in Thai patients with falciparum malaria. European Journal of Clinical Pharmacology 35: 677–680, 1988aPubMedCrossRefGoogle Scholar
  26. Karbwang J, Bunnag D, Breckenridge AM, Back DJ. The pharmacokinetics of mefloquine when given alone or in combination with sulfadoxine and pyrimethamine in Thai male and female subjects. European Journal of Clinical Pharmacology 32: 173–177, 1987bPubMedCrossRefGoogle Scholar
  27. Karbwang J, Looareesuwan S, Back DJ, Migasena S, Bunnag D, et al. Effect of oral contraceptive steroids on the clinical course of malaria infection and on the pharmacokinetics of mefloquine in Thai women. Bulletin of the World Health Organization 66: 763–767, 1988bPubMedGoogle Scholar
  28. Karbwang J, Looareesuwan S, Phillips RE, Wattanagoon Y, Molyneux ME, et al. Plasma and whole blood mefloquine concentrations during treatment of chloroquine-resistant falciparum malaria with the combination mefloquine-sulfadoxine-pyrimethamine. British Journal of Clinical Pharmacology 23: 477–481, 1987aPubMedCrossRefGoogle Scholar
  29. Karbwang J, Molunto P, Na Bangchang K, Bunnag D. Determination of mefloquine in biological fluids using high performance liquid chromatography. Southeast Asian Journal of Tropical Medicine and Public Health 20: 55–60, 1989aPubMedGoogle Scholar
  30. Karbwang J, Na Bangchang K, Supapochana A, Bunnag D, Harinasuta T. Pharmacokinetics of prophylactic mefloquine in Thai healthy volunteers. Southeast Asian Journal of Tropical Medicine and Public Health, in press, 1989bGoogle Scholar
  31. Looareesuwan S, White NJ, Warrell DA, Forgo I, Dubach UC, et al. Studies of mefloquine bioavailability and kinetics using a stable isotope technique: a comparison of Thai patients with falciparum malaria and health Caucasian volunteers. British Journal of Clinical Pharmacology 24: 37–42, 1987PubMedCrossRefGoogle Scholar
  32. Looareesuwan S, Charoenpan P, Ho M, White NJ, Karbwang J, et al. Fatal Plasmodium falciparum malaria after an inadequate response to quinine treatment. Journal of Infectious Diseases, in press, 1990Google Scholar
  33. Mansor SM, Navaratnam V, Mohamad M, Hussein S, Kumar A. et al. Single dose kinetic study of the triple combination mefloquine-sulfadoxine-pyrimethamine (Fansimef) in healthy male volunteers. British Journal of Clinical Pharmacology 27: 381–386, 1989PubMedCrossRefGoogle Scholar
  34. Mimica I, Fry W, Eckert G, Schwartz DE. Multiple dose kinetic study of mefloquine in healthy male volunteers. Chemotherapy 29: 184–187, 1983PubMedCrossRefGoogle Scholar
  35. Mu JY, Israili ZH, Dayton PG. Studies of the disposition and metabolism of mefloquine HCL (WR 142,149), a quinolinemethanol antimalarial, in the rat. Drug Metabolism and Disposition 3: 198–210, 1975PubMedGoogle Scholar
  36. Na Bangchang, Karbwang J, Back DJ, Bunnag D, Harinasuta T. Clinical pharmacology of mefloquine. IIIrd National Congress of Malaria, Chiangmai, Thailand. Abstract, p. 163, 1989cGoogle Scholar
  37. Na Bangchang, Karbwang J, Bunnag D, Harinasuta T. Pharmacokinetics and pharmacodynamics of mefloquine in Thai patients with acute uncomplicated falciparum malaria. IIIrd National Congress of Malaria, Chiangmai, Thailand, Abstract, p. 103, 1989aGoogle Scholar
  38. Na Bangchang, Karbwang J, Davis T. Looareesuwan S, Pukrittayakamee S, et al. Absorption kinetics of mefloquine in pregnant patients with chloroquine-resistant falciparum malaria. Proceedings of the British Pharmacological Society, p. 108, Manchester, September 13-15, 1989bGoogle Scholar
