Pharmacokinetics of protein C and antithrombin in the fetal lamb: a model to predict human neonatal replacement dosing.
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((1/2))), 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((1/2)) 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((1/2)): 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((1/2)) in the fetal lamb. These data can be used to estimate dosing for human neonates in comparison with human adult dosing recommendations.
Manco-Johnson
Marilyn J
MJ
Mountain States Regional Hemophilia and Thrombosis Center, Aurora, CO 80045-0507, USA. marilyn.manco-johnson@uchsc.edu
Hacker
Michele R
MR
Jacobson
Linda J
LJ
Hay
William W
WW
D000818:Animals; D000991:Antithrombins / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020147:Coagulation Protein Disorders / Q000188:drug therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000378:metabolism*; D006801:Humans; D008297:Male; D023421:Models, Animal; D008954:Models, Biological; D011247:Pregnancy; D011486:Protein C / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012756:Sheep
D000991:Antithrombins; D011486:Protein C