Pharmacokinetic modelling and validation of the half‐life extension needed to reduce the burden of infusions compared with standard factor VIII. Issue 3 (6th May 2018)

• Record Type: Journal Article
• Authors: Hermans, C.; Mahlangu, J.; Booth, J.; Schütz, H.; Santagostino, E.; Young, G.; Lee, H.‐Y.; Steinitz‐Trost, K. N.; Blanchette, V.; Berntorp, E.
• Is Part Of: Haemophilia. Volume 24:Issue 3(2018)
• Page Start: 376
• Page End: 384
• Publication Date: 2018-05-06
• Subjects: administration and dosage -- factor VIII -- haemophilia A -- half‐life -- pharmacokinetics -- quality of life; Hemophilia -- Periodicals; 616.1572005
• DOI: 10.1111/hae.13483
• Languages: English
• ISSNs: 1351-8216

Abstract

Abstract : 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.