Comparison of Pharmacokinetic Properties of Two VWF/FVIII Concentrates In Subjects with Inherited Von Willebrand Disease (VWD)- Results of a Prospective, Randomized, Crossover Study.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3672-3672 ◽  
Author(s):  
Craig M. Kessler ◽  
Jerry Powell ◽  
Bruce A. Schwartz
Keyword(s):  
Study Drug ◽  
Von Willebrand Disease ◽  
Multiple Time ◽  
Active Components ◽  
Open Label ◽  
Fviii Activity ◽  
Multiple Time Points ◽  
Type 3 ◽  
Von Willebrand

Abstract Abstract 3672 Objective: Understanding pharmacokinetic (PK) profiles of von Willebrand Factor (VWF)/Factor VIII (FVIII) concentrates is important in the treatment of VWD. This prospective, randomized, open-label, crossover trial investigated the PK characteristics of two plasma-derived (pd) VWF/FVIII concentrates (Wilate® [high-purity (HP)] and Humate-P® [intermediate-purity (IP)]) in subjects with inherited VWD. Methods: After a wash-out period, twenty-two subjects (Type 1, n=6; Type 2, n=9 [6 Type 2A, 1 Type 2B, and 2 Type 2M]; and Type 3, n=7) were randomized in a prospective, controlled, open-labeled, 2-arm crossover, to receive 40 IU VWF:RCo/kg of Wilate® or Humate-P® followed by another washout period and administration of the other study drug. Blood samples were taken at multiple time-points over 72hrs for PK evaluations. Results: A non compartmental statistical model was used to analyze the data. The mean VWF:RCo half-life for Type-3 subjects was similar for the HP product (9.1 hours [±2.6]) and IP product (10.2 hours [±2.1]. For all study participants there were no significant differences in incremental in-vivo recoveries (≂f2.0 IU VWF:RCo/dL per IU/kg), or in clearance. Bioequivalence between the two products was shown for the main VWF PK parameters. The decay-curves for VWF:RCo and FVIII:C in the HP product showed a parallel decay, while the IP product did not and showed an unusually sustained FVIII plateau over the initial decay time period. The data showed an almost a 2 fold decrease in clearance between the two products. The chromogenic FVIII:C terminal half live for the two products were similar (16.1hrs [SD=3.1] HP product and 20.5 hrs [SD=7.6] IP product), although the average half lives were quite different (13 hrs [SD=4.1] HP product and 37.7 hrs [SD=6.4] IP product). This was in spite of the much higher initial FVIII concentration profile of the 1:1 VWF/FVIII HP product. The 2.4:1 VWF/FVIII IP product showed an expected lower mean FVIII:C peak value due to the excess of VWF:RCo activity in the product that was based on VWF:RCo unit dosing, but similar both products had a similar dose adjusted IVR. Conclusions: This study confirms the similarity of the VWF PK properties of the two licensed VWF products. However, the analysis of FVIII activity, in the two products revealed some differences in their PK profiles. With the similar PK-properties for VWF:RCo and FVIII:C, Wilate showed a more parallel course for the two active components. A more predictable PK profile for both VWF and FVIII in a product may facilitate both more accurate dosing and laboratory monitoring of VWF replacement in VWD treatment. A parallel PK profile together with an equal ratio for FVIII and VWF activities may help avoid over or under dosing of either of the two critical coagulation parameters. Disclosures: Kessler: Grifols S.A.: Research Funding. Schwartz:Octapharma: Employment.

The pharmacokinetic diversity of two von Willebrand factor (VWF)/ factor VIII (FVIII) concentrates in subjects with congenital von Willebrand disease

