Hydroxyurea Exposure in Lactation—a Pharmacokinetics Study (HELPS)
Authors: Ware Russell E. , Marahatta Anu , Ware Julie L , McElhinney Kathryn L , Dong Min , Vinks Alexander A. 
Published: October 2019

Abstract
Hydroxyurea is a potent and safe disease-modifying therapy for both children and adults with sickle cell anemia (SCA). Several decades of research data have documented clinical efficacy characterized by fewer acute complications, improved organ function, and reduced mortality. Relatively sparse data exist, however, regarding the risks and benefits of hydroxyurea for mothers with SCA during pregnancy and lactation. Mothers with SCA who wish to breastfeed their babies are discouraged from taking hydroxyurea, due to mostly theoretical concerns about transfer of the drug into breast milk. Determination of the pharmacokinetics (PK) of hydroxyurea in breast milk, along with accurate measurement of the amounts transferred to infants during lactation, are warranted since hydroxyurea is now commonly prescribed to women of child-bearing years.
We designed the prospective HELPS trial (Hydroxyurea Exposure in Lactation: a Pharmacokinetics Study, NCT02990598) with the following objectives: (1) determine the PK profile of hydroxyurea in blood and breast milk; (2) calculate the distribution of hydroxyurea between plasma and milk compartments; (3) measure the amount of hydroxyurea excreted into the milk and urine; and (4) create population PK profiles to estimate infant drug exposure. Lactating women were recruited to receive a single oral dose of hydroxyurea (two 500mg capsules). Breast milk, blood, and urine were collected before the dose and then at scheduled timepoints, including 15, 30, 60, 120, 180, 240, 360, 480, 720, and 1440 minutes. Hydroxyurea concentrations were measured using a validated HPLC assay.
A total of 16 women (14 healthy volunteers and 2 with SCA; 11 white and 5 black) were recruited into HELPS; the median age was 31 years (range 26-38 years) and the median weight was 76.3 kg (range 48.8-115.9 kg). All women were currently lactating and breastfeeding their infants for a median duration of 6 months (range 2-22 months). After the 1000mg dose, peak plasma hydroxyurea concentrations ranged from 10-40 µg/mL, typically at 60-120 minutes after dosing although absorption varied among participants. Hydroxyurea was measured in breast milk at ~80% of the plasma concentration, with both compartments having a similar PK profile for each participant, from absorption through distribution and clearance. No hydroxyurea was detected in either plasma or breast milk 24 hours after the dose. With this frequent collection schedule, an average of 2.2 ± 1.0 mg of hydroxyurea transferred into breast milk over the 24-hour timeframe, with the majority transferred in the first 3-6 hours. Most of the drug was excreted into the urine, with an average of 542 ± 178 mg (range 295-876 mg) measured over the 24-hour timeframe; over 90% of urinary excretion occurred in the first 9 hours after the dose.
The collection schedule was then modified to assess drug accumulation and equilibrium in more physiologically relevant 3-hour intervals, which reduced the average amount of hydroxyurea transfer to 1.1 mg; this 50% reduction in drug transfer indicated a rapid equilibrium between milk and plasma compartments. Two lactating women with SCA had similar hydroxyurea PK curves for plasma and milk to the 14 healthy volunteers. PK analysis based on the frequent milk collection schedule and a standard 150 mL/kg intake per 24 hours concluded that 0.41 ± 0.14 mg hydroxyurea will transfer per kg of infant weight per day. Using the World Health Organization definition of Relative Infant Dosage (RID), defined as the infant dose (mg/kg/day) compared to the maternal dose (mg/kg/day), this infant hydroxyurea exposure is 3.1%, where <5% is generally considered safe and acceptable. However, since 48% of the drug transfers in the first 3 hours, the RID would be 1.6% if the mother fed her baby before the dose and waited 3 hours before the next feeding, and <1% when using a single "pump and dump" process.
The HELPS trial provides definitive measurements and PK data regarding hydroxyurea in human breast milk, confirming that drug does transfer but has a rapid equilibrium between plasma and milk. Breastfeeding mothers will transfer only a small amount of hydroxyurea to their infants, so lactation during hydroxyurea therapy should not be contraindicated. These data are relevant for expanded access to hydroxyurea as a disease-modifying therapy to lactating women around the world.

Disclosures
Ware: Novartis: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Other: advisory board; Bristol Myers Squibb: Research Funding; Addmedica: Research Funding; Agios: Other: advisory board; Nova Laboratories: Consultancy; Biomedomics: Research Funding.