Abstract
The VWF/FVIII concentrate Humate-Pâ (ZLB Behring) was studied in a prospective, uncontrolled, open-label clinical trial in adult and pediatric von Willebrand disease (VWD) patients undergoing elective surgery. During an initial PK phase, a detailed profile of FVIII: C, VWF: RCo, and VWF: Ag levels was obtained for each patient after an infusion of 60 IU/kg VWF: RCo/kg body weight as Humate-P, to guide loading dosing intra- and postoperatively. Forty-one subjects were evaluated for the pharmacokinetic assessment: the median age was 31 years (range 16 to 47 years); 66.7% of subjects were female; 17 had Type 1 VWD, 2 had Type 2A, 4 had Type 2B, 6 had Type 2M, and 13 had Type 3. In the 34 subjects who underwent surgery, the primary endpoint of effective hemostasis (investigator-rated assessment as excellent or good) was achieved in 100% (34/34) of subjects 24 hours after the last infusion. The VWF: RCo PK revealed a median incremental in vivo recovery (IVR) of 2.4% per IU/kg over baseline (range, 1.1% – 4.2%), and an overall median IVR response of 86.7% over baseline (range, 37% – 169%). Median value of Cmax was 159 IU/dL (range 84–334). Median terminal half-life of VWF: RCo was 11.2 hours (range 3.5 to 74.9), median clearance 3.1 ml/kg/h (range, 1.0 to 16.6). The FVIII: C PK revealed a median incremental of 2.7% per IU/kg. A median response of 95.5% (range, 44% – 176%) was achieved 15 minutes after the PK infusion, with values remaining >90% until 4 hours post infusion. At 48 hours post infusion, median levels had decreased to 68% over baseline (range, 17% – 122%). An analysis of the relationship between IVR and dose administered demonstrated the dose linearity of the VWF concentrate within a wide dose range (10–135 IU VWF: RCo/kg b. w.). Using the log-transformed IVR in a repeated measures ANCOVA model, the slope (of log10 IVR vs. dose) was −0.0025 (95% confidence interval: −0.0053 to 0.0004).
Conclusion: The PK results are comparable to PK data from other clinical studies with Humate-Pâ as well as PK data from other VWF-containing products. Dose linearity has been shown over a wide range of dosages. The inter-individual variability observed underlines the importance of performing PK assessments, to guide dosing, prior to surgical interventions.
IVR of all VWF-RCo doses (kg/dL), linear regression with 95% CI of mean
Disclosures: Drs. Knaub and Friedman are employees of ZLB Behring.; Dr. Di Paola has consulted for ZLB Behring; Dr. Leissinger has consulted with ZLB Behring.; The trial was supported by ZLB Behring.