2011 ◽  
Vol 106 (08) ◽  
pp. 279-288 ◽  
Author(s):  
Craig M. Kessler ◽  
Friedman Ken ◽  
Bruce A. Schwartz ◽  
Joan C. Gill ◽  
Jerry S. Powell ◽  
...  
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Coagulation Factor ◽  
Study Drug ◽  
Von Willebrand Disease ◽  
Multiple Time ◽  
Multiple Time Points ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryThe pharmacokinetic (PK) profiles of von Willebrand factor (VWF) /factor VIII (FVIII) concentrates are important for treatment efficacy and safety of von Willebrand disease (VWD) patients. This prospective, head-to-head, randomised crossover study compared the PK profile of a new, high purity, human plasma-derived (pd)VWF/FVIII concentrate, Wilate®, with the PK profile of an intermediate purity (pd)VWF/FVIII concentrate, Humate-P¯, in VWD patients. Subjects with inherited VWD were randomised to a single intravenous dose (40 IU/kg VWF ristocetin cofactor activity [VWF:RCo]) of Wilate® or Humate-P¯ in Period 1, and switched to the other study drug in Period 2. Each period was preceded by a washout time of ≥7 days. Coagulation factor parameters were analysed at multiple time-points. Of 22 randomised subjects, 20 had evaluable PK profiles, which indicated comparability for VWF antigen and VWF:RCo between Wilate® and Humate-P¯. The reported VWF:RCo average and terminal t1/2 of 10.4 and 15.8 hours (h), respectively, for Wilate® and 9.3 h and 12.8 h for Humate-P®, were not statistically different. Also, the mean VWF:RCo in vivo recoveries (Wilate® 1.89, Humate-P® 1.99 IU/dl per IU/kg) were similar between the two replacement therapies. Wilate® showed parallel decay curves for VWF:RCo and FVIII clotting activity (FVIII:C) over time, while FVIII:C of Humate-P® displayed a plateau between 0 and 12–24 h. This study demonstrated bioequivalent PK properties for VWF between Wilate® and Humate-P®. The PK profile of Wilate®, combined with the 1:1 VWF/FVIII ratio, theoretically should facilitate dosing and laboratory monitoring of VWF replacement to prevent bleeding in individuals with VWD.

Recombinant Human Von Willebrand Factor (rhVWF): First-In-Human Study Evaluating Pharmacokinetics, Demonstrating Safety and Tolerability In Type 3 Von Willebrand Disease

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 237-237 ◽  
Author(s):  
Tobias Suiter ◽  
Michael Laffan ◽  
Pier M. Mannucci ◽  
Christine L. Kempton ◽  
Edward H Romond ◽  
...  
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Von Willebrand Factor ◽  
Phase 1 ◽  
Von Willebrand Disease ◽  
Fviii Activity ◽  
Post Infusion ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Abstract 237 Von Willebrand Disease (VWD) is an inherited rare bleeding disorder caused by a deficiency of von Willebrand factor (VWF). VWF is the largest soluble multimeric plasma glycoprotein, which facilitates platelet aggregation and stabilizes FVIII in the circulation. Patients with type 3 disease display severe hemorrhagic symptoms, mainly in mucosal tissues, muscle and joints. Replacement of VWF stabilizes endogenous FVIII to hemostatic levels within hours. Commercially available VWF/FVIII concentrates are plasma-derived (pd) and subject to limitations such as donor dependency, risk of blood-borne pathogen transmission, lack of high molecular weight VWF multimers, and variation in multimer composition. A novel recombinant human VWF (rhVWF) has been developed using a plasma-free method, which represents the largest protein ever produced using recombinant technology. Safety, tolerability and pharmacokinetics of the rhVWF combined at a fixed ratio with rFVIII were investigated in a Phase 1 multicenter, international clinical study in 31 patients with type 3 VWD and severe type 1 VWD. Four concentrations of rhVWF (2, 7.5, 20 and 50 IU VWF:RCo/kg) were administered in a dose-escalating manner in separate cohorts. rhVWF was well tolerated, and no thrombotic events, VWF inhibitors or other serious adverse reactions were observed. Pharmacokinetics of rhVWF/rhFVIII (50 IU VWF:RCo/kg and 38.5 IU FVIII/kg) compared with pdVWF/pdFVIII (50 IU VWF:RCo/kg and 21 IU/kg FVIII/kg) were evaluated in a sub-group of 8/31 patients using a randomized, crossover design (8-day minimum washout period). Interim data in 8 subjects show a higher degree of secondary FVIII activity with rhVWF/rhFVIII compared to pdVWF/pdFVIII (see Figure 1) that is not solely due the difference in the rhVVF:FVIII infusion ratio (1.3:1 rhVWF/rhFVIII vs. approximately 2:1 pdVWF/pdFVIII). The pharmacokinetics of the rhVWF:RCo and pdVWF:RCo were comparable and were also reflected in the VWF:Ag and collagen binding activity. Evidence is also provided for the in vivo cleavage of the ultra-high molecular weight multimers of rhVWF by endogenous ADAMTS13. In summary, interim data from the ongoing Phase 1 study, demonstrate that rhVWF is safe and well tolerated, has VWF:RCo pharmacokinetics that are comparable to pdVWF and enhances stabilization of endogenous FVIII. Multiple doses of rhVWF/rhFVIII would be expected to have beneficial effects in major surgery and severe mucosal bleeding events. These data would also support the treatment concept to administer rhVWF alone once a therapeutic baseline level of endogenous FVIII is achieved (after 1–2 doses).Figure 1:Preliminary PK data from 8 subjects post-infusion of either rhVWF/rhFVIII or pdVWF/pdFVIII. Endogenous FVIII activity reached a plateau after 6 hours and remained stable for at least 30 hours. FVIII was still elevated well above baseline at 96 hoursFigure 1:. Preliminary PK data from 8 subjects post-infusion of either rhVWF/rhFVIII or pdVWF/pdFVIII. Endogenous FVIII activity reached a plateau after 6 hours and remained stable for at least 30 hours. FVIII was still elevated well above baseline at 96 hours Disclosures: Suiter: Baxter BioScience: Employment. Laffan:Baxter BioScience: Consultancy. Mannucci:Baxter BioScience: Consultancy. Kempton:Baxter BioScience: Consultancy. Romond:Baxter BioScience: Consultancy. Shapiro: Baxter BioSci- ence: Consultancy. Birschmann:Baxter BioScience: Consultancy. Gill:Baxter BioScience: Consultancy. Ragni:Baxter BioScience: Consultancy. Turecek:Baxter BioScience: Employment. Ewenstein:Baxter Bioscience: Employment. Baxter BioScience:Baxter BioScience: Employment.

