title: In vitro studies, pharmacokinetic studies and clinical use of a high purity double virus inactivated FVIII/VWF concentrate (Immunate) in the treatment of von Willebrand disease.
abstract: Patients with type 2 and 3 von Willebrand disease (VWD) are treated with factor VIII/VWF concentrate in case of bleeding or surgery. Immunate (Baxter, Vienna, Austria) is a double virus inactivated FVIII/VWF concentrate and is registered in several countries for patients with VWD with reduced FVIII levels. We performed an in vitro, a pharmacokinetic and a clinical study to evaluate Immunate in VWD. In vitro studies showed a significant variation in VWF levels in 9 different batches. The median (range) values (in IU/mL) were 1.10 (0.98-1.30) for FVIII:C, 1.34 (0.95-1.61) for VWF:Ag, 0.60 (0.27-1.08) for VWF:CBA and 0.73 (0.59-0.94) for VWF:RCo. The relatively low VWF activity is mainly due to the lack of high molecular weight multimers (HMWM), as determined by electrophoresis. A pharmacokinetic study showed, based on a content of FVIII:C of 1 U/mL, in vivo recoveries (%) of 106 (56-150) (median and range) for FVIII:C, 105 (62-187) for VWF:Ag, 25 (7-41) for VWF:CBA and 43 (11-76) for VWF:RCo. Half-lives were 14.1 h (7.4-36.9) for FVIII:C, 10.8 h (7.7-26.2) for VWF:Ag, 15.3 h (7.8-44.6) for VWF:CBA and 16.4 h (4.2-26.5) for VWF:RCo. In a clinical study efficacy was determined after infusion given before surgery or dental extractions in ten patients. In two patients the hemostatic response was classified as inadequate. In conclusion, there is a wide variability in VWF concentration and activity in various batches of Immunate. In the clinical study in which the dosage was based on FVIII:C contents of the concentrate, two out of ten patients had an insufficient haemostatic response. Therefore dosing of Immunate dosing should not be based on FVIII:C levels, but should be based on VWF activity of the individual batches. Future studies using a VWF activity-guided dosage regimen have to be performed to establish the efficacy of Immunate in the treatment of von Willebrand disease.
authors.affiliation: Department of Haematology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
authors.forename: Kristien M M
authors.initials: KM
authors.lastname: Ver Elst
authors.forename: Huub D M
authors.initials: HD
authors.lastname: van Vliet
authors.forename: Mies C
authors.initials: MC
authors.lastname: Kappers-Klunne
authors.forename: Frank W G
authors.initials: FW
authors.lastname: Leebeek
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004340:Drug Contamination; D005169:Factor VIII / Q000008:administration & dosage / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D011300:Preoperative Care; D012449:Safety; D014842:von Willebrand Diseases / Q000097:blood / Q000145:classification / Q000188:drug therapy*; D014841:von Willebrand Factor / Q000008:administration & dosage / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D014841:von Willebrand Factor; D005169:Factor VIII