title: Optimal Antimalarial Dose Regimens for Sulfadoxine-Pyrimethamine with or without Azithromycin in Pregnancy Based on Population Pharmacokinetic Modeling.
abstract: Optimal dosing of sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment in pregnancy remains to be established, particularly when coadministered with azithromycin (AZI). To further characterize SP pharmacokinetics in pregnancy, plasma concentration-time data from 45 nonpregnant and 45 pregnant women treated with SP-AZI (n= 15 in each group) and SP-chloroquine (n= 30 in each group) were analyzed. Population nonlinear mixed-effect pharmacokinetic models were developed for pyrimethamine (PYR), sulfadoxine (SDOX), andN-acetylsulfadoxine (the SDOX metabolite NASDOX), and potential covariates were included. Pregnancy increased the relative clearance (CL/F) of PYR, SDOX, and NASDOX by 48, 29, and 70%, respectively, as well as the relative volumes of distribution (V/F) of PYR (46 and 99%) and NASDOX (46%). Coadministration of AZI resulted in a greater increase in PYR CL/F (80%) and also increased NASDOX V/F by 76%. Apparent differences between these results and those of published studies of SP disposition may reflect key differences in study design, including the use of an early postpartum follow-up study rather than a nonpregnant comparator group. Simulations based on the final population model demonstrated that, compared to conventional single-dose SP in nonpregnant women, two such doses given 24 h apart should ensure that pregnant women have similar drug exposure, while three daily SP doses may be required if SP is given with AZI. The results of past and ongoing trials using recommended adult SP doses with or without AZI in pregnant women may need to be interpreted in light of these findings and consideration given to using increased doses in future trials.
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Sam
authors.identifier: 0000-0002-8276-6784
authors.initials: S
authors.lastname: Salman
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
authors.forename: Francisca
authors.initials: F
authors.lastname: Baiwog
authors.affiliation: School of Pharmacy, Curtin University of Technology, Bentley, Western Australia, Australia.
authors.forename: Madhu
authors.initials: M
authors.lastname: Page-Sharp
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
authors.forename: Susan
authors.initials: S
authors.lastname: Griffin
authors.affiliation: Population Health and Immunity, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia.
authors.forename: Harin A
authors.initials: HA
authors.lastname: Karunajeewa
authors.affiliation: Population Health and Immunity, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia.|Barcelona Institute for Global Health (ISGLOBAL), Barcelona, Spain.
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.affiliation: Department of Medicine (RMH), The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Rogerson
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siba
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Ilett
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia tim.davis@uwa.edu.au.
authors.forename: Timothy M E
authors.identifier: 0000-0003-0749-7411
authors.initials: TME
authors.lastname: Davis
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D017963:Azithromycin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic; D008288:Malaria / Q000188:drug therapy / Q000517:prevention & control*; D011247:Pregnancy; D011739:Pyrimethamine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013413:Sulfadoxine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011795:Surveys and Questionnaires
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D017963:Azithromycin; D013413:Sulfadoxine; D011739:Pyrimethamine
keywords: azithromycin; malaria; pharmacokinetics; population pharmacokinetics; pregnancy; sulfadoxine-pyrimethamine