Pharmacokinetics of Concentrates for the Treatment of von Willebrand’s Disease
Von Willebrand's disease (vWD) is characterized by a deficiency or reduced functional capacity of von Willebrand factor (vWF) and, in more severe cases, by a deficiency of coagulation factor VIII (FVIII). Treatment usually requires repeated infusions of vWF and FVIII concentrate, with available products having different factor ratios. Repeated infusions of concentrates can lead to different FVIII exposures when using different products. The pharmacokinetics of two products with varying vWF and FVIII ratios have been compared in experimental preclinical and clinical studies.
Experimental Studies
A study conducted in rabbits evaluated the trough and peak FVIII concentrations and other pharmacokinetic parameters with repeated administration of concentrates with higher and lower vWF to FVIII ratios.1 The animals were randomized to receive repeated infusions of concentrates with high or low vWF/FVIII ratios at 4-hour intervals at a dose corresponding to 150 IU/kg ( potency determined by ristocetin cofactor activity − vWF:RCo). The trough plasma levels of FVIII and vWF were measured after each infusion. The mean trough FVIII concentration after the first infusion of the low vWF/FVIII ratio concentrate was 50.6 IU/dL compared to 31.8 IU/dL for the high vWF/FVIII ratio concentrate (p < 0.001). The trough FVIII levels progressively increased after subsequent infusions in both groups. After the final infusion, the trough FVIII level was significantly higher with the low vWF/FVIII ratio concentrate (167 IU/dL) compared to the high vWF/FVIII ratio concentrate (100 IU/dL; p = 0.002). The mean cumulative FVIII exposure measured as the area under the plasma concentration curve was 84% higher in animals with the low vWF/FVIII ratio concentrate. The biological half-life did not differ between the products.
A similar experimental study compared these two concentrates in mice.2 Mice with a vWF deficiency received repeated infusions of concentrates with different vWF/FVIII ratios at a dose of 150 IU/kg vWF:RCo at 3-hour intervals. The trough levels of vWF and FVIII were determined after each infusion. After the first infusion, the mean trough FVIII level was 82% higher with the low vWF/FVIII ratio concentrate (31.7 IU/dL) compared to the high ratio concentrate (17.4 IU/dL; p = 0.017). The trough FVIII levels significantly increased after subsequent infusions with the low vWF/FVIII ratio concentrate (p < 0.001), but not in animals receiving the high ratio concentrate (p = 0.058). After the final infusion, the trough FVIII level in the low vWF/FVIII ratio group reached 55.1 IU/dL compared to 30.2 IU/dL in the high ratio group (p < 0.001). The trough level of vWF did not differ between the groups.
These animal studies suggest that excessive FVIII exposure can be avoided by using concentrates with a high vWF to FVIII ratio.1, 2
Clinical Study
A prospective randomized crossover study compared the pharmacokinetics of both concentrates in humans.3 Twenty-two patients with congenital von Willebrand disease were included. The patients were randomized to receive a single i.v. dose of concentrate with either a high or low vWF/FVIII ratio at a dose corresponding to 40 IU/kg vWF:RCo. After a 7-day washout phase, the same patients received the second concentrate. A series of tests were performed after each administration to determine the levels of coagulation factors. The pharmacokinetics were assessable in 20 patients.
The results showed comparable terminal biological half-lives and vWF level adjustments measured by vWF:RCo after administration. After administering the low vWF/FVIII ratio concentrate, the clotting activities of vWF:RCo and FVIII decreased in parallel over time after peaking, whereas with the high vWF/FVIII ratio concentrate, the peak FVIII activity was lower, and it exhibited a plateau during the first 24 hours before it started to decline. The authors concluded that the pharmacokinetic profile of the low vWF/FVIII ratio concentrate (1:1) might facilitate dosing and laboratory monitoring of patients undergoing this replacement therapy.
Conclusion
These studies provide insights into some aspects of replacement therapy for von Willebrand's disease arising from the pharmacokinetics of products with different vWF/FVIII ratios.
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Sources:
1. Raquet E., Stockschläder M., Dickneite G. Repeated infusions of VWF/FVIII concentrate: impact of VWF:FVIII ratio on FVIII trough and peak levels in a rabbit model. Haemophilia 2011; 17 (5): 808−814, doi: 10.1111/j.1365-2516.2011.02603.x.
2. Raquet E., Stockschlaeder M., Mueller-Cohrs J. et al. Utility of a high VWF: FVIII ratio in preventing FVIII accumulation: a study in VWF-deficient mice. Blood Coagul Fibrinolysis 2015; 26(5): 515−521, doi: 10.1097/MBC.0000000000000269.
3. Kessler C. M., Friedman K., Schwartz B. A. et al.; Wilate PK Study Investigators. The pharmacokinetic diversity of two von Willebrand factor (VWF)/factor VIII (FVIII) concentrates in subjects with congenital von Willebrand disease. Results from a prospective, randomised crossover study. Thromb Haemost 2011; 106 (2): 279−288, doi: 10.1160/TH11-02-0057.
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