Comparative pharmacokinetics of plasma- and albumin-free recombinant factor VIII in children and adults: the influence of blood sampling schedule on observed age-related differences and implications for dose tailoring.
BACKGROUND
Dose tailoring of coagulation factors requires reliably estimated and reproducible pharmacokinetics (PK) in the individual patient.


OBJECTIVE
To investigate the contribution of both biological and methodological factors to the observed variability of factor VIII (FVIII) PK, with the focus on differences between children and adults, and to examine the implications for dosing.


METHODS
Data from 52 1-6-year-old and 100 10-65-year-old patients with hemophilia A (FVIII < or = 2 IU dL(-1)) in three clinical studies were included.


RESULTS
In vivo recovery was lower, weight-adjusted clearance was higher and FVIII half-life was on average shorter in children than in adults. However, a reduced blood sampling schedule for children was estimated to account for up to one half of the total observed differences. Intrapatient variance in PK was smaller than interpatient variance in 10-65-year-olds. Age and ratio of actual to ideal weight only showed weak relationships with PK parameters. Variance in PK caused large variance in the calculated dose required to maintain a target FVIII trough level during prophylactic treatment.


CONCLUSIONS
Differences in blood sampling schedules should be taken into account when results from different PK studies are compared. However, even with this consideration, PK cannot be predicted from observable patient characteristics but must be determined for the individual. Because the influence of reducing the blood sampling was minor in comparison to the true variance between patients, a reduced blood sampling protocol can be used. Low intrapatient variability supports the use of PK measurements for dose tailoring of FVIII.
Björkman
S
S
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. sven.bjorkman@farmbio.uu.se
Blanchette
V S
VS
Fischer
K
K
Oh
M
M
Spotts
G
G
Schroth
P
P
Fritsch
S
S
Patrone
L
L
Ewenstein
B M
BM
Collins
P W
PW
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D001827:Body Height; D015992:Body Mass Index; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003029:Coagulants / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D005169:Factor VIII / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006207:Half-Life; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D007223:Infant; D016014:Linear Models; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D016032:Randomized Controlled Trials as Topic; D055815:Young Adult
D003029:Coagulants; C078147:F8 protein, human; D005169:Factor VIII
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