title: Trimester-Specific Population Pharmacokinetics and Other Correlates of Variability in Sulphadoxine-Pyrimethamine Disposition Among Ugandan Pregnant Women.
abstract: BACKGROUND
  Sulphadoxine-pyrimethamine (SP) is widely used as an intermittent preventive treatment for malaria in pregnancy (IPTp). However, pharmacokinetic studies in pregnancy show variable and often contradictory findings. We describe population and trimester-specific differences in SP pharmacokinetics among Ugandan women.
  
  
  METHODS
  SP (three tablets) were administered to 34 nonpregnant and 87 pregnant women in the second trimester. Seventy-eight pregnant women were redosed in the third trimester. Blood was collected over time points ranging from 0.5 h to 42 days postdose. Data on the variables age, body weight, height, parity, gestational age, and serum creatinine, alanine transaminase and albumin levels were collected at baseline. Plasma drug assays were performed using high-performance liquid chromatography with ultraviolet detection. Population pharmacokinetic analysis was done using NONMEM software.
  
  
  RESULTS
  A two-compartment model with first-order absorption and a lag time best described both the sulphadoxine and pyrimethamine data. Between trimesters, statistically significant differences in central volumes of distribution (V(2)) were observed for both drugs, while differences in the distribution half-life and the terminal elimination half-life were observed for pyrimethamine and sulphadoxine, respectively. Significant covariate relationships were identified on clearance (pregnancy status and serum albumin level) and V(2) (gestational age) for sulphadoxine. For pyrimethamine, clearance (pregnancy status and age) and V(2) (gestational age and body weight) were significant. Considering a 25 % threshold for clinical relevance, only differences in clearance of both drugs between pregnant and nonpregnant women were significant.
  
  
  CONCLUSIONS
  While clinically relevant differences in SP disposition between trimesters were not seen, increased clearance with pregnancy and the increasing volume of distribution in the central compartment with gestational age lend support to the revised World Health Organization guidelines advocating more frequent dosing of SP for IPTp.
authors.affiliation: Department of Pharmacology and Therapeutics, Makerere University College of Health Sciences, P.O. Box 7072, Kampala, Uganda. codongo76@gmail.com.|Department of Pharmacology and Therapeutics, Gulu University Faculty of Medicine, P.O. Box 166, Gulu, Uganda. codongo76@gmail.com.
authors.forename: Charles O
authors.initials: CO
authors.lastname: Odongo
authors.affiliation: Department of Pharmacology and Therapeutics, Makerere University College of Health Sciences, P.O. Box 7072, Kampala, Uganda.|Breakthrough Analytics Ltd, Kampala, Uganda.
authors.forename: Kuteesa R
authors.initials: KR
authors.lastname: Bisaso
authors.affiliation: Department of Chemistry, Makerere University College of Natural and Applied Sciences, P.O. Box 7062, Kampala, Uganda.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ntale
authors.affiliation: Department of Pharmacology and Therapeutics, Makerere University College of Health Sciences, P.O. Box 7072, Kampala, Uganda.
authors.forename: Gordon
authors.initials: G
authors.lastname: Odia
authors.affiliation: Department of Pharmacology and Therapeutics, Gulu University Faculty of Medicine, P.O. Box 166, Gulu, Uganda.
authors.forename: Francis W
authors.initials: FW
authors.lastname: Ojara
authors.affiliation: Department of Obstetrics and Gynaecology, Makerere University College of Health Sciences, Mulago Hospital Complex, P.O. Box 7062, Kampala, Uganda.
authors.forename: Josaphat
authors.initials: J
authors.lastname: Byamugisha
authors.affiliation: Department of Pharmacology and Therapeutics, Makerere University College of Health Sciences, P.O. Box 7072, Kampala, Uganda.
authors.forename: Jackson K
authors.initials: JK
authors.lastname: Mukonzo
authors.affiliation: Mbarara University of Science and Technology, P.O. Box 1410, Mbarara, Uganda.
authors.forename: Celestino
authors.initials: C
authors.lastname: Obua
mesh_terms: D000962:Antimalarials / Q000493:pharmacokinetics*; D016022:Case-Control Studies; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008954:Models, Biological; D011247:Pregnancy; D011264:Pregnancy Trimesters / Q000097:blood*; D011739:Pyrimethamine / Q000493:pharmacokinetics*; D013413:Sulfadoxine / Q000493:pharmacokinetics*; D014454:Uganda; D055815:Young Adult
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D011739:Pyrimethamine