title: Pharmacokinetics of recombinant human antithrombin in delivery and surgery patients with hereditary antithrombin deficiency.
abstract: 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.
authors: 1LAP&P Consultants BV, Leiden, the Netherlands.
authors: Joost
authors: J
authors: DeJongh
authors: Johan
authors: J
authors: Frieling
authors: Simon
authors: S
authors: Lowry
authors: Henk-Jan
authors: HJ
authors: Drenth
mesh_terms: D020152:Antithrombin III Deficiency / Q000188:drug therapy / Q000378:metabolism* / Q000601:surgery; D000991:Antithrombins / Q000493:pharmacokinetics*; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D011994:Recombinant Proteins / Q000493:pharmacokinetics
chemical_list: D000991:Antithrombins; D011994:Recombinant Proteins
keywords: dosing; model validation; population pharmacokinetics; recombinant antithrombin