Pharmacokinetic-Pharmacodynamic Comparison of Recombinant and Plasma-Derived von Willebrand Factor in Patients with von Willebrand Disease Type 3.

Background: Recombinant von Willebrand factor (rVWF, vonicog alfa, Vonvendi/Veyvondi, Takeda Pharmaceuticals USA, Lexington, MA) and several plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrates are available for treating bleeding episodes in patients with von Willebrand disease (VWD).

Purpose: To develop population pharmacokinetic (PK)/pharmacodynamic (PD) models that describe VWF:ristocetin cofactor (VWF:RCo) activity and its relationship with FVIII activity (FVIII:C) over time following intravenous administration of either rVWF or a pdVWF/FVIII concentrate (VWF:RCo/FVIII:C 2.4:1) in patients with VWD; to use the final PK/PD models for an in silico comparison of rVWF and pdVWF/FVIII.

Critical Remarks on Reference-Scaled Average Bioequivalence.

Purpose: More than a decade ago the option to assess highly variable drugs / drug products by reference-scaled average bioequivalence was introduced in regulatory practice. Recommended approaches differ between jurisdictions and may lead to different conclusions even for the same data set. According to our knowledge, implemented methods have not been directly compared for their operating characteristics (Type I Error and power).

Assessment of pharmacokinetic linearity after repeated drug administration.

The prediction of drug concentration time courses after different dosing scenarios is greatly facilitated if the pharmacokinetics (PK) can be assumed linear. The assumption of linear PK thus needs careful evaluation for any new drug in development. Under linear PK, exposure is proportional to dose (linear PK across doses) and exposure at steady state can be predicted from a single dose based on the superposition principle (linear PK over time).

Assessing goodness-of-fit for evaluation of dose-proportionality.

For the clinical development of a new drug, the determination of dose-proportionality is an essential part of the pharmacokinetic evaluations, which may provide early indications of non-linear pharmacokinetics and may help to identify sub-populations with divergent clearances. Prior to making any conclusions regarding dose-proportionality, the goodness-of-fit of the model must be assessed to evaluate the model performance. We propose the use of simulation-based visual predictive checks to improve the validity of dose-proportionality conclusions for complex designs.

Modeling to Predict Factor VIII Levels Associated with Zero Bleeds in Patients with Severe Hemophilia A Initiated on Tertiary Prophylaxis.

Background:  Factor VIII (FVIII) trough levels > 1 IU/dL in patients with severe hemophilia A receiving regular prophylaxis may optimize bleed protection.

Objectives:  In this post hoc analysis of patients receiving tertiary prophylaxis for approximately 1 year, the relationship between estimated FVIII levels and reported bleeds was investigated to predict the potential for zero bleeds.

Methods:  Sixty-three patients (median [range] age, 28 [7-59] years) with severe hemophilia A (229 bleeds) were included.