Results of a Prospective, Open-Label Trial to Assess the Efficacy, Safety and Immunogenicity of Wilate® in Children Under 6 Years of Age with Inherited Von Willebrand Disease,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3330-3330
Author(s):  
Ulrike Nowak-Gottl ◽  
Alexandra Russo ◽  
Anne Kruempel ◽  
Martina Jansen ◽  
Sigurd Knaub
Keyword(s):  
Von Willebrand Disease ◽  
Clinical Event ◽  
Open Label ◽  
Insufficient Response ◽  
Dosing Regimens ◽  
The Mean ◽  
Good For ◽  
Von Willebrand ◽  
In Vivo Recovery

Abstract Abstract 3330 Introduction: Wilate® is a new-generation plasma-derived concentrate of von Willebrand factor (VWF) and factor VIII (FVIII) developed for treatment of patients with von Willebrand disease (VWD) and haemophilia A. The objective of this study was to assess efficacy, safety and immunogenicity of Wilate in children below 6 years of age with inherited VWD. Methods: The prospective, multi-centre trial included patients with inherited VWD of any type below 6 years of age with insufficient response to DDAVP. Any clinical event requiring VWF/FVIII concentrate treatment within 1 year was treated with Wilate. Efficacy was recorded by using a 4-point VRS and in vivo recovery of FVIII:C and VWF:RCo was analyzed. Immunogenicity was assessed by determination of inhibitors against VWF and FVIII. Safety was measured by monitoring of adverse events. Tolerability was rated as “very good” or “good” for all cases by the investigator. Results: Fifteen subjects (6 type 3) were analyzed. Dosing regimens were dependent on specific clinical situations of each subject. The mean incremental in vivo recovery was 1.2 IU/dL per IU/kg for VWF:RCo and 1.6 IU/dL per IU/kg for FVIII:C (n = 7). Forty five bleeding episodes required treatment with Wilate. In all cases the overall haemostatic efficacy ratings by the investigator were “excellent” or “good”. The mean dose was 35.9 IU VWF:RCo/kg. Nine surgical procedures (3 major) were performed in 7 subjects, requiring 2 to 12 infusions/procedure with a mean dose per exposure day of 61.7 VWF:RCo/kg. Haemostatic efficacy for a total of 419 infusions was rated as “excellent” for 362, “good” for 54, “moderate” for 2 (1 missing) infusions. No notable changes in thrombogenicity markers and no thromboembolic events occurred. No inhibitors against VWF or FVIII were detected. Conclusion: This study demonstrates the efficacy, safety and tolerability of Wilate® in treatment of VWD in patients below 6 years of age. Disclosures: Jansen: Octapharma: Employment. Knaub:Octapharma AG: Employment. Off Label Use: the product, Octanate, is approved in many countries worldwide but is not currently approved in the US.

