Tolerability and age-dependent toxicokinetics following perinatal hydroxyurea treatment in Sprague Dawley rats

Area of Science:

• Pharmacology
• Developmental Toxicology
• Pediatric Pharmacology

Background:

• Hydroxyurea (HU) is a crucial treatment for sickle cell anemia.
• Increasing HU use in children necessitates understanding its long-term effects on development and fertility.
• Appropriate dosing for preclinical studies is essential to assess these impacts.

Purpose of the Study:

• To determine safe doses for examining long-term effects of prenatal and early postnatal HU exposure.
• To investigate the pharmacokinetics of HU across different life stages in a rodent model.
• To establish clinically relevant exposure levels for future animal studies.

Main Methods:

• Pregnant Sprague Dawley rats received HU (0-150 mg/kg/day) during late gestation and lactation.
• Offspring were dosed from postnatal day 10 to 34 with corresponding maternal doses.
• Toxicokinetic studies were performed to assess HU exposure and transfer.

Main Results:

• No significant maternal toxicity or littering effects were observed.
• Offspring exhibited skin discoloration and alopecia at doses ≥75 mg/kg/day starting around postnatal day 16.
• Lower body weight was noted in offspring at doses ≥100 mg/kg/day.
• Gestational transfer of HU occurred, but lactational transfer was minimal.
• Offspring internal exposure (AUC) was significantly lower than human therapeutic doses.

Conclusions:

• Prenatal and early postnatal HU exposure can cause developmental effects in offspring.
• Age influences offspring's internal HU dose, while sex does not.
• Current animal study exposures are not directly comparable to human therapeutic doses.
• Further research is needed to refine nonclinical study designs for evaluating long-term HU effects in pediatric sickle cell anemia.