Transfer of chloroquine and desethylchloroquine across the placenta and into milk in Melanesian mothers

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The literature on placental and milk transfer of chloroquine and its major bioactive metabolite desethylchloroquine is sparse and incomplete. WHAT THIS STUDY ADDS• We have provided data on the transplacental transfer of chloroquine and desethylchloroquine in Melanesian women (n = 19), measured transfer of these drugs into breast milk (n = 16) and estimated absolute and relative infant doses for the breastfed infant.• The data for desethylchloroquine are novel.• In all three areas we have significantly increased both quantity and quality of the available database. AIMSTo investigate the transfer of chloroquine and its major bioactive metabolite desethylchloroquine across the placenta and into breast milk. METHODSIn Papua New Guinea, chloroquine (CQ; 25 mg base kg ) is recommended for prophylaxis of malaria during pregnancy, and at the Alexishafen Health Centre women are routinely prescribed CQ at the time of delivery. Fetal-cord and maternal serum samples were collected at delivery (n = 19) and milk samples were collected from day 3 to day 17-21 after delivery (n = 16). CQ and its primary active metabolite desethylchloroquine (DECQ) were quantified by high-performance liquid chromatography. For both CQ and DECQ cord/maternal ratios (C/M) were calculated to characterize placental transfer, and infant exposure via milk was estimated by standard methods. RESULTSThe median (interquartile range) C/M was 1.1 (0.9, 1.6) for CQ and 1.2 (0.5, 1.8) for DECQ. The average concentration in milk over the time of sampling was 167 mg l -1 (27, 340) for CQ and 54 mg l -1 (22, 106) for DECQ. Estimated absolute and relative infant doses were 34 mg kg -1 day -1 (7, 50) and 15 mg kg -1 day -1 (4, 26), and 2.3% (0.5, 3.6) and 1.0% (0.4, 2.0) for CQ and DECQ (as CQ equivalents), respectively. CONCLUSIONInfant exposure to CQ and DECQ during pregnancy will be similar to that in the maternal circulation, and dependent on maternal dose and frequency. The median CQ + DECQ relative infant dose of 3.2% (as CQ equivalents) was low, confirming that use of CQ during lactation is compatible with breastfeeding.

Pharmacokinetics of Piperaquine Transfer into the Breast Milk of Melanesian Mothers

“…This is similar to the 3.2% for the combination of CQ and desethyl chloroquine, a CQ metabolite with antimalarial activity (27), that was included in a previous study of PNG women given a treatment dose of CQ at delivery (20). Whether PQ also has an active metabolite is unknown and, despite the possibility of cytochrome P450 (CYP) enzyme involvement (28), there is chromatographic evidence that PQ is not extensively metabolized in adults and older children (29).…”

“…A limitation of the present study was the variability in breast milk concentrations, which may have been attenuated had we been able to measure milk crematocit, a significant determinant of drug transfer between the plasma and milk compartments in other contexts (31). The present study was opportunistic, and a more definitive pharmacokinetic characterization would be facilitated by standardizing the time of dosing (such as at delivery, as in the CQ study [20]) and optimizing the sampling schedule based on the current relatively sparse data. Collection of fore-and hindmilk samples with measurement of crematocrit may also facilitate understanding of transfer processes.…”

“…Analysis of PQ in breast milk was based on the method used for CQ (20) with some modifications. Breast milk samples (1 ml) in polypropylene tubes were spiked with the internal standards CQ (100 ng) and AQ (200 ng).…”

Milk Excretion and Placental Transfer Studies

“…Secretion of the antimalaria drug CQ, and its pharmacologically active metabolite desethylchloroquine ( DECQ ), into human breast milk was investigated following three oral doses of CQ (750 mg of CQ phosphate, 465 mg free base) to women on days 1 -3 following delivery (Law et al, 2008 ). CQ is a weak base (p K a of 10.2) that is not particularly lipophilic (log D of 0.96 at pH 7.4).…”

Looking back: editors' pick of 2008

“…Given the potentially important role that desethylchloroquine might play in the efficacy and toxicity of chloroquine, it is surprising that few studies have been conducted on their placental transfer and infant exposure through breast milk. In a logistically challenging study, Law and colleagues studied such transfers in Melanesian women in a Health Centre on the north coast of Papua New Guinea [4]. They showed that cord to maternal plasma concentration ratios of both compounds were almost unity and that the relative infant dose via breast milk was about 3%.These essentially negative pharmacokinetic observations (no increased concentration in fetal compared with maternal plasma, a trivial dose to the suckling infant) support the safety of chloroquine when used at the recommended dose in pregnant women and during breast feeding.…”