title: Pharmacokinetics of mefloquine and its effect on sulfamethoxazole and trimethoprim steady-state blood levels in intermittent preventive treatment (IPTp) of pregnant HIV-infected women in Kenya.
abstract: BACKGROUND
  Intermittent preventive treatment in pregnancy with sulfadoxine/pyrimethamine is contra-indicated in HIV-positive pregnant women receiving sulfamethoxazole/trimethoprim prophylaxis. Since mefloquine is being considered as a replacement for sulfadoxine/pyrimethamine in this vulnerable population, an investigation on the pharmacokinetic interactions of mefloquine, sulfamethoxazole and trimethoprim in pregnant, HIV-infected women was performed.
  
  
  METHODS
  A double-blinded, placebo-controlled study was conducted with 124 HIV-infected, pregnant women on a standard regimen of sulfamethoxazole/trimethoprim prophylaxis. Seventy-two subjects received three doses of mefloquine (15 mg/kg) at monthly intervals. Dried blood spots were collected from both placebo and mefloquine arms four to 672 h post-administration and on day 7 following a second monthly dose of mefloquine. A novel high-performance liquid chromatographic method was developed to simultaneously measure mefloquine, sulfamethoxazole and trimethoprim from each blood spot. Non-compartmental methods using a naïve-pooled data approach were used to determine mefloquine pharmacokinetic parameters.
  
  
  RESULTS
  Sulfamethoxazole/trimethoprim prophylaxis did not noticeably influence mefloquine pharmacokinetics relative to reported values. The mefloquine half-life, observed clearance (CL/f), and area-under-the-curve (AUC0→∞) were 12.0 days, 0.035 l/h/kg and 431 µg-h/ml, respectively. Although trimethoprim steady-state levels were not significantly different between arms, sulfamethoxazole levels showed a significant 53% decrease after mefloquine administration relative to the placebo group and returning to pre-dose levels at 28 days.
  
  
  CONCLUSIONS
  Although a transient decrease in sulfamethoxazole levels was observed, there was no change in hospital admissions due to secondary bacterial infections, implying that mefloquine may have provided antimicrobial protection.
authors.affiliation: Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, Center for Global Health, Atlanta, GA, USA. MGreen@cdc.gov.
authors.forename: Michael
authors.initials: M
authors.lastname: Green
authors.affiliation: Kenya Medical Research Institute, Centre for Global Health Research, Kisumu, Kenya. kotieno@kemricdc.org.
authors.forename: Kephas
authors.initials: K
authors.lastname: Otieno
authors.affiliation: Kenya Medical Research Institute, Centre for Global Health Research, Kisumu, Kenya. wvf0@cdc.gov.
authors.forename: Abraham
authors.initials: A
authors.lastname: Katana
authors.affiliation: Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, Center for Global Health, Atlanta, GA, USA. lms5@cdc.gov.
authors.forename: Laurence
authors.initials: L
authors.lastname: Slutsker
authors.affiliation: Kenya Medical Research Institute, Centre for Global Health Research, Kisumu, Kenya. skariuki@kemricdc.org.
authors.forename: Simon
authors.initials: S
authors.lastname: Kariuki
authors.affiliation: Kenya Medical Research Institute, Centre for Global Health Research, Kisumu, Kenya. pouma@kemricdc.org.
authors.forename: Peter
authors.initials: P
authors.lastname: Ouma
authors.affiliation: ISGlobal, Barcelona Ctr Int Health Res. (CRESIB), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain. raquel.gonzalez@cresbo.cat.
authors.forename: Raquel
authors.initials: R
authors.lastname: González
authors.affiliation: ISGlobal, Barcelona Ctr Int Health Res. (CRESIB), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain. menendez@clinic.ub.es.
authors.forename: Clara
authors.initials: C
authors.lastname: Menendez
authors.affiliation: Liverpool School of Tropical Medicine, Liverpool, UK. Feiko.terkuile@lstmed.ac.uk.
authors.forename: Feiko
authors.initials: F
authors.lastname: ter Kuile
authors.affiliation: Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, Center for Global Health, Atlanta, GA, USA. mud8@cdc.gov.
authors.forename: Meghna
authors.initials: M
authors.lastname: Desai
mesh_terms: D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000097:blood* / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy; D006801:Humans; D007630:Kenya; D008288:Malaria / Q000097:blood* / Q000188:drug therapy*; D008297:Male; D015767:Mefloquine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000097:blood / Q000188:drug therapy; D015597:Pregnancy Complications, Parasitic / Q000097:blood / Q000188:drug therapy; D013420:Sulfamethoxazole / Q000097:blood / Q000627:therapeutic use*; D014295:Trimethoprim / Q000097:blood / Q000627:therapeutic use*; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000097:blood / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000962:Antimalarials; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D014295:Trimethoprim; D013420:Sulfamethoxazole; D015767:Mefloquine