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Factor VIII concentrate dosing with lean body mass, ideal body weight and total body weight in overweight and obesity: A randomized, controlled, open-label, 3 × 3 crossover trial
Seaman CD, Yabes JG, Lalama CM, Ragni MV
Haemophilia : the official journal of the World Federation of Hemophilia. 2021
Abstract
INTRODUCTION Obesity alters the pharmacokinetic (PK) properties of drugs making it difficult to determine the appropriate dose when administering weight-based medications. Alternative descriptors of body weight, such as lean body mass (LBM) and ideal body weight (IBW), are sometimes used in these situations. METHODS We performed a single-centre, randomized, controlled, open-label, 3 × 3 crossover trial to determine whether recombinant factor VIII (rFVIII) dosing based on LBM and IBW achieves a targeted FVIII recovery with better precision than based on total body weight (TBW) in overweight and obese, adult males with haemophilia A. Participants were randomized to 1 of 6 possible FVIII concentrate dosing sequence scenarios (TBW, LBM and IBW). Recombinant FVIII was administered on 3 separate weeks following a washout period of at least 72 hours. RESULTS A total of 19 participants were randomized and completed the study. FVIII recovery was lower at 30 minutes post-rFVIII infusion in LBM vs TBW and IBW vs TBW-based dosing, mean difference -0.38 (95% CI: -0.56, -0.20) and -0.28 (95% CI: -0.47, -0.10) IU/dL per IU/kg, respectively. In LBM vs TBW and IBW vs TBW-based dosing, there was a non-significant increase in the proportion of participants with a targeted FVIII recovery of 2.00 ± 0.20 IU/dl per IU/kg, OR = 1.93 (95% CI: 0.44, 8.55) and OR = 3.65 (0.80, 16.72), respectively. DISCUSSION Based on our study's findings, overweight and obese patients with haemophilia A may benefit from an individualized PK analysis using LBM and IBW to determine the most accurate, and potentially cost-effective, method of achieving targeted FVIII recovery.
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BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A
Konkle BA, Shapiro AD, Quon DV, Staber JM, Kulkarni R, Ragni MV, Chhabra ES, Poloskey S, Rice K, Katragadda S, et al
The New England journal of medicine. 2020;383(11):1018-1027
Abstract
BACKGROUND Factor VIII replacement products have improved the care of patients with hemophilia A, but the short half-life of these products affects the patients' quality of life. The half-life of recombinant factor VIII ranges from 15 to 19 hours because of the von Willebrand factor chaperone effect. BIVV001 (rFVIIIFc-VWF-XTEN) is a novel fusion protein designed to overcome this half-life ceiling and maintain high sustained factor VIII activity levels. Data are lacking on the safety and pharmacokinetics of single-dose BIVV001. METHODS In this phase 1-2a open-label trial, we consecutively assigned 16 previously treated men (18 to 65 years of age) with severe hemophilia A (factor VIII activity, <1%) to receive a single intravenous injection of recombinant factor VIII at a dose of 25 IU per kilogram of body weight (lower-dose group) or 65 IU per kilogram (higher-dose group). This injection was followed by a washout period of at least 3 days. The patients then received a single intravenous injection of BIVV001 at the same corresponding dose of either 25 IU or 65 IU per kilogram. Adverse events and pharmacokinetic measurements were assessed. RESULTS No inhibitors to factor VIII were detected and no hypersensitivity or anaphylaxis events were reported up to 28 days after the injection of single-dose BIVV001. The geometric mean half-life of BIVV001 was three to four times as long as that of recombinant factor VIII (37.6 hours vs. 9.1 hours in the lower-dose group and 42.5 vs. 13.2 hours in the higher-dose group); the area under the curve (AUC) for product exposure was six to seven times as great in the two dose groups (4470 hours vs. 638 hours × IU per deciliter in the lower-dose group and 12,800 hours vs. 1960 hours × IU per deciliter in the higher-dose group). After the injection of BIVV001 in the higher-dose group, the mean factor VIII level was in the normal range (≥51%) for 4 days and 17% at day 7, which suggested the possibility of a weekly interval between treatments. CONCLUSIONS In a small, early-phase study involving men with severe hemophilia A, a single intravenous injection of BIVV001 resulted in high sustained factor VIII activity levels, with a half-life that was up to four times the half-life associated with recombinant factor VIII, an increase that could signal a new class of factor VIII replacement therapy with a weekly treatment interval. No safety concerns were reported during the 28-day period after administration. (Funded by Sanofi and Sobi; ClinicalTrials.gov number, NCT03205163.).
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Pilot randomized, non-inferiority, cross-over trial of once-weekly vs. three times-weekly recombinant factor VIII prophylaxis in adults with severe haemophilia A
Ragni MV, Yabes JG, Fogarty PF, Josephson NC, Kessler CM, Neff AT, Raffini L, Brummel-Ziedins K, Moore CG
Haemophilia : the Official Journal of the World Federation of Hemophilia. 2016;23((1):):e43-e46
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A subcutaneously administered investigational RNAi therapeutic (ALN-AT3) targeting antithrombin for treatment of hemophilia: interim weekly and monthly dosing results in patients with hemophilia A or B
Pasi KJ, Georgiev P, Mant T, Creagh MD, Lissitchkov T, Bevan D, Austin S, Hay CR, Brand B, Kazmi R, et al
Blood. 2015;126((23)): Abstract No. 551.
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Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial
Mannucci PM, Kempton C, Millar C, Romond E, Shapiro A, Birschmann I, Ragni MV, Gill JC, Yee TT, Klamroth R, et al
Blood. 2013;122((5):):648-57.
Abstract
Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasma-derived (pd) VWF-pdFVIII. In vivo cleavage of ultra-large molecular-weight rVWF multimers by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; the endogenous VWF protease) and generation of characteristic satellite bands were demonstrated. In 2 subjects with specific nonneutralizing anti-VWF-binding antibodies already detectable before rVWF infusion, a reduction in VWF multimers and VWF activity was observed. Stabilization of endogenous FVIII was enhanced following post-rVWF-rFVIII infusion as shown by the difference in area under the plasma concentration curve compared with pdVWF-pdFVIII (AUC0-) (P < .01). These data support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved.
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Recombinant human von Willebrand Factor (rhVWF): first-in-human study evaluating pharmacokinetics, demonstrating safety and tolerability in Type 3 von Willebrand Disease
Suiter T, Laffan M, Mannucci PM, Kempton CL, Romond EH, Shapiro AD, Birschmann I, Gill JC, Ragni MV, Turecek P, et al
Blood. 2010;116((21):): Abstract No. 237.