Cross-evaluation of Pharmacokinetic-Guided Dosing Tools for Factor VIII

Abstract

Background Patients with severe and moderate haemophilia A are treated prophylactically with factor VIII (FVIII) concentrate. Individualization of prophylaxis can be achieved by pharmacokinetic (PK)-guided dosing.

Aim In this study, the performance of three PK tools (myPKFiT, Web-Accessible Population Pharmacokinetic Service-Hemophilia [WAPPS] and NONMEM) is compared.

Methods In 39 patients, with severe or moderate haemophilia A, blood samples were collected 4, 24 and 48 hours after administration of 50 IU kg⁻¹ of recombinant FVIII (Advate [n = 30] or Kogenate [n = 9]). FVIII dose, FVIII activity and patient characteristics were entered into the three PK tools. Obtained PK parameters and dosing advises were compared.

Results myPKFiT provided PK parameters for 24 of 30 patients receiving Advate, whereas WAPPS and NONMEM provided estimates for all patients. Half-life was different among the three methods: medians were 12.6 hours (n = 24), 11.2 hours (n = 30) and 13.0 hours (n = 30) for myPKFiT, WAPPS and NONMEM (p < 0.001), respectively. To maintain a FVIII trough level of 0.01 IU mL⁻¹ after 48 hours, doses for myPKFiT and NONMEM were 15.1 and 11.0 IU kg⁻¹ (p < 0.01, n = 11) and for WAPPS and NONMEM were 9.0 and 8.0 IU kg⁻¹ (p < 0.01, n = 23), respectively. In nine patients receiving Kogenate, WAPPS and NONMEM produced different PK-parameter estimates; half-life was 15.0 and 12.3 hours and time to 0.05 IU mL⁻¹ was 69.2 and 60.8 hours, respectively (p < 0.01, n = 9). However, recommended doses to obtain these levels were not different.

Conclusion The three evaluated PK tools produced different PK parameters and doses for recombinant FVIII. Haematologists should be aware that recommended doses may be influenced by the choice of PK tool.

Keywords

Bayesian analysis - factor VIII - haemophilia A - pharmacokinetics - Patient-specific Modeling

Authors' Contribution

T.P. and R.A.A.M. performed data analysis and are the main authors of the article. I.V.M. enrolled patients and performed blood sampling for PK analysis. I.V.M. and T.P. performed data collection. M.H.C., F.W.G.L. and K.F. gave critical guidance during the project. All authors substantially contributed to the writing and critically revised the article, with approval of the final draft.

Both authors contributed equally to this article.

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