The safety and efficacy of B‐domain deleted recombinant factor VIII concentrate in patients with severe haemophilia A

Lusher, Jeanne M.; Lee, C. A.; Kessler, Craig M.; Bedrosian, Camille L.

doi:10.1046/j.1365-2516.2003.00708.x

Cited by 170 publications

(180 citation statements)

References 42 publications

(67 reference statements)

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“…Differences between the CHS and OSC assay methods, which can be clinically significant at low quantification levels, may also contribute to the overall complexity [7]. In any case, the B-domain-deleted formulations do not seem to differ from other formulations [1,2,7]. From a practical point of view, the interpatient variability is attributed to the PK, and consequently, characterisation of individual patient PK is necessary for appropriate dosing of this costly treatment.…”

Section: Discussionmentioning

confidence: 99%

“…as on-demand treatment for spontaneous bleeding episodes, before surgical procedures or as long-term prophylactic treatment to prevent haemophilic arthropathy. The relatively recent (2002) B-domain-deleted recombinant (BDDr) albumin-free antihaemophilia factor ReFacto® has been shown to have similar haemostatic properties to fulllength serum-derived factor VIII:C [1,2]. The dose amount of factor VIII:C is expressed in international units (IU), and activity in plasma can be expressed as a percent of normal, then 100% of normal is equivalent to 1 IU/dl.…”

Section: Introductionmentioning

confidence: 99%

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Population pharmacokinetics of recombinant factor VIII:C (ReFacto®) in adult HIV-negative and HIV-positive haemophilia patients

Karafoulidou¹,

Súárez

Anastasopoulou³

et al. 2009

Eur J Clin Pharmacol

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Purpose The aim of this study was to explore possible differences in the pharmacokinetics (PK) of recombinant factor VIII:C (ReFacto® -ReFacto ) in HIV+ vs. HIVpatients and also differences in the chromogenic substrate bioassay (CHS) and one-stage clotting (OSC) methods. Methods Twenty-eight haemophilia A adults (20 HIV-and eight HIV+) were assayed with both the CHS and OSC methods. An average of two and six samples were collected per patient for HIV-/+, respectively, after one, and occasionally two more, prophylactic doses (mean 2,003 IU; range 1,000-4,300 IU). The observations were analysed with the mixed-effects (population) compartmental PK modelling package NONMEM (nonlinear mixed-effects modelling) and the FOCE (first-order conditional estimation) method. Base modelling was performed independently for the CHS and OSC bioassays for comparison, and covariate models and simulation tests were done only for the commonly used OSC bioassay. The final covariate model was validated using the bootstrap method. Monte Carlo simulations were used to estimate the expected probability of exceeding 20%, 40% or 60% of normal factor VIII:C in plasma after a single dose, corresponding to required levels for preventing mild, moderate and lifethreatening haemorrhages. Results One-compartment base-model population PK parameters were [mean parameter (interpatient variability %)] for CHS: clearance (CL)=2.56 dl h −1 (33.2%); volume of distribution (V)=34.8 dl (12.8%); and for OSC: CL= 3.83 dl h −1 (47.8%), V=53.7 dl (22.4%). The volumes differed significantly between the CHS and OSC methods (p<0.0001), and variabilities were higher for OSC. Nevertheless, the empirical half-lives (t 1/2 =l n (2) × V/CL) were similar for CHS and OSC, [(mean ± standard deviation (SD)], 9.5 ± 3 h and 10.2 ± 4 h, respectively. In covariate modelling with the OSC-derived model, HIV status (VIR) was a significant categorical predictor (p<0.005) for V.The final covariate models with OSC were for CL=3.93 + 0.09 × (WT-75) and for V=48.6 × (1 + 0.36 × VIR) + 0.55 × (WT-75); therefore, V for the typical HIV+ patient was 36% higher than for the HIV-patient. Conclusions Both HIV-and HIV+ patients showed 100% success with the 20% threshold at doses >20 IU/kg. HIVpatients receiving >50 IU/kg had a 100% expected chance of success for all thresholds. HIV+ patients for moderate or life-threatening haemorrhage treatment need 10 IU/kg more than the HIV-patient equivalent to have the same probability of success.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics of recombinant factor VIII:C (ReFacto®) in adult HIV-negative and HIV-positive haemophilia patients

Karafoulidou¹,

Súárez

Anastasopoulou³

et al. 2009

Eur J Clin Pharmacol

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“…[1][2][3] However, a major impediment for fVIII replacement therapy is the development of inhibitory antibodies (inhibitors) against infused fVIII, a complication, which affects approximately 30% of severe hemophilia A patients. [4][5][6] By contrast, acquired hemophilia A is caused by an inhibitory autoimmune response to otherwise functional, endogenous fVIII. 7 FVIII inhibitors result in partially or fully inactivated fVIII, which results in loss of proper blood coagulation.…”

Section: Introductionmentioning

confidence: 99%

Structure of the factor VIII C2 domain in a ternary complex with 2 inhibitor antibodies reveals classical and nonclassical epitopes

Walter

Werther

Brison

et al. 2013

Blood

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“…[1][2][3][4] These antibodies increase the morbidity and mortality and the cost of care of these patients. Treatment options include bypassing the requirement for fVIII using activated coagulation factor concentrates or recombinant fVIIa and using porcine fVIII.…”

Section: Introductionmentioning

confidence: 99%

Reduction of the inhibitory antibody response to human factor VIII in hemophilia A mice by mutagenesis of the A2 domain B-cell epitope

Parker

Healey

Barrow

et al. 2004

Blood

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Approximately 25% of patients with hemophilia A develop inhibitory antibodies after treatment with factor VIII. Most of the inhibitory activity is directed against epitopes in the A2 and C2 domains. Anti-A2 inhibitory antibodies recognize a 25-residue segment bounded by R484-I508. Several antigenic residues in this segment have been identified, including R484, R489, and P492. The immunogenicity of purified recombinant B domaindeleted (BDD) human factor VIII molecules containing mutations at R484A/ R489A or R484A/R489A/P492A was studied in hemophilia A mice. Inhibitory antibody titers in mice receiving the R484A/R489A/P492A mutant, but not the R484A/R489A mutant, were significantly lower than in mice receiving control human BDD factor VIII. The specific coagulant activity and the in vivo clearance and hemostatic efficacy in hemophilia A mice of the R484A/R489A/P492A mutant were indistinguishable from human BDD factor VIII. Thus, the inhibitory antibody response to human factor VIII can be reduced by mutagenesis of a B-cell epitope without apparent loss of function, suggesting that this approach may be useful for developing a safer form of factor VIII in patients with hemophilia A. (Blood. 2004; 104:704-710)

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The safety and efficacy of B‐domain deleted recombinant factor VIII concentrate in patients with severe haemophilia A

Abstract: The results of these clinical studies indicate that BBDrFVIII is safe and effective and has haemostatic activity similar to that of full-length FVIII concentrates.

Cited by 170 publications

References 42 publications

Population pharmacokinetics of recombinant factor VIII:C (ReFacto®) in adult HIV-negative and HIV-positive haemophilia patients

Population pharmacokinetics of recombinant factor VIII:C (ReFacto®) in adult HIV-negative and HIV-positive haemophilia patients

Structure of the factor VIII C2 domain in a ternary complex with 2 inhibitor antibodies reveals classical and nonclassical epitopes

Reduction of the inhibitory antibody response to human factor VIII in hemophilia A mice by mutagenesis of the A2 domain B-cell epitope

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