Pharmacokinetics of chloroquine and monodesethylchloroquine in pregnancy

Abstract

In order to determine the pharmacokinetic disposition of chloroquine (CQ) and its active metabolite, desethylchloroquine (DECQ), when administered as intermittent presumptive treatment in pregnancy (IPTp) for malaria, 30 Papua New Guinean women in the second or third trimester of pregnancy and 30 age-matched nonpregnant women were administered three daily doses of 450 mg CQ (8.5 mg/kg of body weight/day) in addition to a single dose of sulfadoxine-pyrimethamine. For all women, blood was taken at baseline; at 1, 2, 4, 6, 12, 18, 24, 30, 48, and 72 h posttreatment; and at 7, 10, 14, 28, and 42 days posttreatment. Plasma was subsequently assayed for CQ and DECQ by high-performance liquid chromatography, and population pharmacokinetic modeling was performed. Pregnant subjects had significantly lower area under the plasma concentration-time curve for both CQ (35,750 versus 47,892 microg.h/liter, P < 0.001) and DECQ (23,073 versus 41,584 microg.h/liter, P < 0.001), reflecting significant differences in elimination half-lives and in volumes of distribution and clearances relative to bioavailability. Reduced plasma concentrations of both CQ and DECQ could compromise both curative efficacy and posttreatment prophylactic properties in pregnant patients. Higher IPTp CQ doses may be desirable but could increase the risk of adverse hemodynamic effects.

FIG. 1.

CQ (A) and DECQ (B) concentrations in pregnant (solid line) and nonpregnant (dashed line) groups. Data are medians and interquartile ranges. Significant differences (P < 0.001) between pregnant and nonpregnant subjects at individual time points are indicated by asterisks.

FIG. 2.

Structural model used in the final pharmacokinetic analysis. k_a, first-order absorption rate constant; V_C/F_CQ, central compartment volume of distribution for CQ; V_P/F_CQ, peripheral compartment volume of distribution for CQ, Q/F_CQ, intercompartment clearance for CQ, CL/F_CQ, clearance of CQ; CL_M/F_CQ, metabolic clearance for CQ to DECQ (fixed ratio CL_M/CL_CQ = 15.2/84.8; see Materials and Methods), V_C/F_DECQ, central volume of distribution for DECQ; V_P/F_DECQ, peripheral volume of distribution for DECQ; Q/F_DECQ, intercompartment clearance for DECQ; CL/F_DECQ, clearance of DECQ.

FIG. 3.

Visual predicted check plots showing simulated 10th (short dashed line), 50th (long dashed line), and 90th (solid line) percentile concentrations and observed concentration (log scale) data (○) versus time (log scale) for CQ (panel A, nonpregnant; panel B, pregnant) and DECQ (panel C, nonpregnant; panel D, pregnant). The 10th (×), 50th (•), and 90th (▪) percentiles for the observed data are also shown.