A Real-World Population Pharmacokinetic (PK) Study of Two Recombinant Factor VIII (rFVIII) Concentrates in Boys with Severe Hemophilia a without Inhibitors

Introduction To personalize long-term prophylaxis in boys with hemophilia A with a severe bleeding phenotype, the individual's pharmacokinetic (PK) profile must be established. Traditional FVIII PK assessment has required a 2-3-day washout, which can place boys at risk of bleeding, and up to 11 post-infusion blood samples collected over a 48h period (Lee et al., ISTH guidelines, 2001). Population PK models with Bayesian forecasting are currently available that permit the use of a no-washout PK protocol with sparse sampling, which is clinically practical and less demanding for patients and their families. Our previous experience with a no-washout, single-clinic visit, reverse 2-sampling time point (24 and 3h) PK protocol established that this practical, patient-friendly PK protocol was sufficiently accurate for generating clinically useful individual PK profiles in patients receiving a standard half-life (SHL) FVIII concentrate [antihemophilic factor (recombinant) plasma/albumin-free method (Advate®)] for long-term prophylaxis (Blanchette et al., Thromb Haemost, 2021).

Aim To determine the accuracy of a clinically practical single-clinic visit, reverse 2-sampling time point population PK protocol for generating individual PK profiles [clearance (Cl) and terminal half-life (t1/2)] in boys with severe hemophilia A without inhibitors receiving either an SHL [antihemophilic factor (recombinant) BAY 81-8973 (Kovaltry®)] or an extended half-life (EHL) FVIII concentrate [antihemophilic factor (recombinant) PEGylated BAY 94-9027 (Jivi®)] for long-term prophylaxis.

Methods In this multicenter observational study, participants had their first infusion given at home. Of a total of 14 boys with hemophilia A without inhibitors receiving long-term prophylaxis, 5 receiving a SHL completed a single clinic visit, reverse 2-point (24 and 3h) and a multiple clinic visit 6-point (baseline, 1, 3, 8, 24 and 48h) PK sampling protocol; and 4 boys completed a SHL single clinic visit reverse 2-point (48 and 3h) and a 2 clinic visit reverse 3-point (48, 3 and 24h) PK sampling protocol. 5 boys receiving EHL completed single clinic visit, reverse 2-point (72 and 3h) and 2-clinic visit 3-point (72, 3 and 48h) PK sampling protocols and they had multiple spot samplings (n=12) at various post-infusion times to evaluate the precision of their predicted PK profiles based on their 2-point PK sampling protocol.

One-stage (OS) and chromogenic (CHR) FVIII:C and von Willebrand factor antigen (VWF:Ag) assays were performed in a central reference coagulation laboratory in Kingston, Ontario. PK parameters (Cl and t1/2) were estimated using the WAPPS-Hemo population PK program. The median of the % difference between the 2-sampling time point PK protocol compared to the 6- and 3- sampling time point PK protocols is reported.

Results 14 boys with hemophilia A (FVIII:C <2%; median age: 14.5 yrs, range: 5-19 yrs) participated in the study. The 2-point PK protocol for both SHL and EHL showed a higher Cl and lower t1/2 when compared to either a 6-sampling time point (for SHL) or a 3-sampling time point (for either SHL or EHL) PK assessment (Table 1). The difference was greatest for the 2-point (24 and 3h) vs the 6-point (Table 1). In the case of the 2-point (48 and 3h for SHL and 72 and 3h for EHL) vs 3-point (an additional 24h time point for SHL and 48h for EHL) PK parameter estimates, the 2-point protocol gave values that were all within 6% of those obtained with the 3-sampling time point PK (Table 1). The OS and CHR assays gave similar estimations for Cl and t1/2 with the exception of t1/2 when comparing the 6-point to the 2-point PK protocol (Table 1). Evaluation of the 2-sampling time point PK protocol through spot sampling showed approximately 66% and 81% of FVIII:C values falling within the 95% prediction limits for the OS and CHR assays, respectively (n=12 for EHL OS; n=11 for EHL CHR). There was a strong association between the observed FVIII:C levels from the spot sampling and their predicted values from the 2-point PK for EHL (R²=94% and 71% for the OS and CHR assays, respectively) (Fig. 1).

Conclusion The reverse 2-point, single clinic visit, PK protocol (24/48 or 72h and 3h) is a practical approach to generate PK parameters that provide clinically useful information for guiding personalized prophylaxis regimens for boys receiving SHL or EHL for long-term prophylaxis.

Funding Supported by Bayer (Investigator-Initiated Research grant)

Edginton:Novo Nordisk: Research Funding; GC Biopharma: Research Funding; Grifols: Research Funding. Stoffman:Hoffman La Roche: Other: Consulting Honorarium; Bayer: Other: Consulting Honorarium. Blanchette:Novo Nordisk: Research Funding; GC Biopharma: Research Funding; Grifols: Research Funding.