Pharmacokinetics of Amodiaquine and Desethylamodiaquine in Pregnant and Postpartum Women with Plasmodium vivax Malaria

Abstract

In order to study the pharmacokinetic properties of amodiaquine and desethylamodiaquine during pregnancy, 24 pregnant women in the second and third trimesters of pregnancy and with Plasmodium vivax malaria were treated with amodiaquine (10 mg/kg of body weight/day) for 3 days. The same women were studied again at 3 months postpartum. Plasma was analyzed for amodiaquine and desethylamodiaquine by use of a liquid chromatography-tandem mass spectrometry method. Individual concentration-time data were evaluated using noncompartmental analysis. There were no clinically relevant differences in the pharmacokinetics of amodiaquine and desethylamodiaquine between pregnant (n ‫؍‬ 24) and postpartum (n ‫؍‬ 18) women. The results suggest that the current amodiaquine dosing regimen is adequate for the treatment of P. vivax infections during pregnancy.Amodiaquine (AQ) is a 4-aminoquinoline with a structure similar to that of chloroquine (CHQ). Both AQ and its principal biologically active metabolite, desethylamodiaquine (DEAQ), have antimalarial properties, but DEAQ is eliminated much more slowly than AQ and is therefore the main agent responsible for treatment efficacy. AQ is generally more effective than CHQ against chloroquine-resistant Plasmodium falciparum and P. vivax infections, and it has been used both as treatment for symptomatic malaria and intermittent preventive treatment (IPT) during pregnancy (3,4,11,12,20,22). In Southeast Asia, amodiaquine is no longer effective for falciparum malaria but may be used increasingly if chloroquine resistance in P. vivax spreads (1). According to the World Health Organization, there is no evidence to contraindicate the use of amodiaquine during pregnancy, although data are limited and additional safety data are needed (2, 23, 25). The pharmacokinetic properties of AQ and DEAQ have been described for children and adults (5,7,13,16,19,21,29) but not for pregnancy. The pharmacokinetic properties of many antimalarials are altered during pregnancy (27). Ideally, drug regimens for pregnant women should be recommended on the basis of pharmacokinetic and pharmacodynamic studies to maximize efficacy (28). We report the pharmacokinetics of AQ and its principal biologically active metabolite, DEAQ, in the treatment of P. vivax infections in 24 pregnant women. The pharmacokinetic parameters during 42 days posttreatment are compared with those measured in the same women 3 months after delivery. MATERIALS AND METHODSAntenatal clinics. The study was carried out in two antenatal clinics of the Shoklo Malaria Research Unit (SMRU). These clinics are located on the northwestern border of Thailand, an area of malaria endemicity where transmission is low and seasonal for P. falciparum and P. vivax. The majority of the people in this region belong to the Karen ethnic group. All women have a dating ultrasound scan at their first antenatal clinic attendance (18) and are invited to attend weekly consultations providing early detection and treatment of all malaria episodes (14). Women routinely receive fe...

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

“…This study was conducted in an area of low seasonal malaria transmission along the northwestern border of Thailand. Clinical details and noncompartmental analysis results are reported in full elsewhere (48). The study was carried out at weekly antenatal clinics at the Shoklo Malaria Research Unit (SMRU).…”

“…However, CYP2C8 and CYP1A1 activities have not been reported to be altered during pregnancy (14). A noncompartmental analysis of amodiaquine and desethylamodiaquine reported no significant pharmacokinetic difference in pregnant women and postpartum women (48). Studies in pregnant women with malaria reported relatively unchanged pharmacokinetic properties of chloroquine and quinine (1,27).…”

“…Pharmacokinetic results from a noncompartmental analysis of this study have been reported elsewhere (48). Here, the pharmacokinetic and pharmacodynamic properties of amodiaquine and desethylamodiaquine were addressed by using nonlinear mixedeffects modeling.…”

Population Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Malaria

“…This may contribute to lower antimalarial cure rates in pregnant than nonpregnant adults (58). Other studies report no pharmacokinetic differences in pregnant women compared to nonpregnant women (e.g., pyrimethamine and amodiaquine/desethylamodiaquine) or even a higher drug exposure during pregnancy (pyrimethamine) (15,25,46).…”

“…This may contribute to lower antimalarial cure rates in pregnant than nonpregnant adults (58). Other studies report no pharmacokinetic differences in pregnant women compared to nonpregnant women (e.g., pyrimethamine and amodiaquine/desethylamodiaquine) or even a higher drug exposure during pregnancy (pyrimethamine) (15,25,46).Artemisinin-based combination therapy (ACT) is now recommended as first-line treatment for falciparum malaria in nearly all countries where malaria is endemic. ACTs are recommended by the World Health Organization in the second and third trimester of pregnancy (60).…”