Pharmacokinetic modelling and validation of the half‐life extension needed to reduce the burden of infusions compared with standard factor VIII

Introduction Currently, no universally accepted definition of extended half‐life ( EHL ) recombinant FVIII ( rFVIII ) exists. Identifying the minimum half‐life extension ratio required for a reduction in dosing frequency compared with standard rFVIII could enable a more practical approach to decisions around prophylaxis with EHL rFVIII . Aim To identify the half‐life extension ratio required to decrease rFVIII dosing frequency by at least 1 day while maintaining the proportion of patients with plasma rFVIII levels above 1 IU / dL and without increasing the total weekly dose. Methods A previously published population pharmacokinetic model for standard rFVIII was used to estimate the percentage of patients with factor VIII ( FVIII ) levels always >1 IU / dL using various benchmark regimens. Using modelling, dosing frequency was reduced while rFVIII half‐life was extended until the percentage of patients with FVIII >1 IU / dL equalled that of the benchmark regimen. Results Benchmark 3×/wk dosing totalling 100 IU /kg/wk of rFVIII resulted in 56.6% of patients with FVIII levels always >1 IU / dL . With 2×/wk dosing, totalling 80 or 90 IU /kg/wk, half‐life extensions required to maintain 56.6% of patients at FVIII levels >1 IU / dL were 1.30 and 1.26, respectively. A half‐life extension ratio of 1.33 was required to change dosing from every 48 hours to every 72 hours (both at 105 IU /kg/wk) while maintaining 92.8% of patients with FVIII >1 IU / dL . Conclusion Based on this investigation, EHL rFVIII products should have a minimum half‐life extension ratio of 1.3 to provide a reduction in dosing frequency from 3× to 2×/wk compared with standard rFVIII products while maintaining the same minimum FVIII trough level.