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.

Multicentre pharmacokinetic evaluation of rFVIII‐Fc (efmoroctocog alfa) in a real life and comparison with non‐extended half‐life FVIII concentrates

“…This observation, not related to age, BMI or blood group, could be explained in part by slightly longer half-lives of BHK-derived rFVIII in comparison with CHO-derived rFVIII. 19,20 Some other limitations of our study have to be outlined. Firstly, a washout period was not systematic in our population, since threshold FVIII:C levels before injection were most frequently low (median 0.01 IU/mL; range 0.001-0.13 IU/mL).…”

Comparative pharmacokinetics of two extended half‐life FVIII concentrates (Eloctate and Adynovate) in adolescents with hemophilia A: Is there a difference?

“…Fortunately, recently developed population PK tools, such as WAPPS and MyPKFiT, have been shown to produce reliable estimates of PK parameters with significantly fewer blood samples and with no washout. Both of these programs use population PK models and Bayesian forecasting to determine the PK profiles of infused FVIII.…”

Population Pharmacokinetics of Clotting Factor Concentrates and Desmopressin in Hemophilia

“…It is important to correct the predicted factor levels using the residual or endogenous baseline levels, as doing not so will affect the estimation of the model parameters [77]. Not correcting for a residual pre-dose or baseline factor level may result in underestimation of Vd and/or overprediction of CL [78]. Therefore, the endogenous baseline factor level and the residual pre-dose factor level should be taken into account when a population PK model is constructed at least for patients with non-severe hemophilia.…”