Primaquine Pharmacokinetics in Lactating Women and Breastfed Infant Exposures

Mary Ellen Gilder, Warunee Hanpithakphong, Richard M Hoglund, Joel Tarning, Htun Htun Win, Naw Hilda, Cindy S Chu, Germana Bancone, Verena I Carrara, Pratap Singhasivanon, Nicholas J White, François Nosten, Rose McGready, Mary Ellen Gilder, Warunee Hanpithakphong, Richard M Hoglund, Joel Tarning, Htun Htun Win, Naw Hilda, Cindy S Chu, Germana Bancone, Verena I Carrara, Pratap Singhasivanon, Nicholas J White, François Nosten, Rose McGready

Abstract

Background: Primaquine is the only drug providing radical cure of Plasmodium vivax malaria. It is not recommended for breastfeeding women as it causes hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals, and breast milk excretion and thus infant exposure are not known.

Methods: Healthy G6PD-normal breastfeeding women with previous P. vivax infection and their healthy G6PD-normal infants between 28 days and 2 years old were enrolled. Mothers took primaquine 0.5 mg/kg/day for 14 days. Primaquine and carboxyprimaquine concentrations were measured in maternal venous plasma, capillary plasma, and breast milk samples and infant capillary plasma samples taken on days 0, 3, 7, and 13.

Results: In 20 mother-infant pairs, primaquine concentrations were below measurement thresholds in all but 1 infant capillary plasma sample (that contained primaquine 2.6 ng/mL), and carboxyprimaquine was likewise unmeasurable in the majority of infant samples (maximum value 25.8 ng/mL). The estimated primaquine dose received by infants, based on measured breast milk levels, was 2.98 µg/kg/day (ie, ~0.6% of a hypothetical infant daily dose of 0.5 mg/kg). There was no evidence of drug-related hemolysis in the infants. Maternal levels were comparable to levels in nonlactating patients, and adverse events in mothers were mild.

Conclusions: The concentrations of primaquine in breast milk are very low and therefore very unlikely to cause adverse effects in the breastfeeding infant. Primaquine should not be withheld from mothers breastfeeding infants or young children. More information is needed in neonates.

Clinical trials registration: NCT01780753.

Figures

Figure 1.
Figure 1.
Inclusion flow diagram. Abbreviations: CQ, chloroquine; FST, fluorescent spot test; G6PD, glucose-6-phosphate dehydrogenase; MS, malaria smear; PF, Plasmodium falciparum; PK, pharmacokinetic; PV, Plasmodium vivax.
Figure 2.
Figure 2.
Concentration-time curves for primaquine. A and B, Venous primaquine samples. C and D, Primaquine concentrations in breast milk. Concentration-time curves have been stratified on sampling day 0 (A and C) and sampling day 13 (B and D). Mean and 95% confidence interval are shown.
Figure 3.
Figure 3.
Concentration-time curves for carboxyprimaquine. A and B, Venous carboxyprimaquine samples. C and D, Carboxyprimaquine concentrations in breast milk. The concentration-time curves have been stratified on sampling day 0 (A and C) and sampling day 13 (B and D). Mean and 95% confidence interval are shown.

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Source: PubMed

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