Efficacy and safety of a new generation von Willebrand factor/factor VIII concentrate (Wilate®) in the management of perioperative haemostasis in von Willebrand disease patients undergoing surgery

2011 ◽  
Vol 105 (06) ◽  
pp. 1072-1079 ◽  
Author(s):  
Mario von Depka-Prondzinski ◽  
Jerzy Windyga ◽  
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Perioperative Management ◽  
Von Willebrand Disease ◽  
Major Surgery ◽  
Open Label ◽  
New Generation ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryThe aim of this study was to assess the efficacy of Wilate®, a new generation, plasma-derived, high-purity, double virus-inactivated von Willebrand factor (VWF) and factor VIII (FVIII) concentrate (ratio close to physiological 1:1) in the perioperative management of haemostasis in von Willebrand disease (VWD). Data for VWD patients who received Wilate® for perioperative management were obtained from four European, prospective, open-label, non-controlled, non-randomised, multicentre phase II or III clinical trials. A total of 57 surgical procedures were performed (major: n = 27; minor n = 30) in 32 patients. The majority of patients (n = 19, 59.4%) had type 3 VWD, 9 (28.1%) had type 2 VWD and four (12.5%) had type 1 VWD. During major surgery, median daily FVIII dose and mean number of infusions were 25 IU•kg-1 FVIII (VWF:RCô23 IU•kg-1) and 11.0, respectively. Corresponding values for minor surgery were 35 IU•kg-1 (VWF:RCo ~32 IU•kg-1) and 1.5. The efficacy of Wilate® was rated by the investigator as excellent or good in 51 of 53 (96%) procedures. Tolerability was rated as very good or good in 100% of major surgeries (27 of 27) and minor surgeries (29 of 29). Wilate® is an effective and well-tolerated VWF/FVIII replacement therapy in the perioperative management of haemostasis in patients with VWD. It can be administered at a similar FVIII dose, but at a lower VWF dose, as compared to older generation products. Clinical benefits were shown in a population with a high proportion of type 3 VWD patients.

Monitoring of coagulation factor therapy in patients with von Willebrand disease type 3 using a microchip flow chamber system

2017 ◽  
Vol 117 (01) ◽  
pp. 75-85 ◽  
Author(s):  
Margareta Holmström ◽  
David E. Schmidt ◽  
Kazuya Hosokawa ◽  
Margareta Blombäck ◽  
Paul Hjemdahl ◽  
...  
Keyword(s):  
Whole Blood ◽  
Thrombus Formation ◽  
Flow Chamber ◽  
Von Willebrand Disease ◽  
High Shear ◽  
Fviii Activity ◽  
Concentrate Treatment ◽  
Type 3 ◽  
Von Willebrand ◽  
Low Shear

SummaryPatients with type 3 von Willebrand disease (VWD-3) have no measurable levels of VW factor (VWF) and usually require treatment with VWF-FVIII concentrate to prevent and/or stop bleeding. Even though the patients are treated prophylactically, they may experience bleeding symptoms. The aim of this study was to evaluate the effect of VWF-FVIII concentrate treatment in VWD-3 patients with the Total Thrombus Analysis System (T-TAS®), which measures thrombus formation under flow conditions. Coagulation profiles of 10 VWD-3 patients were analysed using T-TAS before and 30 minutes after VWF-FVIII concentrate (Haemate®) injection. Results were compared to VWF- and FVIII activity in plasma, and results with thromboelastometry and ris-tocetin-activated platelet impedance aggregometry (Multiplate®) in whole blood. For comparison, 10 healthy controls were also analysed with T-TAS. A median dose of 27 (range 15–35) IU/kg of VWF-FVIII concentrate increased VWF- and FVIII activity as expected. T-TAS thrombus formation was enhanced when a tissue factor/collagen-coated flow chamber was used at low shear, but treatment effects at high shear using a collagen-coated flow chamber were minimal. Whole blood coagulation assessed by thromboelastometry was normal and did not change (p > 0.05) but ristocetin-induced platelet aggregation improved (p < 0.001). In conclusion, T-TAS detects effects of VWF-FVIII concentrate treatment on coagulation-dependent thrombus formation at low shear, but minor effects are observed on platelet-dependent thrombus formation at high shear. The poor prediction of bleeding by conventional laboratory monitoring in VWD-3 patients might be related to insufficient restoration of platelet-dependent thrombus formation.

