Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight

Abstract

Comparison of the pharmacokinetics (PK) of a coagulation factor between groups of patients can be biased by differences in study protocols, in particular between blood sampling schedules. This could affect clinical dose tailoring, especially in children. The aim of this study was to describe the relationships of the PK of factor VIII (FVIII) with age and body weight by a population PK model. The potential to reduce blood sampling was also explored. A model was built for FVIII PK from 236 infusions of recombinant FVIII in 152 patients (1-65 years of age) with severe hemophilia A. The PK of FVIII over the entire age range was well described by a 2-compartment model and a previously reported problem, resulting from differences in blood sampling, to compare findings from children and adults was practically abolished. The decline in FVIII clearance and increase in half-life with age could be described as continuous functions. Retrospective reduction of blood sampling from 11 to 5 samples made no important difference to the estimates of PK parameters. The obtained findings can be used as a basis for PKbased dose tailoring of FVIII in clinical practice, in all age groups, with minimal blood sampling. (Blood. 2012;119(2): 612-618)

Recombinant full‐length factor VIII (FVIII) and extended half‐life FVIII products in prophylaxis – new insight provided by pharmacokinetic modelling

“…They have been built independently and separately and are characterized by different covariates. The structural PopPK models for rAHF-PFM [15] and rFVIIIFc [16] are two-compartmental models with the primary PK parameters being clearance (CL), volumes of distribution of the central and peripheral compartment (V 1 , V 2 ), and intercompartmental clearance (Q). The model for rAHF-PFM uses body weight and age as covariates on clearance and body weight as covariate on V 1 and V 2 .…”

A population pharmacokinetic model for perioperative dosing of factor VIII in hemophilia A patients

“…9 In the prophylactic setting, Carlsson et al have shown that FVIII consumption can be significantly reduced by application of pharmacokinetic (PK) modeling to individualize dosing regimens. [11][12][13][14] In the perioperative setting, Longo et al have reported excessive FVIII consumption and clearance in 50% of surgical hemophilia patients due to unidentified factors. 15 This suggests mechanisms of increased clearance due to hemostatic challenges during surgery.…”

Response to Gringeri et al.: ‘recombinant full‐length factor VIII (FVIII) and extended half‐life FVIII products in prophylaxis – new insight provided by pharmacokinetic modelling’

“…In the recent article by Gringeri et al [1] entitled 'Recombinant full-length factor VIII (FVIII) and extended half-life FVIII products in prophylaxis -new insight provided by pharmacokinetic modelling', the authors present data from simulations based on independent population pharmacokinetic models for rAHF-PFM [2], a third-generation standard half-life recombinant FVIII (rFVIII) therapy, and rFVIII Fc fusion protein (rFVIIIFc) [3], a prolonged half-life rFVIII. These simulations predict that dosing patients with an extended half-life FVIII product at 1.5-fold longer intervals compared with a standard half-life FVIII product (i.e.…”

“…The clinical data for rFVIIIFc clearly demonstrate that patients treated prophylactically with rFVIIIFc can achieve low bleeding rates with fewer infusions. Combined factor V (FV) and FVIII deficiency (F5F8D), characterized with simultaneous decreases of FV and FVIII activity to 5-30% of normal plasma [1], generally has spontaneous bleeding and excessive bleeding after trauma or surgery [2,3]. F5F8D is a rare bleeding disease first reported in 1954 [4].…”