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Population pharmacokinetics of mefloquine in military personnel for prophylaxis against malaria infection during field deployment

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

The purpose of this study was to determine the population pharmacokinetics of mefloquine in healthy military personnel during prophylaxis for malaria infections.

Methods

The subjects were 1,111 Australian soldiers participating in two studies: a randomised double-blinded study (group A, 161 subjects) and an open-label study (group B, 950 subjects). Following a loading dose (250 mg mefloquine base daily, 3 days), subjects received an oral weekly maintenance dose of 250 mg over 6 months. Blood was collected after the last split loading dose then at weeks 4, 8 and 16 for group A, and at weeks 13 and 26 for group B. Plasma mefloquine concentrations were measured by high-performance liquid chromatography (HPLC). Pharmacokinetic modelling was performed using NONMEM.

Results

A two-compartment model with inter-occasion variability (IOV) for clearance satisfactorily described the pharmacokinetics. Typical values were clearance (CL/F, 2.09 l/h), central volume of distribution (V1/F, 528 l), absorption rate constant (KA, 0.24 h−1), inter-compartmental clearance (Q/F, 12.5 l/h), peripheral volume of distribution (V2/F, 483 l) and elimination half-life (t 1/2, 14.0 days). Weight had a positive influence on central volume but was insufficient to warrant dosage adjustments. The inter-individual variability (coefficient of variation, CV%) for CL/F and V1/F was 24.4% and 29.6%, respectively. The IOV for CL/F was 17.8%. The proportional residual error (CV%) for groups A and B was 11.5% and 19.5%, respectively, and the additive error standard deviation (SD) was 57 ng/ml and 149 ng/ml, respectively.

Conclusion

The typical parameter values were comparable with those estimated in much smaller cohorts of healthy subjects and in malaria patients treated with single-dose mefloquine. The lower unexplained variability in the blinded study suggested these subjects may have been more compliant in taking their medication than soldiers in the open-label study.

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Acknowledgments

The authors thank the Australian military personnel who participated as the subjects in this study and the co-ordinational and monitoring support of Squadron Leader Karen Leshinkas, Captain Kym Ward, Captain John Cunningham, Captain Damien Wood and Captain Tracy Carthew. We are grateful to Lieutenant Colonel William Prescott [US Army Medical Materiel Development Activity (USAMMDA)] and Philip Pickford [GlaxoSmithKline (GSK)] for being the project managers for the Phase III clinical study. The technical contribution of Mr. Tom Travers and Sergeant Hamish Barbour to the mefloquine HPLC analysis is gratefully acknowledged. We also thank the military staff from the Australian Army Malaria Institute who assisted with the blood collections and processing, and Mr. Tom Travers and Sergeants Hamish Barbour, Kerry Rowcliffe and Christine Atkins for data entry. Financial support for the study was provided by USAMMDA, GSK and the Australian Defence Force. The opinions expressed in this paper are those of the authors and do not necessarily reflect those of the Australian Defence Health Service or any extant Australian Defence Force policy. The experimental work complies with the current laws of Australia. The work reported herein forms part of a dissertation by Ms. Anna Blomgren to Uppsala University, Sweden, for the MSc degree (Chemical Engineering).

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Authors and Affiliations

  1. School of Pharmacy, Steele Building, The University of Queensland, Brisbane, 4072, QLD, Australia

    B. G. Charles & A. Blomgren

  2. Australian Army Malaria Institute, Brisbane, QLD, Australia

    P. E. Nasveld, S. J. Kitchener, A. Jensen, R. M. Gregory, B. Robertson, I. E. Harris, M. P. Reid & M. D. Edstein

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  1. B. G. Charles
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  2. A. Blomgren
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  3. P. E. Nasveld
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  4. S. J. Kitchener
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  6. R. M. Gregory
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  7. B. Robertson
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  10. M. D. Edstein
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Correspondence to B. G. Charles.

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Charles, B.G., Blomgren, A., Nasveld, P.E. et al. Population pharmacokinetics of mefloquine in military personnel for prophylaxis against malaria infection during field deployment. Eur J Clin Pharmacol 63, 271–278 (2007). https://doi.org/10.1007/s00228-006-0247-3

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  • DOI: https://doi.org/10.1007/s00228-006-0247-3

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