The effect of unmeasurable endogenous plasma factor activity levels on factor VIII dosing in patients with severe hemophilia A

BACKGROUND: Patients with hemophilia A are defined as "severe" if they present <0.01 IU mL^-1 of clotting factor VIII (FVIII) activity endogenously (i.e. in absence of FVIII concentrate administration). However, an exact measurement of baseline FVIII is often impossible in such patients as the lower limit of quantification for most FVIII assays is around 0.01 IU mL^-1, forcing assumptions to be made regarding endogenous circulating level. OBJECTIVE: This work aims to assess the consequences of different assumptions when selecting a prophylaxis regimen for the treatment of hemophilia A using a pharmacokinetics (PK)-driven approach. METHODS: Using a validated population PK model for conventional FVIII, we simulated the dose and frequency required to maintain various target troughs as a function of different postulated baseline levels. RESULTS: Patients with a true baseline of 0 IU mL^-1 would require an additional 40 IU kg^-1 to achieve any target trough below 0.05 IU mL^-1, as compared to those with a true baseline close to 0.01 IU mL^-1. When tailoring individual treatment regimens using a PK-based approach, baseline assumptions were highly influential and the assumption producing the most conservative dosing regimen was not consistent; rather, it depended on the particular scenario (e.g. increase vs. decrease of an observed trough). CONCLUSIONS: Targeting a trough close to the assay sensitivity creates a unique problem in forecasting the dose needed for optimal treatment of hemophilia that, while still without solution, deserves consideration when making dosing decisions.