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

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.

Analysis of current perioperative management with Haemate® P/Humate P® in von Willebrand disease: Identifying the need for personalized treatment.

INTRODUCTION: Patients with Von Willebrand disease (VWD) are regularly treated with VWF-containing concentrates in case of acute bleeding, trauma and dental or surgical procedures. AIM: In this multicentre retrospective study, current perioperative management with a von Willebrand factor (VWF)/Factor VIII (FVIII) concentrate (Haemate® P) in patients with VWD was evaluated. PATIENTS/METHODS: Patients with VWD undergoing minor or major surgery between 2000 and 2015, requiring treatment with a VWF/FVIII concentrate (Haemate® P), were included. Achieved VWF activity (VWF:Act) and FVIII during FVIII-based treatment regimens were compared to predefined target levels in national guidelines. RESULTS: In total, 103 patients with VWD (148 surgeries) were included: 54 type 1 (73 surgeries), 43 type 2 (67 surgeries) and 6 type 3 (8 surgeries). Overall, treatment resulted in high VWF:Act and FVIII levels, defined as ≥0.20 IU/mL above predefined levels. In patients with type 1 VWD, respectively, 65% and 91% of trough VWF:Act and FVIII levels were higher than target levels. In patients with type 2 and type 3 VWD, respectively, 53% and 57% of trough VWF:Act and 72% and 73% of trough FVIII levels were higher than target level. Furthermore, FVIII accumulation over time was observed, while VWF:Act showed a declining trend, leading to significantly higher levels of FVIII than VWF:Act. CONCLUSION: High VWF:Act and accumulation of FVIII were observed after perioperative FVIII-based replacement therapy in patients with VWD, both underlining the necessity of personalization of dosing regimens to optimize perioperative treatment.

Setting the stage for individualized therapy in hemophilia: What role can pharmacokinetics play?

Replacement therapy with clotting factor concentrates (CFC) is the mainstay of treatment in hemophilia. Its widespread application has led to a dramatic decrease in morbidity and mortality in patients, with concomitant improvement of quality of life. However, dosing is challenging and costs are high. This review discusses benefits and limitations of pharmacokinetic (PK)-guided dosing of replacement therapy as an alternative for current dosing regimens. Dosing of CFC is now primarily based on body weight and based on its in vivo recovery (IVR). Benefits of PK-guided dosing include individualization of treatment with better targeting, more flexible blood sampling, increased insight into association of coagulation factor levels and bleeding, and potential overall lowering of overall costs. Limitations include a slight burden for the patient, and availability of closely collaborating, experienced clinical pharmacologists.