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  1. Population pharmacokinetics of orally administered mefloquine in healthy volunteers and patients with uncomplicated Plasmodium falciparum malaria
    Reuter SE, Upton RN, Evans AM, Navaratnam V, Olliaro PL
    J Antimicrob Chemother, 2015 Mar;70(3):868-76.
    PMID: 25377567 DOI: 10.1093/jac/dku430
    BACKGROUND: The determination of dosing regimens for the treatment of malaria is largely empirical and thus a better understanding of the pharmacokinetic/pharmacodynamic properties of antimalarial agents is required to assess the adequacy of current treatment regimens and identify sources of suboptimal dosing that could select for drug-resistant parasites. Mefloquine is a widely used antimalarial, commonly given in combination with artesunate.

    PATIENTS AND METHODS: Mefloquine pharmacokinetics was assessed in 24 healthy adults and 43 patients with Plasmodium falciparum malaria administered mefloquine in combination with artesunate. Population pharmacokinetic modelling was conducted using NONMEM.

    RESULTS: A two-compartment model with a single transit compartment and first-order elimination from the central compartment most adequately described mefloquine concentration-time data. The model incorporated population parameter variability for clearance (CL/F), central volume of distribution (VC/F) and absorption rate constant (KA) and identified, in addition to body weight, malaria infection as a covariate for VC/F (but not CL/F). Monte Carlo simulations predict that falciparum malaria infection is associated with a shorter elimination half-life (407 versus 566 h) and T>MIC (766 versus 893 h).

    CONCLUSIONS: This is the first known population pharmacokinetic study to show falciparum malaria to influence mefloquine disposition. Protein binding, anaemia and other factors may contribute to differences between healthy individuals and patients. As VC/F is related to the earlier portion of the concentration-time profiles, which occurs during acute malaria, and CL/F is more related to the terminal phase during convalescence after treatment, this may explain why malaria was found to be a covariate for VC/F but not CL/F.

    Matched MeSH terms: Mefloquine/pharmacokinetics*
  2. 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
    Lai CS, Nair NK, Mansor SM, Olliaro PL, Navaratnam V
    J Chromatogr B Analyt Technol Biomed Life Sci, 2007 Oct 01;857(2):308-14.
    PMID: 17719858
    The combination of two sensitive, selective and reproducible reversed phase liquid chromatographic (RP-HPLC) methods was developed for the determination of artesunate (AS), its active metabolite dihydroartemisinin (DHA) and mefloquine (MQ) in human plasma. Solid phase extraction (SPE) of the plasma samples was carried out on Supelclean LC-18 extraction cartridges. Chromatographic separation of AS, DHA and the internal standard, artemisinin (QHS) was obtained on a Hypersil C4 column with mobile phase consisting of acetonitrile-0.05 M acetic acid adjusted to pH 5.2 with 1.0M NaOH (42:58, v/v) at the flow rate of 1.50 ml/min. The analytes were detected using an electrochemical detector operating in the reductive mode. Chromatography of MQ and the internal standard, chlorpromazine hydrochloride (CPM) was carried out on an Inertsil C8-3 column using methanol-acetonitrile-0.05 M potassium dihydrogen phosphate adjusted to pH 3.9 with 0.5% orthophosphoric acid (50:8:42, v/v/v) at a flow rate of 1.00 ml/min with ultraviolet detection at 284 nm. The mean recoveries of AS and DHA over a concentration range of 30-750 ng/0.5 ml plasma and MQ over a concentration of 75-1500 ng/0.5 ml plasma were above 80% and the accuracy ranged from 91.1 to 103.5%. The within-day coefficients of variation were 1.0-1.4% for AS, 0.4-3.4% for DHA and 0.7-1.5% for MQ. The day-to-day coefficients of variation were 1.3-7.6%, 1.8-7.8% and 2.0-3.4%, respectively. Both the lower limit of quantifications for AS and DHA were at 10 ng/0.5 ml and the lower limit of quantification for MQ was at 25 ng/0.5 ml. The limit of detections were 4 ng/0.5 ml for AS and DHA and 15 ng/0.5 ml for MQ. The method was found to be suitable for use in clinical pharmacological studies.
    Matched MeSH terms: Mefloquine/pharmacokinetics
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