A phase I and pharmacokinetic (PK) study of continuous daily administration of P1446A-05, a potent and specific oral Cdk4 inhibitor.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3013-3013 ◽  
Author(s):  
Desiree Hao ◽  
Quincy Chu ◽  
Stephen Welch ◽  
Cindy Y. F. Yau ◽  
Jennifer L. Spratlin ◽  
...  
Keyword(s):  
Phase Ii ◽  
Study Drug ◽  
Multiple Time ◽  
Time Points ◽  
Phase Ii Studies ◽  
Elevated Creatinine ◽  
Multiple Time Points ◽  
Ecog Ps

3013 Background: P1446A-05 is a novel oral inhibitor of Cdk4-D1, Cdk1-B, and Cdk9-T, and has been shown to inhibit tumor growth both in vitro and in vivo. Pharmacodynamic studies demonstrate that activation of Cdk1 reappears within 48 hours after P1446A-05 is withdrawn, suggesting the need for prolonged administration hence, we sought to evaluate the feasibility, safety and tolerability of a continuous daily schedule of P1446A-05 in patients (pts) with advanced malignancies. Methods: P1446A-05 was given at escalating doses of 75, 150, 250, 350 and 500mg. Samples were collected for PK at multiple time points over 24 hours on cycle 1 day 1 and 15, as well as at single time points on cycle 1 day 8, 22 and cycle 2 day 1. Results: Thirty-nine pts (median age=63 years, 51% male, 51% ECOG PS=1) collectively received more than 100 cycles of P1446A-05. The majority of drug-related toxicities were ≤Grade 2, the most common of which were diarrhea (n=54), nausea/vomiting (n=27/17), fatigue (n=22) and anorexia (n=16). Two pts developed study-drug related diarrhea with hypokalemia/elevated creatinine and died during cycle 1. Dose-limiting toxicities (DLT) at 500mg (Table) led to subsequent de-escalation and expansion of the 350mg cohort. A total of 24 pts were treated at 350mg; only one patient experienced dose-limiting diarrhea. PK data are summarized below. Accumulation ratios across dose levels suggest moderate accumulation with continuous dosing. Nine pts achieved stable disease (SD) for at least 2 cycles. One pt with alveolar soft tissue sarcoma, whose disease was progressing at enrollment, remains on treatment with SD after 11 cycles. Conclusions: The recommend phase II dose of P1446A-05 is 350mg. Further phase II studies at this dose will be conducted with potential enrichment strategies. [Table: see text]

scholarly journals VWF Modulates the in Vivo FVIII Recovery of Different FVIII Concentrates in a Mice Model of Severe Hemophilia with Inhibitors

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2826-2826
Author(s):  
María Isabel Bravo ◽  
Bibiana Da Rocha-Souto ◽  
Salvador Grancha ◽  
Juan I Jorquera
Keyword(s):  
Protective Effect ◽  
Empirical Finding ◽  
Von Willebrand Disease ◽  
In Vivo Model ◽  
Severe Hemophilia ◽  
Mice Model ◽  
Fviii Activity ◽  
Von Willebrand ◽  
The Impact

