title: Presurgical pharmacokinetic analysis of a von Willebrand factor/factor VIII (VWF/FVIII) concentrate in patients with von Willebrand's disease (VWD) has limited value in dosing for surgery.
abstract: Optimal doses of von Willebrand Factor/Factor VIII (VWF/FVIII) concentrates for surgical procedures in patients with VWD need to be determined. A prospective, multicenter study was performed that included an initial pharmacokinetic (PK) assessment following a standard dose of VWF/FVIII concentrate (Humate-P®) to determine individual PK parameters and guide therapeutic dosing during surgery. Forty one subjects received 60 IU kg⁻¹ VWF: RCo. Median plasma levels, half-life, mean change from baseline and in vivo recovery (IVR) values were determined for VWF:RCo, VWF:Ag, and FVIII: C, and area under the plasma time-concentration curve (AUC), mean residence time (MRT), clearance, volume of distribution and dose linearity were also assessed for VWF:RCo at various time points. Median baseline VWF:RCo level was 13 IU dL⁻¹ (range, 6-124); with a mean change from baseline >100 IU dL⁻¹ immediately after the infusion, decreasing to 10 IU dL⁻¹ at 48 h postinfusion. The group median incremental in vivo recovery (IVR) for VWF:RCo was 2.4 IU dL⁻¹ per IU kg⁻¹, for VWF:Ag 2.3 IU dL⁻¹ kg⁻¹ and for FVIII:C was 2.7 IU dL⁻¹ per IU kg⁻¹. When analysing individual recovery values on repeated infusions, a very weak correlation was observed between presurgery IVR and IVR for both VWF:RCo and FVIII, measured at various times just prior to and after the surgical procedure. Although group median values were fairly consistent among repeated IVR measurements, the intra-individual IVR values for FVIII and VWF:RCo with repeated infusions showed a large degree of variability. IVR values obtained from pharmacokinetic analyses performed in advance of anticipated surgery do not reliably predict postinfusion circulating levels of VWF:RCo or FVIII attained preoperatively or with subsequent peri-operative infusions.
authors.affiliation: University of Colorado Denver, Aurora, CO, USA. jorge.dipaola@ucdenver.edu
authors.forename: J
authors.initials: J
authors.lastname: Di Paola
authors.forename: S
authors.initials: S
authors.lastname: Lethagen
authors.forename: J
authors.initials: J
authors.lastname: Gill
authors.forename: P
authors.initials: P
authors.lastname: Mannucci
authors.forename: M
authors.initials: M
authors.lastname: Manco-Johnson
authors.forename: J
authors.initials: J
authors.lastname: Bernstein
authors.forename: W L
authors.initials: WL
authors.lastname: Nichols
authors.forename: G E
authors.initials: GE
authors.lastname: Bergman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D003029:Coagulants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004359:Drug Therapy, Combination; D005169:Factor VIII / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006488:Hemostasis, Surgical; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D011300:Preoperative Care; D011446:Prospective Studies; D055815:Young Adult; D014842:von Willebrand Diseases / Q000188:drug therapy* / Q000601:surgery
chemical_list: D003029:Coagulants; C078147:F8 protein, human; D005169:Factor VIII