title: Pharmacokinetics and bioequivalence evaluation of three commercial tablet formulations of mefloquine when given in combination with dihydroartemisinin in patients with acute uncomplicated falciparum malaria.
abstract: OBJECTIVE
  To assess the pharmacokinetics and relative bioavailability/bioequivalence of three commercial tablet formulations of mefloquine, i.e. Lariam (reference formulation), Mephaquin 100 Lactab and Eloquin-250, when given sequentially after dihydroartemisinin in Thai patients with acute uncomplicated falciparum malaria.
  
  
  METHODS
  Twenty-nine Thai patients with acute uncomplicated falciparum malaria were randomised to receive an initial dose of 300 mg dihydroartemisinin, followed by 1250 mg mefloquine (at 24 h and 30 h after dihydroartemisinin) given as either Lariam (n=10 cases), Mephaquin (n=9 cases) or Eloquin-250 (n=10 cases). Serial blood samples were obtained up to day 42 after treatment with mefloquine. Mefloquine concentrations were determined in whole blood by means of ultraviolet high-performance liquid chromatography. The pharmacokinetic parameters of mefloquine were estimated using non-compartmental and compartmental analysis.
  
  
  RESULTS
  The three combination regimens were well tolerated. Patients in all treatment groups had a rapid initial response. However, nine patients (four and five cases in regimen containing Mephaquin 100 Lactab and Eloquin-250, respectively) had reappearance of parasitaemia during the follow-up period. Mefloquine from the three formulations showed significantly different pharmacokinetic and bioavailability metrics. Significantly lower peak plasma concentrations (C(max)) and areas under the plasma concentration-time curve (AUC; AUC(0-48h), AUC(0-7days), and total AUC) were observed with Mephaquin 100 Lactab than with the other two formulations. Mean values for relative bioavailability of the test to standard products were 49.1% (Mephaquin 100 Lactab) and 72.4% (Eloquine-250). Based on the criteria set, the bioavailability of the two test products (Mephaquin 100 Lactab and Eloquine-250) was considered non-equivalent to the reference product with respect to the rate (t(max), C(max)) and extent (AUC(0-48h), AUC(0-7days), total AUC) of mefloquine absorption.
authors.affiliation: Clinical Pharmacology Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand.
authors.forename: K
authors.initials: K
authors.lastname: Na-Bangchang
authors.forename: J
authors.initials: J
authors.lastname: Karbwang
authors.forename: P A
authors.initials: PA
authors.lastname: Palacios
authors.forename: R
authors.initials: R
authors.lastname: Ubalee
authors.forename: S
authors.initials: S
authors.lastname: Saengtertsilapachai
authors.forename: W H
authors.initials: WH
authors.lastname: Wernsdorfer
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage*; D037621:Artemisinins; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004359:Drug Therapy, Combination; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D015767:Mefloquine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D012008:Recurrence; D012717:Sesquiterpenes / Q000008:administration & dosage* / Q000009:adverse effects; D013607:Tablets; D013785:Thailand; D013810:Therapeutic Equivalency; D013997:Time Factors
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; D013607:Tablets; C039060:artenimol; D015767:Mefloquine