Hydroxyurea tolerability and toxicokinetics in rats
Researchers in the Division of the National Toxicology Program (DNTP) examined the long-term use of hydroxyurea (HU) therapy, the most effective strategy for managing sickle cell anemia, a genetic disorder of the blood. HU effectively increases healthy fetal hemoglobin production, but through a mechanism that is harmful to cells. The use of HU and its adverse side-effects are well-managed in adults. However, the U.S. Food and Drug Administration only recently approved HU for use in children and data is limited for understanding the impact the drug may have on child development.
The scientists conducted critical preliminary studies to identify appropriate doses for evaluating long-term effects. They assessed HU kinetics, or the movement of the chemical in the body, during critical periods of rodent development. HU was administered to pregnant rats from late gestation through lactation and to their offspring for 34 days after birth. Decreased body weight and adverse clinical observations, such as hair loss, appeared in offspring receiving at least 75 milligrams per kilogram per day. Data revealed gestational transfer of HU, but minimal lactational transfer. There was no difference in the half-life of HU between age and sex, but systemic exposure decreased with increasing age. (SM)
Citation: Huang MC, Turner KJ, Vallant M, Robinson VG, Lu Y, Price CJ, Fennell TR, Silinski MA, Waidyanatha S, Ryan KR, Black SR, Fernando RA, McIntyre BS. 2020. Tolerability and age-dependent toxicokinetics following perinatal hydroxyurea treatment in Sprague Dawley rats. J Appl Toxicol; doi:10.1002/jat.4087 [Online 25 November 2020].