  39. Nakagawa T, Higuchi J, Haslam L, Shaffer RD, Mendenhall DW. GLC determination of whole blood antimalarial concentrations. Journal of Pharmaceutical Science 68: 718–721, 1979CrossRefGoogle Scholar
  40. Patchen LC, Campbell CC, Williams SB. Neurologic reactions after a therapeutic dose of mefloquine. New England Journal of Medicine 321: 1415–1416, 1989PubMedCrossRefGoogle Scholar
  41. Riviere JH, Back DJ, Breckenridge AM, Howells RE. The pharmacokinetics of mefloquine in man: lack of effect of mefloquine on antipyrine metabolism. British Journal of Clinical Pharmacology 20: 469–474, 1985PubMedCrossRefGoogle Scholar
  42. Rozman RS, Molek NA, Koby R. The absorption, distribution and excretion in mice of the antimalarial mefloquine, erythro-2, 8-bis (trifluoromethyl)-(2-piperidyl)-4-quinolinemethanol hydrochloride. Drug Metabolism and Disposition 6: 654–658, 1978PubMedGoogle Scholar
  43. San George RC, Nagel RL, Fabryl ME. On the mechanism for the red-cell accumulation of mefloquine, an antimalarial drug. Biochimica et Biophysica Acta 803: 174–181, 1984PubMedCrossRefGoogle Scholar
  44. Schwartz DE. Quantitative determination of the antimalarial drug mefloquine and its main metabolite in plasma by direct densitometric measurement on TLC-plates. In Frigero & McCamish (Eds) Recent developments in chromatography and electrophoresis, Vol. 10, pp. 69–74, Elsevier, Amsterdam, 1980Google Scholar
  45. Schwartz DE, Eckert G, Ekue JMK. Urinary excretion of mefloquine and some of its metabolites in African volunteers at steady state. Chemotherapy 33: 305–308, 1987PubMedCrossRefGoogle Scholar
  46. Schwartz DE, Eckert G, Hartmann D, Weber B, Richard-Lenoble D, et al. Single dose kinetics of mefloquine in man. Chemotherapy 28: 70–84, 1982PubMedCrossRefGoogle Scholar
  47. Schwanz DE, Ranalder UB. Highly sensitive and specific determination of mefloquine in biological fluids using gas chromatography mass spectrometry with selected ion monitoring. Biomedical Mass Spectrometry 8: 589–592, 1981CrossRefGoogle Scholar
  48. Schwartz DE, Weber W, Richard-Lenoble D, Gentilini M. Kinetic studies of mefloquine and of one of its metabolites. RO 215104. in the dog and in man. Acta Tropica 37: 238–242, 1980PubMedGoogle Scholar
  49. Silamut K, White NJ, Looareesuwan S, Warrell DA. Binding of quinine to plasma proteins in falciparum malaria. American Journal of Tropical Medicine and Hygiene 34: 681–686, 1985PubMedGoogle Scholar
  50. Tin F, Hlaing N, Lasserre R. Single dose treatment of falciparum malaria with mcfloquine: field studies with different doses in semi-immune adults and children in Burma. Bulletin of the World Health Organization 60: 913–917, 1982PubMedGoogle Scholar
  51. Weidekamm E, Schwartz ED, Dubach UC, Weber B. Single dose investigation of possible interaction between the components of the antimalarial combination Fansimef. Chemotherapy 33: 259–265, 1987PubMedCrossRefGoogle Scholar
  52. White NJ. Clinical pharmacokinetics of the antimalarial drugs. Clinical Pharmacokinetics 10: 187–215, 1985PubMedCrossRefGoogle Scholar
  53. White NJ. Combination treatment for P. falciparum prophylaxis. Lancet 1: 680–681, 1987PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1990

Authors and Affiliations

  • Jantra Karbwang
    • 1
    • 2
  • Nicholas J. White
    • 1
    • 2
  1. 1.Department of Clinical Tropical Medicine and Hospital for Tropical DiseasesFaculty of Tropical Medicine, Mahidol UniversityBangkokThailand
  2. 2.Nuffield Department of Clinical MedicineUniversity of OxfordEngland

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