The Transfer of Domperidone into Human Milk Remains Low at High Doses

Domperidone is a dopamine-2 (D2) receptor antagonist. It is prescribed off-label in Canada and Australia as a galactagogue to promote lactation in prolactin-deficient women by stimulating the release of stored prolactin in the anterior pituitary.

Domperidone has been considered to have limited central nervous system effects due to its limited transfer across the blood–brain barrier at standard doses. ¹ However, some reports raise concerns about the peripheral action of the drug. ² One explanation for these reports is possible saturable kinetics at the blood–brain and lactocyte barriers. Excessive domperidone transfer into human milk could cause altered cardiac conduction, gastrointestinal discomfort, and irritability in the breastfed infant. Therefore, quantifying domperidone in human milk is essential to evaluate this risk.

We describe the case of a 43-year-old woman taking a total daily domperidone dose of 160 mg who participated in the InfantRisk Human Milk Biorepository (HMB), Texas Tech University Health Sciences Center Amarillo IRB # A21-4214. The participant consented to research and publication through the HMB and completed the medical, lactation, and infant history questionnaire. She was advised to provide milk samples at timed intervals on the same day by emptying both breasts, gently mixing the milk, and mailing frozen aliquots using provided supplies in the collection kit.

Although timed milk samples are requested based on the pharmacokinetic parameters of the drug, it is stressed to the mother that if the suggested times are not feasible, unscheduled milk samples are preferable to no samples for analysis. This mother provided samples outside of the requested schedule, nearer to expected trough values. Upon overnight arrival at our facility, samples are stored at −80°C until analysis. This participant had been taking 40 mg of domperidone four times daily for 7 months, reporting overproduction of milk while on the drug. She reported taking no concomitant medications. Her child was born at term, now 1 year old and is fed expressed breast milk two to three times daily along with complementary foods. She reported no observed adverse effects in her infant; he is meeting developmental and growth milestones.

Milk sample analysis was done using a validated high-performance liquid chromatography-mass spectrometry method (LC\MS\MS) to detect domperidone. Chromatography conditions were isocratic, with a mobile phase consisting of water:acetonitrile (25:75 vol/vol) at a flow rate of 0.4 mL/minute on a Phenomenex biphenyl column, 100 × 4.6 mm, 5 μm. Multiple reaction monitoring was done at m/z 426 > 175 transitions for domperidone. The calibration curve was determined using known concentrations of domperidone and its internal standard, and was calculated in the range of 0.19–100 ng/mL with r² = 0.99.

A timeline of activity, domperidone concentration results, and pharmacokinetic parameters are reported in Figure 1. Even at high doses, the transfer of domperidone into breast milk is negligible, with a relative infant dose (RID) of 0.05%. In a simulation of the “worst-case” scenario using the maximum drug concentration found, 8.4 ng/mL, the RID remained low at 0.06%.

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FIG. 1.

(A) Timeline of domperidone dosing and its levels in collected milk samples. (B) Pharmacokinetic parameters of domperidone in lactating participant (n = 1). An unweighted average concentration of domperidone was used to calculate the RID. RID was calculated as a percentage of estimated infant dose through breast milk (7.0 ng/mL * 150 mL/kg/day) divided by maternal daily dose (160 mg/day/81.8 kg). RID, relative infant dose.

The RID estimates an infant's potential exposure to a drug through lactation as a percentage of the weight-adjusted maternal dose for a 24-hour period and is calculated by taking the average concentration in milligram per liter, multiplying by 0.15 L/kg/day of breast milk and by the maternal weight, and then dividing by the maternal dose. The standard threshold for reasonable infant exposure to maternal medication through breast milk is 10% of the RID. ³ Similarly, the RID at doses of 30–60 mg daily is <0.012% (0.28–6.9 ng/mL).^4,5 Although more research is necessary, this letter provides a minimal degree of assurance that high-dose domperidone does not transfer into the breast compartment to a greater degree than standard doses.

Maternal safety and efficacy of high-dose domperidone are outside the scope of this report. Independent of that debate, the infant's exposure to domperidone through breast milk will likely pose little risk, even at high doses. More research is necessary to come to a conclusive evidence-based decision.