Background: Optimal treatment ofpatients with moderate to severe hemophilia A (HA) entails prophylactic administration of factor VIII (FVIII) concentrate to prevent spontaneous bleeds. Population pharmacokinetic (PopPK)-based dosing is an effective way to ensure that FVIII plasma activity levels remain above a desired target. Currently, two PK-based dosing tools are available that can individualize FVIII prophylactic therapy with rAHF-PFM (Advate®). Objective:To compare the PK parameter outputs and dosing estimates of two PopPK-based dosing tools (i.e. Web Accessible Population Pharmacokinetics Service - Hemophilia (WAPPS) and myPKFiT) and to compare these outputs to a two-stage PK analysis. Methods:Infusion and post-infusion measurements were extracted from the WAPPS database. The same data were analysed using WAPPS v3.0, the Advate® model (2CO_2_V0, built by externally validating and updating the Bjorkmann published model), myPKFiT v2.0 (web-based Bayesian algorithm), and compartmental analysis in WinNonLin. For each case and for each approach, we reported: (1) success of fitting, (2) clearance (CL; dL/hr/kg), (3) volume at steady state (VdSS; dL/kg), (4) FVIII half-life (HL; hours), and (5) time to 0.01 above baseline IU/mL (hours). We also generated dosing estimates according to a 48-hour dosing schedule and a target trough of 0.03 IU/mL. A two-tailed t-test was used to assess for differences in dosing estimates. Data were anonymized as dictated by the WAPPS user DTA agreement. Results: 232 patients on Advate were found in the WAPPS database, of which 92 had post-infusion samples at 4 ± 2, 24 ± 4, and 48 ± 6 hours. Of the 42 cases dosed with 50 ± 5 IU/kg of FVIII, 29 allowed calculation of all required outcome measures and are reported here. Six patients were moderate. A comparison of the results for WAPPS and myPKFiT is shown in Table 1. The best-fit using a two-stage approach was a two-compartment model on 9 patients (CL 0.037, 0.026 - 0.043; HL 11.2, 11.1 - 14.4) and a one- compartment model on 16 patients (CL 0.019, 0.016-0.023; HL 9.9, 9.3 - 10.5). Dose estimates were produced for severe patients and were significantly lower for WAPPS as compared to myPKFIT; t(23) = -3.302, p=0.003. Conclusions:Differences in PopPK individual estimates between WAPPS and myPKFiT are on average small and non-directional. The lower dose estimates from WAPPS were similar to those determined using a NONMEM implementation of the Bjorkman et al 2012 model and similar patients [1939 IU (985-3824)] (van Moort et al. ISTH 207 Congress. ASY 27.3). Prospective studies are required to assess the clinical implications of adopting different PopPK solutions.

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Disclosures

Staibano: American Society of Hematology: Research Funding.

Topics:
albumins, factor viii, hemophilia a, plasma, infusion procedures, compartment models, half-life, international society of thrombosis and haemostasis, internet

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2017 by The American Society of Hematology
2017
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