Journal
CLINICAL AND APPLIED THROMBOSIS-HEMOSTASIS
Volume 20, Issue 4, Pages 355-364Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/1076029613516188
Keywords
recombinant antithrombin; population pharmacokinetics; dosing; model validation
Categories
Funding
- rEVO Biologics
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Population pharmacokinetic (PK) analyses were conducted to refine dosing recommendations for recombinant human anti-thrombin therapy in surgery and delivery patients with hereditary antithrombin deficiency (HD). Single-dose PK data from patients with HD and nonlinear mixed-effects modeling were used to devise a dosing regimen to target antithrombin (AT) activity levels between 80% and 120% of normal. External validation with data from a phase 3 trial confirmed the correctness of a covariate-free model for surgery patients, but dosing adjustment was necessary for delivery patients. After different covariates were tested, the model was updated to incorporate the influential covariate, delivery. Simulations were used to develop a therapeutic drug-monitoring scenario that results in steady state AT activity levels within the target range as quickly as practically feasible. Data from a second clinical trial provided additional external validation and confirmed the accuracy of the dosing model for both groups of patients.
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