Background: Pregnant women are one of the groups for which malaria presents a particular concern, not only for the mother but also the fetus. Treatment of symptomatic infections and the use of intermittent preventive treatment in pregnancy (IPTp) may help reduce malaria associated maternal and infant morbidity and mortality. Despite the widespread use of conventional antimalarials in pregnancy, such as chloroquine (CQ), little data exists regarding the pharmacokinetic (PK) properties of these compounds in pregnant subjects. To assist in dose optimization in this group the present study aims to describe the effect of pregnancy on the PK of CQ and desethylchloroquine (DECQ), an active metabolite of CQ, for a study group of 30 pregnant women and 30 non-pregnant women in Papua New Guinea using a population PK (PPK) model.
Methods: All study participants received three days of chloroquine (450 mg base/day) and a single dose of sulfadoxine-pyrimethamine (1500-75 mg) on the first day. Up to 16 blood samples per participant were taken at predetermined intervals over the 42 days after the commencement of treatment and plasma was assayed for CQ and desethylchloroquine (DECQ) using a validated HPLC method. A PPK model for both CQ and DECQ simultaneously was developed using NONMEM (Ver 6.2.0). First order conditional estimation (FOCE) with interaction was utilized for modeling. A Visual predictive check was performed to asses the predictive performance of the model.
Results: A two compartment model for both CQ and DECQ with first order absorption of CQ was found to be most appropriate for the data with metabolic conversion to DECQ fixed to 15.2 % based on previous studies1 to overcome unidentifiability. Allometric scaling was used on all clearance and volume terms. Between subject variability was able to be estimated on clearance of CQ and DECQ, central volume for both CQ and DECQ and absorption and a proportional error model was used for both compounds. An investigation into potential covariates showed several significant (C2, P<0.01) relationships; an increase in the clearance of both CQ and DECQ in pregnancy and a decrease in the central volume of CQ with increased hemoglobin (Hb) levels. VPC plots stratified according to pregnancy and Hb demonstrated a suitable predictive performance for the model.
Conclusions: The PPK model suggests that the current dose of CQ given to pregnant women is too low due to a higher clearance for both CQ and DECQ and a higher central volume of CQ which results in lower observed plasma concentrations. An appropriate dosing regime for pregnant women in Papua New Guinea can be designed based on simulations from the developed model.
- Ette et al Journal of Clinical Pharmacology 1989;(29):457-464