title: Population pharmacokinetics, tolerability, and safety of dihydroartemisinin-piperaquine and sulfadoxine-pyrimethamine-piperaquine in pregnant and nonpregnant Papua New Guinean women.
abstract: The tolerability, safety, and disposition of dihydroartemisinin (DHA) and piperaquine (PQ) were assessed in 32 pregnant (second/third trimester) and 33 nonpregnant Papua New Guinean women randomized to adult treatment courses of DHA-PQ (three daily doses) or sulfadoxine-pyrimethamine (SP)-PQ (three daily PQ doses, single dose of SP). All dose adminstrations were observed, and subjects fasted for 2 h postdose. Plasma PQ was assayed by using high-performance liquid chromatography, and DHA was assessed by using liquid chromatography-mass spectrometry. Compartmental pharmacokinetic models were developed using a population-based approach. Both regimens were well tolerated. There was an expected increase in the rate-corrected electrocardiographic QT interval which was independent of pregnancy and treatment. Two pregnant and two nonpregnant women had Plasmodium falciparum parasitemia which cleared within 48 h, and no other subject became slide positive for malaria during 42 days of follow-up. Of 30 pregnant women followed to delivery, 27 (90%) delivered healthy babies and 3 (10%) had stillbirths; these obstetric outcomes are consistent with those in the general population. The area under the plasma PQ concentration-time curve (AUC0-∞) was lower in the pregnant patients (median [interquartile range], 23,721 μg · h/liter [21,481 to 27,951 μg · h/liter] versus 35,644 μg · h/liter [29,546 to 39,541 μg · h/liter]; P < 0.001) in association with a greater clearance relative to bioavailability (73.5 liters/h [69.4 to 78.4] versus 53.8 liters/h [49.7 to 58.2]; P < 0.001), but pregnancy did not influence the pharmacokinetics of DHA. The apparent pharmacokinetic differences between the present study and results from other studies of women with uncomplicated malaria that showed no effect of pregnancy on the AUC0-∞ of PQ and greater bioavailability may reflect differences in postdose fat intake, proportions of women with malaria, and/or racial differences in drug disposition.
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea.
authors.forename: John M
authors.initials: JM
authors.lastname: Benjamin
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Brioni R
authors.initials: BR
authors.lastname: Moore
authors.affiliation: School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Sam
authors.initials: S
authors.lastname: Salman
authors.affiliation: School of Pharmacy, Curtin University of Technology, Bentley, Western Australia, Australia Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia.
authors.forename: Madhu
authors.initials: M
authors.lastname: Page-Sharp
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea.
authors.forename: Somoyang
authors.initials: S
authors.lastname: Tawat
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea.
authors.forename: Gumal
authors.initials: G
authors.lastname: Yadi
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea.
authors.forename: Lina
authors.initials: L
authors.lastname: Lorry
authors.affiliation: School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia Department of Microbiology, Division of Veterinary and Biomedical Sciences, James Cook University, Townsville, Australia.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siba
authors.affiliation: School of Pharmacy, Curtin University of Technology, Bentley, Western Australia, Australia Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Batty
authors.affiliation: Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea Infection and Immunity, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia Department of Medical Biology, University of Melbourne, Victoria, Australia.
authors.forename: Leanne J
authors.initials: LJ
authors.lastname: Robinson
authors.affiliation: Department of Microbiology, Division of Veterinary and Biomedical Sciences, James Cook University, Townsville, Australia Department of Medical Biology, University of Melbourne, Victoria, Australia Center de Recerca en Salut Internacional de Barcelona, Barcelona, Spain.
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.affiliation: School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia tim.davis@uwa.edu.au.
authors.forename: Timothy M E
authors.initials: TM
authors.lastname: Davis
mesh_terms: D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D037621:Artemisinins / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D004041:Dietary Fats; D004338:Drug Combinations; D005260:Female; D005500:Follow-Up Studies; D018565:Food-Drug Interactions; D006801:Humans; D007231:Infant, Newborn; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000378:metabolism; D015233:Models, Statistical; D010219:Papua New Guinea / Q000453:epidemiology; D011247:Pregnancy; D011256:Pregnancy Outcome; D011739:Pyrimethamine / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011804:Quinolines / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013413:Sulfadoxine / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055815:Young Adult; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004041:Dietary Fats; D004338:Drug Combinations; D011739:Pyrimethamine; D011804:Quinolines; D013413:Sulfadoxine; C001205:fanasil, pyrimethamine drug combination; C039060:artenimol; C034759:piperaquine; D010879:Piperazines