Pharmacokinetics of Protein C and Antithrombin in the Fetal Lamb: A Model to Predict Human Neonatal Replacement Dosing

Abstract

Background: The preterm infant is at risk for consumptive coagulopathy and thrombosis due to late maturation of coagulation regulatory proteins. Replacement proteins are available, but neonatal pharmacokinetic data are lacking. Objective: The objective was to determine the pharmacokinetic properties of antithrombin (AT) and protein C (PC) in order to provide data for estimating doses in human infants. Methods: A catheterized ovine model was used to determine pharmacokinetic properties of AT and PC, including plasma recovery, volume of distribution (V_d), clearance (Cl) and half-life (t_½), in the fetal lamb relative to the ewe. Results: AT studies showed statistically significant differences between ewes and fetuses in recovery (p < 0.0001), V_d (p = 0.0002) and Cl (p < 0.0001). The AT t_½ was significantly shortened among fetuses (5.55 h, 95% CI: 4.01–7.08) compared to ewes (18.7 h, 95% CI: 11.6–25.8). PC recovery (p < 0.0001), V_d (p < 0.0001) and Cl (p = 0.004) differed significantly between ewes and singleton fetuses as did the t_½: 3.86 h (95% CI: 3.35–4.36) and 11.9 h (95% CI: 10.9–12.9) in the singletons and ewes, respectively. All PC parameters were significantly different for twins compared to ewes. Conclusions: AT and PC show decreased recovery and t_½ in the fetal lamb. These data can be used to estimate dosing for human neonates in comparison with human adult dosing recommendations.

Hemostasis in the Pregnant Woman, the Placenta, the Fetus, and the Newborn Infant

“…78 Pharmacokinetic studies of ovine antithrombin and protein C showed increased volume of distribution and shortened half-life of both proteins in the fetal lamb compared with the ewe indicating more rapid turnover. 79 Thus, the neonatal hemostasis system exhibits differential effects of regulation of expression, protein kinetics, and impact of maternal conditions.…”