Population Pharmacokinetic and Pharmacodynamic Modeling of Amodiaquine and Desethylamodiaquine in Women with Plasmodium vivax Malaria during and after Pregnancy

Abstract

f 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 mixedeffects 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. The total global annual burden of P. vivax infections has been estimated at between 80 and 400 million cases, and about 3 billion people are at risk, mainly in Central and Southeast Asia (91%) (7,16). Approximately 93 million pregnancies occur in areas where P. vivax is endemic, of which 40 million are in temperate regions with P. vivax transmission only (i.e., no P. falciparum transmission) (12). Vivax malaria rarely causes mortality but is associated with multiple relapses, anemia, abortion, and a reduction in birth weight in pregnant women with malaria (5, 32, 39, 47). Pregnant women with P. vivax infections are also more likely to experience relapses than nonpregnant women (39). Low birth weight increases the risk of infant mortality and may also have adverse consequences in the longer term (13).Relapses of P. vivax arise from dormant liver stages (i.e., hypnozoites). Primaquine is the only generally available antimalarial drug with a parasiticidal effect on this dormant liver stage of the pathogen (61). However, primaquine may cause hemolysis and is not considered safe in the treatment of P. vivax malaria during pregnancy (42). Chloroquine has traditionally been used as prophylaxis and treatment of P. vivax malaria during pregnancy, but the increasing prevalen...

Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia

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An optimised age-based dosing regimen for single low-dose primaquine for blocking malaria transmission in Cambodia

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