Abstract About 25% of severe hemophilia A patients undergoing factor VIII (FVIII) replacement therapy develop antibodies against FVIII (FVIII inhibitors). The formation of inhibitor is generally accepted as the most common and challenging complication of hemophilia treatment. In the circulation, FVIII is tightly bound to von Willebrand factor (VWF), forming a complex that plays a significant role in FVIII protection from premature degradation (Delignat S et al, Haemophilia 2012;18:248-54). Several laboratory and clinical studies suggest that the presence of VWF in FVIII concentrates might have some benefits due to the protective effect against antibodies (Shi Q et al, J Thromb Haemost 2012;10:2328-37; Mannucci PM, Haemophilia 2012;18 Suppl 2:2-7). Plasma-derived (pd) FVIII/VWF concentrates show higher residual FVIII activity and more thrombin generation after incubation with inhibitors compared to isolated FVIII concentrates (pdFVIII or recombinant, rFVIII). The protective effect of VWF observed in native pdFVIII/VWF complex is not completely restored for isolated FVIII even after mixing with VWF before analyzing the reaction with inhibitors (Bravo MI et al, Haemophilia 2014; in press). This study analyzes the impact of VWF on FVIII protection against inhibitors in an in vivo model, by evaluating the differences of FVIII in vivo recovery between FVIII concentrates with or without VWF in FVIIInull E16Knockout (KO) mice infused with inhibitors purified from hemophilic patients’ plasma. Inhibitor IgG was purified from a pool of human plasmas from hemophilic patients (Technoclone GmbH, Vienna, Austria) by using Protein G Sepharose chromatography as described elsewhere. IgGs were tail vein infused to achieve 3.2 BU/ml (or buffer as a control) prior to FVIII treatment. Five minutes after IgG infusion, animals (n=5-6 for each treatment group) were infused with FVIII therapeutic concentrates (100 IU/kg) from different sources, including native pdFVIII/VWF complex; isolated pdFVIII and full-length recombinant FVIII (rFVIII). In addition, some animal groups were treated with in vitro preformed complexes with pdVWF (therapeutic concentrate for von Willebrand disease) and FVIII (rFVIII+pdVWF and pdFVIII+pdVWF mixed at 1IU:1IU ratio; 15 min at 25ºC). After 5 min post-FVIII infusion, plasma samples were obtained by abdominal cave vein sampling and residual FVIII:C was measured using chromogenic assay. FVIII recovery was estimated according on the empirical finding that 1IUFVIII/kg body weight raises the plasma FVIII activity by 2.1±0.4% of normal activity. In the absence of inhibitor, in vivo FVIII recovery in FVIIInull E16 KO mice was similar for all FVIII concentrates as expected, with values ranging from 107% to 124% (see table). In contrast, in the presence of inhibitors the FVIII recovery showed marked differences among treatment groups. Recovery was higher for the native VWF-containing FVIII concentrate (pdFVIII/VWF: 71.1±17.4%) when compared to concentrates composed of isolated FVIII (rFVIII: 31.4±9.9%; pdFVIII: 25.0±2.7%). When the products containing isolated FVIII were premixed with VWF prior to infusion, FVIII recovery was only partially restored (rFVIII+VWF: 67.1±15.1%; pdFVIII+VWF: 45.2±8.8%). FVIII:C recovery and ratio FVIII:C, 5 min post-infusion of FVIII products (100 IU/kg), without inhibitor and with inhibitor (3.2±0.4 BU/ml) in severe hemophilic mice. Abstract 2826. TableFVIII productsFVIII:C Recovery (%) [mean±SD (n)]FVIII:C ratio (IU) in absence vs. presence of inhibitorWithout inhibitorWith inhibitorpdFVIII /VWF107.9 ± 6.1 (6)71.1 ± 17.4 (5)1.52rFVIII106.9 ± 8.3 (6)31.4 ± 9.9 (5)3.41pdFVIII120.5 ± 5.1 (6)25.0 ± 2.7 (5)4.77rFVIII+pdVWF124.3 ± 11.2 (6)67.1 ± 15.1 (6)1.84pdFVIII+pdVWF111.8 ± 5.9 (6)45.2 ± 8.8 (6)2.47 Our data indicate that VWF-containing FVIII concentrates are more efficient in the restoration of FVIII circulating levels in the FVIIInull E16 KO mice model with inhibitors. Moreover, results also suggest that this protection would be higher in native pdFVIII/VWF complex that in the complex of FVIII+VWF formed from the isolated proteins. Disclosures Bravo: Instituto Grifols: Employment. Da Rocha-Souto:Instituto Grifols: Employment. Grancha:Instituto Grifols: Employment. Jorquera:Grifols Bioscience: Employment.

Von Willebrand Disease (VWD) - A Disease with Dual Factor Deficiencies- Discrepant FVIII:C Pharmacokinetic (PK) Characteristics in a Head to Head Trial of Two VWF/FVIII Concentrates.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2141-2141
Author(s):  
Craig M. Kessler ◽  
Bruce A. Schwartz
Keyword(s):  
High Purity ◽  
Coagulation Factor ◽  
Von Willebrand Disease ◽  
Multiple Time ◽  
Random Allocation ◽  
Fviii Activity ◽  
The Mean ◽  
Type 3

