Pharmacokinetic and pharmacodynamic modeling of humanized anti-factor IX antibody (SB 249417) in humans.
BACKGROUND
SB 249417 is a humanized anti-factor IX/IXa antibody that, on administration to rats and monkeys, produces an immediate suppression of factor IX activity and prolongation of activated partial thromboplastin times (aPTT).


OBJECTIVE
Our objective was to establish the pharmacokinetics of SB 249417 and to explore its effects on factor IX activity levels and aPTT in humans.


METHODS
In this phase I, single-blind, randomized, placebo-controlled, parallel-group, single intravenous infusion study, individual and mean data from a total of 26 healthy volunteers at 5 dosing levels were analyzed. A 2-compartment pharmacokinetic model was used in the analysis of total SB 249417 concentration-time profiles. A modified indirect-response model was used, with the total concentration indirectly serving as the driving force for the suppression of free factor IX concentration (as assessed by factor IX activity). The aPTT was related to factor IX activity with a biexponential equation, and a population approach was used to generate posterior parameter estimates for the individual fittings.


RESULTS
Mean parameter estimates from individual fittings are 0.092 L/kg for volume of distribution, 0.15 L/kg for steady-state volume of distribution, and 0.0021 L/kg per hour for systemic clearance. The model described well the factor IX activity and aPTT time course in response to SB 249417 at 5 dose levels. The estimated half-life of factor IX in blood was 21 hours.


CONCLUSIONS
This model was stable and robust in fitting both mean and individual data. Endogenous factor IX baseline levels and dose were the major determinants of the decline in factor IX activity during the infusion period. Thereafter the recovery of factor IX activity was governed solely by the endogenous factor IX turnover rate.
Chow
Fung-Sing
FS
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA, USA. vincent_fung-sing_chow@groton.pfizer.com
Benincosa
Lisa J
LJ
Sheth
Sunita B
SB
Wilson
Douglas
D
Davis
Charles B
CB
Minthorn
Elisabeth A
EA
Jusko
William J
WJ
D000328:Adult; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001666:Binding Sites, Antibody; D004306:Dose-Response Relationship, Immunologic; D005164:Factor IX / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D008954:Models, Biological; D008956:Models, Chemical; D010314:Partial Thromboplastin Time; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D016037:Single-Blind Method
D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins; C447080:SB 249417; D005164:Factor IX