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Antimicrobial Agents and Chemotherapy, October 2009, p. 4368-4376, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00335-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Pharmacokinetic Properties of Sulfadoxine-Pyrimethamine in Pregnant Women{triangledown}

Harin A. Karunajeewa,1,2 Sam Salman,1 Ivo Mueller,3 Francisca Baiwog,3 Servina Gomorrai,3 Irwin Law,1 Madhu Page-Sharp,1 Stephen Rogerson,4 Peter Siba,3 Kenneth F. Ilett,1,5 and Timothy M. E. Davis1*

School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia,1 Western Health, Melbourne, Victoria, Australia,2 Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea,3 Faculty of Medicine, University of Melbourne, Melbourne, Victoria, Australia,4 Clinical Pharmacology and Toxicology Laboratory, Path West Laboratory Medicine, Nedlands, Western Australia, Australia5

Received 11 March 2009/ Returned for modification 10 June 2009/ Accepted 10 July 2009

To determine the pharmacokinetic disposition of sulfadoxine (SDOX) and pyrimethamine (PYR) when administered as intermittent presumptive treatment during pregnancy (IPTp) for malaria, 30 Papua New Guinean women in the second or third trimester of pregnancy and 30 age-matched nonpregnant women were given a single dose of 1,500 mg of SDOX plus 75 mg of pyrimethamine PYR. Blood was taken at baseline and 1, 2, 4, 6, 12, 18, 24, 30, 48, and 72 h and at 7, 10, 14, 28, and 42 days posttreatment in all women. Plasma samples were assayed for SDOX, N-acetylsulfadoxine (NASDOX), and PYR by high-performance liquid chromatography. Population pharmacokinetic modeling was performed using NONMEM v6.2.0. Separate user-defined mamillary models were fitted to SDOX/NASDOX and PYR. When the covariate pregnancy was applied to clearance, there was a significant improvement in the base model for both treatments. Pregnancy was associated with a significantly lower area under the concentration-time curve from 0 to {infty} for SDOX (22,315 versus 33,284 mg·h/liter), NASDOX (801 versus 1,590 mg·h/liter), and PYR (72,115 versus 106,065 µg·h/liter; P < 0.001 in each case). Because lower plasma concentrations of SDOX and PYR could compromise both curative efficacy and posttreatment prophylaxis in pregnant patients, IPTp regimens incorporating higher mg/kg doses than those recommended for nonpregnant patients should be considered.

* Corresponding author. Mailing address: School of Medicine and Pharmacology, Fremantle Hospital, P.O. Box 480, Fremantle 6959, Western Australia, Australia. Phone: (618) 9431 3229. Fax: (618) 9431 2977. E-mail: tdavis{at}cyllene.uwa.edu.au

{triangledown} Published ahead of print on 20 July 2009.

Antimicrobial Agents and Chemotherapy, October 2009, p. 4368-4376, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00335-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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