Abstract Introduction: The PK profile of VWF/FVIII concentrate is very important in the treatment of individuals with VWD since this coagulopathy is a combined deficiency of qualitative and/or quantitative VWF functions specifically and of FVIII activity indirectly. A prospective randomized, crossover study was performed to investigate the PK properties of two VWF/FVIII concentrates (Wilate® and Humate-P®) in subjects with inherited VWD. This is the first head-to-head PK study performed within the same subject, comparing two plasma derived concentrates, one a new high purity VWF/FVIII product (Wilate) and an existing first generation intermediate purity concentrate (Humate-P). Methods: This prospective, randomized, controlled, open-labeled, 2-arm crossover, multi-center study included subjects with inherited and defined VWD, who underwent PK assessments after random allocation in Period 1 to a single 40 IU VWF:RCo /kg bolus dose of either Wilate or with Humate-P. After a washout period of at least 7 days, subjects received the other study VWD replacement concentrate for Period 2. During both study periods, plasma samples were tested at multiple time points for coagulation factor activities. The objective of the study was to evaluate the PK profiles of both, including the in-vivo terminal half-life (t1/2) of FVIII:C, VWF:RCo, VWF:Ag, and VWF:CB. Results: A total of 22 subjects with inherited VWD (Type 1, n=6; Type 2, n=9 [6 Type 2A, 1 Type 2B, and 2 Type 2M]; and Type 3, n=7) were randomized in the study. The VWF PK profiles for VWF after Wilate or Humate-P were similar with no appreciable difference in the mean t1/2 for VWF activities in Type 3 and Type 1 subjects (10 hrs for Humate-P and 12.6 hrs for Wilate using the VWF:RCo assay). For VWD Type 2 subjects the mean t1/2 was longer, but with no consistent differences between the concentrates. There were no significant differences in recovery, and consequently Cmax and AUC between Wilate and Humate-P. In patients receiving Wilate, there were almost parallel decay curves and t1/2 between VWF (RCo-12.6hr) and FVIII (FVIIIC -13hr) activity. In the analysis of FVIII:C PK profiles, Humate- P showed an unusually sustained FVIII:C decay curve plateau, which may represent the net combined effects of decreasing exogenous and increasing endogenous FVIII activities in the patient and the increased FVIII:C binding capacity of the excessive quantity of non-functional VWF:Ag present in this product. There was a significant discrepancy in the mean t1/2 for FVIII:C measured in VWD Type 3 subjects (35.7 hrs for Humate-P and 13 hrs for Wilate), using either one stage or chromogenic FVIII:C assays. Conclusions: This study confirms the similarity of the VWF PK properties of Wilate and Humate-P. However, this was not the case for FVIII activity, which revealed a significantly prolonged t1/2 versus the t1/2 of VWF:RCo for Humate-P measured in type 3 VWD patients after infusion. In contrast, following infusion of Wilate there was the initial expected FVIII:C peak followed by a parallel decay curves for both VWF:RCo and FVIII:C activities. This favorable PK profile for the new high purity VWF/FVIII concentrate, Wilate, should facilitate the dosing and laboratory monitoring of VWF replacement in VWD and should improve safety and efficacy by avoiding over or under dosing of each of the two critical coagulation parameters, especially in the situation of repeated dosing of the concentrates.

A Novel Mutation Glyl672→Arg in Type 2A and a Homozygous Mutation in Type 2B von Willebrand Disease

1996 ◽  
Vol 76 (02) ◽  
pp. 253-257 ◽  
Author(s):  
Takeshi Hagiwara ◽  
Hiroshi Inaba ◽  
Shinichi Yoshida ◽  
Keiko Nagaizumi ◽  
Morio Arai ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Novel Mutation ◽  
Point Mutations ◽  
Japanese Patients ◽  
Von Willebrand Disease ◽  
Homozygous Mutation ◽  
Missense Mutations ◽  
Reaction Products ◽  
Type 3 ◽  
Von Willebrand

SummaryGenetic materials from 16 unrelated Japanese patients with von Willebrand disease (vWD) were analyzed for mutations. Exon 28 of the von Willebrand factor (vWF) gene, where point mutations have been found most frequent, was screened by various restriction-enzyme analyses. Six patients were observed to have abnormal restriction patterns. By sequence analyses of the polymerase chain-reaction products, we identified a homozygous R1308C missense mutation in a patient with type 2B vWD; R1597W, R1597Q, G1609R and G1672R missense mutations in five patients with type 2A; and a G1659ter nonsense mutation in a patient with type 3 vWD. The G1672R was a novel missense mutation of the carboxyl-terminal end of the A2 domain. In addition, we detected an A/C polymorphism at nucleotide 4915 with HaeIII. There was no particular linkage disequilibrium of the A/C polymorphism, either with the G/A polymorphism at nucleotide 4391 detected with Hphl or with the C/T at 4891 detected with BstEll.

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