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Antimicrob Agents Chemother. Nov 2012; 56(11): 5764–5773.
PMCID: PMC3486620
Population Pharmacokinetic and Pharmacodynamic Modeling of Amodiaquine and Desethylamodiaquine in Women with Plasmodium vivax Malaria during and after Pregnancy
Joel Tarning,corresponding authorab Palang Chotsiri,a Vincent Jullien,c Marcus J. Rijken,d Martin Bergstrand,e Mireille Cammas,c Rose McGready,abd Pratap Singhasivanon,f Nicholas P. J. Day,ab Nicholas J. White,ab Francois Nosten,abd and Niklas Lindegardhab
aMahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
bCentre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom
cUniversité Paris Descartes, INSERM U663, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Vincent de Paul, Paris, France
dShoklo Malaria Research Unit, Mae Sot, Thailand
eDepartment of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
fFaculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
corresponding authorCorresponding author.
Address correspondence to Joel Tarning, joel/at/
Deceased 18 January 2012.
Received June 18, 2012; Revisions requested July 21, 2012; Accepted August 18, 2012.
Amodiaquine is effective for the treatment of Plasmodium vivax malaria, but there is little information on the pharmacokinetic and pharmacodynamic properties of amodiaquine in pregnant women with malaria. This study evaluated the population pharmacokinetic and pharmacodynamic properties of amodiaquine and its biologically active metabolite, desethylamodiaquine, in pregnant women with P. vivax infection and again after delivery. Twenty-seven pregnant women infected with P. vivax malaria on the Thai-Myanmar border were treated with amodiaquine monotherapy (10 mg/kg/day) once daily for 3 days. Nineteen women, with and without P. vivax infections, returned to receive the same amodiaquine dose postpartum. Nonlinear mixed-effects modeling was used to evaluate the population pharmacokinetic and pharmacodynamic properties of amodiaquine and desethylamodiaquine. Amodiaquine plasma concentrations were described accurately by lagged first-order absorption with a two-compartment disposition model followed by a three-compartment disposition of desethylamodiaquine under the assumption of complete in vivo conversion. Body weight was implemented as an allometric function on all clearance and volume parameters. Amodiaquine clearance decreased linearly with age, and absorption lag time was reduced in pregnant patients. Recurrent malaria infections in pregnant women were modeled with a time-to-event model consisting of a constant-hazard function with an inhibitory effect of desethylamodiaquine. Amodiaquine treatment reduced the risk of recurrent infections from 22.2% to 7.4% at day 35. In conclusion, pregnancy did not have a clinically relevant impact on the pharmacokinetic properties of amodiaquine or desethylamodiaquine. No dose adjustments are required in pregnancy.
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