Developmental changes in pharmacokinetics and pharmacodynamics of warfarin enantiomers in Japanese children.
OBJECTIVE
To clarify developmental changes in the pharmacokinetics and dynamics of warfarin enantiomers to establish rational pediatric dosage.


METHODS
Plasma concentrations of unbound warfarin enantiomers, vitamin K1 and vitamin K-dependent proteins (that is, prothrombin fragments 1+2, protein C, and the protein-induced by vitamin K absence) and international normalized ratio were measured in 38 prepubertal (1 to 11 years), 15 pubertal (12 to 18 years), and 81 adult (37 to 76 years) patients given long-term warfarin therapy. Unbound oral clearance values for warfarin enantiomers and its body weight-, body surface area-, and liver weight-normalized values, as well as the pharmacodynamic parameters, were compared among the groups.


RESULTS
The prepubertal, pubertal, and adult patients exhibited comparable mean plasma concentrations of unbound warfarin enantiomers for pharmacologically more active (S)-warfarin. Although the unbound oral clearance of (S)-warfarin for the prepubertal patients was significantly (P < .01) less than that for the adult group (346 versus 637 mL/min), the body weight-normalized unbound oral clearance for the prepubertal patients was significantly (P < .01) greater than that for the adults and showed a negative correlation (P < .05) with age. In contrast, no differences were observed in the liver weight-normalized unbound oral clearance for (S)-warfarin between the prepubertal and adult groups. The prepubertal patients showed significantly (P < .01 or .05) lower plasma concentrations of protein C and prothrombin fragments 1+2 and greater international normalized ratio and international normalized ratio/dose than the adults. In contrast, the pubertal patients showed largely similar pharmacokinetic and pharmacodynamic properties to adults.


CONCLUSIONS
Liver weight may be a better parameter than body weight for estimating the warfarin doses for prepubertal patients on the basis of the corresponding adult values. Augmented responses to warfarin in children should also be taken into account for estimating warfarin doses for children.
Takahashi
H
H
Department of Pharmacotherapy, Meiji Pharmaceutical University, Tokyo, Japan.
Ishikawa
S
S
Nomoto
S
S
Nishigaki
Y
Y
Ando
F
F
Kashima
T
T
Kimura
S
S
Kanamori
M
M
Echizen
H
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000097:blood / Q000378:metabolism*; D000925:Anticoagulants / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases; D002648:Child; D002675:Child, Preschool; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005260:Female; D006207:Half-Life; D006801:Humans; D007223:Infant; D007564:Japan; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D011516:Prothrombin / Q000378:metabolism; D013237:Stereoisomerism; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics; D014812:Vitamin K / Q000097:blood; D014859:Warfarin / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology
D000925:Anticoagulants; D014812:Vitamin K; D014859:Warfarin; D011516:Prothrombin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase