scholarly journals Body Mass Index Best Predicts Recovery of Recombinant Factor VIII in Underweight to Obese Patients with Severe Haemophilia A

2019 ◽  
Vol 120 (02) ◽  
pp. 277-288
Author(s):  
Andreas Tiede ◽  
Ana Rosa Cid ◽  
Georg Goldmann ◽  
Victor Jiménez-Yuste ◽  
Michael Pluta ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Body Composition ◽  
Haemophilia A ◽  
Activity Levels ◽  
Obese Patients ◽  
Severe Haemophilia ◽  
Obese Class ◽  
Fviii Activity ◽  
Recombinant Fviii ◽  
Similar Peak

Abstract Background Factor VIII (FVIII) products are usually dosed according to body weight (BW). This may lead to under- or over-dosing in underweight or obese patients, respectively. Objective This article evaluates the pharmacokinetics (PK) of recombinant FVIII concentrate, particularly recovery, in relation to body mass index (BMI) and other body composition descriptors. Materials and Methods Thirty-five previously treated adults with severe haemophilia A from five BMI categories (underweight, normal, overweight, obese class I and II/III) were included. PK was evaluated after 50 IU per kilogram of BW single-dose recombinant FVIII (turoctocog alfa). The body composition variable was based on measurements of weight, height, bioimpedance analysis, and dual-energy X-ray absorptiometry. A dosing model was derived to achieve similar peak FVIII activity levels across BMI categories. Results A statistically significant positive association between BMI and C30min, IR30min, and AUC0–inf was observed; CL and Vss showed a significant negative association with BMI; t½ was independent of BMI and other parameters. The dosing model introduced a correction factor ‘M’ for each BMI category, based on linear regression analysis of C30min against BMI, which ranged from 0.55 for underweight to 0.39 for obese class II/III. This model achieved similar peak FVIII activity levels across BMI categories, estimating an average dose adjustment of +243.3 IU (underweight) to –1,489.6 IU (obese class II/III) to achieve similar C30min. Conclusion BMI appears to be the best predictor of recombinant FVIII recovery; however, PK endpoints were also dependent on other body composition variables. The model demonstrated that dosing can be adjusted for individual BMI to achieve better FVIII predictability across BMI categories.

Clinical evaluation of glycoPEGylated recombinant FVIII: Efficacy and safety in severe haemophilia A

2017 ◽  
Vol 117 (02) ◽  
pp. 252-261 ◽  
Author(s):  
Paul Giangrande ◽  
Tatiana Andreeva ◽  
Pratima Chowdary ◽  
Silke Ehrenforth ◽  
Hideji Hanabusa ◽  
...  
Keyword(s):  
Randomised Trial ◽  
Phase Iii ◽  
Haemophilia A ◽  
Activity Levels ◽  
Severe Haemophilia ◽  
Open Label ◽  
Favourable Safety Profile ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Recombinant Fviii

SummaryTuroctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products. This phase III (NCT01480180), multinational, open-label, non-randomised trial evaluated the safety and clinical efficacy of N8-GP when administered for treatment of bleeds and for prophylaxis, in previously treated patients aged ≥12 years with severe haemophilia A. Patients were allocated to receive N8-GP for prophylaxis or on-demand treatment for up to 1.8 years. Patients on prophylaxis were administered one dose of 50 IU/kg of N8-GP every fourth day. Bleeds were treated with doses of 20–75 IU/kg. Total exposure to N8-GP in the trial was 14,114 exposure days (159 patient-years). For the prophylaxis arm (n=175), the median annualised bleeding rate (ABR) was 1.33 (interquartile range, 0.00–4.61), the mean ABR was 3.70 (95 % confidence interval 2.94–4.66) and 70 (40 %) patients had no bleeds during the trial. Across treatment arms, 83.6 % of bleeds resolved with one injection and 95.5 % with up to two injections. N8-GP had a favourable safety profile and was well tolerated. The frequency and types of adverse events reported were as expected in this population. One patient developed inhibitory antibodies against FVIII (≥0.6 Bethesda units [BU]) after 93 N8-GP exposure days. No clinically significant safety concerns were identified and N8-GP was effective for prophylaxis and treatment of bleeds in previously treated patients.

Inhibitor development in haemophilia according to concentrate

2015 ◽  
Vol 113 (05) ◽  
pp. 968-975 ◽  
Author(s):  
Riita Lassila ◽  
Flora Peyvandi ◽  
Gabriele Calizzani ◽  
Alex Gatt ◽  
Thierry Lambert ◽  
...  
Keyword(s):  
Calculated Data ◽  
Incidence Rates ◽  
Clotting Factor ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Inhibitor Development ◽  
Haemophilia B ◽  
Number Of Patients ◽  
Recombinant Fviii ◽  
Set Up

SummaryInhibitor development represents the most serious side effect of haemophilia treatment. Any difference in risk of inhibitor formation depending on the product used might be of clinical relevance. It was this study’s objective to assess inhibitor development according to clotting factor concentrate in severe haemophilia A and B. The European Haemophilia Safety Surveillance (EUHASS) was set up as a study monitoring adverse events overall and according to concentrate. Since October 2008, inhibitors were reported at least quarterly. Number of treated patients was reported annually, specifying the number of patients completing 50 exposure days (Previously Untreated Patients, PUPs) without inhibitor development. Cumulative incidence, incidence rates and 95 % confidence intervals (CI) were calculated. Data from October 1, 2008 to December 31, 2012 were analysed for 68 centres that validated their data. Inhibitors developed in 108/417 (26 %; CI 22–30 %) PUPs with severe haemophilia A and 5/72 (7 %; CI 2–16%) PUPs with severe haemophilia B. For Previously Treated Patients (PTPs), 26 inhibitors developed in 17,667 treatment years [0.15/100 treatment years; CI 0.10–0.22) for severe haemophilia A and 1/2836 (0.04/100; (CI 0.00–0.20) for severe haemophilia B. Differences between plasma-derived and recombinant concentrates, or among the different recombinant FVIII concentrates were investigated. In conclusion, while confirming the expected rates of inhibitors in PUPs and PTPs, no class or brand related differences were observed.

scholarly journals The Single Nucleotide PolymorphismPPARG2Pro12Ala Affects Body Mass Index, Fat Mass, and Blood Pressure in Severely Obese Patients

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Ana Paula dos Santos Rodrigues ◽  
Lorena Pereira Souza Rosa ◽  
Hugo Delleon da Silva ◽  
Elisângela de Paula Silveira-Lacerda ◽  
Erika Aparecida Silveira
Keyword(s):  
Physical Activity ◽  
Blood Pressure ◽  
Body Mass Index ◽  
Body Composition ◽  
Body Mass ◽  
Fat Mass ◽  
Obese Patients ◽  
Pro12ala Polymorphism ◽  
Logistic Regression Models ◽  
Severely Obese

Background. ThePPARG2Pro12Ala (rs1801282) andIL6-174G >C (rs1800795) have important function in body weight regulation and a potential role in obesity risk. We aimed to investigate the association betweenPPARG2Pro12Ala andIL6-174G >C variants and the genotypes interaction with body composition, metabolic markers, food consumption, and physical activity in severely obese patients.Methods. 150 severely obese patients (body mass index (BMI) ≥ 35 kg/m2) from Central Brazil were recruited. Body composition, metabolic parameters, physical activity, and dietary intake were measured. The genotype was determined by the qPCR TaqMan Assays System. Multiple linear regression and multiple logistic regression models were fitted adjusting for confounders.Results. Ala carriers of the Pro12Ala polymorphism had higher adiposity measures (BMI:p=0.031, and fat mass:p=0.049) and systolic blood pressure (p=0.026) compared to Pro homozygotes. We found no important associations between the -174G >C polymorphism and obesity phenotypes. When genotypes were combined, individuals with genotypes ProAla + AlaAla and GC + CC presented higher BMI (p=0.029) and higher polyunsaturated fatty acids (PUFAs) consumption (p=0.045) compared to the ones with genotypes ProPro and GG, and individuals carriers of thePPARG2Ala allele only (genotype ProAla + AlaAla and GG) had higher fat mass and systolic and diastolic blood pressure compared to the ones with genotypes ProPro and GG.Conclusions. Severely obese individuals carrying the Ala allele of thePPARG2Pro12Ala polymorphism had higher measures of adiposity and blood pressure, while no important associations were found for theIL6-174G >C polymorphism.

Effect of F8 B domain gene variants on synthesis, secretion, activity and stability of factor VIII protein

2014 ◽  
Vol 111 (01) ◽  
pp. 58-66 ◽  
Author(s):  
Saskia Pahl ◽  
Anna Pavlova ◽  
Julia Driesen ◽  
Johannes Oldenburg
Keyword(s):  
Intracellular Transport ◽  
Coagulation Factor ◽  
Haemophilia A ◽  
Missense Mutations ◽  
Severe Haemophilia ◽  
Wild Type ◽  
Mild Phenotype ◽  
Cell Lysate ◽  
Fviii Activity

SummaryThe B domain of the coagulation factor (F)VIII comprises some unique characteristics. Though the B domain is important for processing, intracellular transport and secretion of FVIII protein, its role in the coagulation still remains unclear. This study aims to investigate the influence of 19 reported B domain variants on quantity and quality of expressed FVIII protein. F8 variants were transiently expressed in HEK293T cells. Media and cell lysates were collected after 72 hours. FVIII synthesis, relative secretion, activity and thermostability were analysed in comparison to FVIII wild-type. Eleven of 19 analysed B domain variants showed normal FVIII activity (FVIII:C), and antigen values (40–150 %). Eight variants exhibited a decreased FVIII:C, corresponding to a mild phenotype most likely due to impaired expression and secretion mechanism, reduced thermostability or combined mechanisms. One variant, p.His1066Tyr, showed markedly reduced FVIII antigen in cell lysate. The variants p.Asp845Glu, p.His998Gln, and p.Ala1610Ser revealed a significantly decreased relative secretion. Additionally, six B domain variants significantly reduced stability of FVIII. In conclusion, none of the analysed missense mutations was causative for a severe haemophilia A (HA) phenotype. Nevertheless, the mutations p.Asp845Glu, p.Pro947Arg, p.Glu1057Lys, p.His1066Tyr, p.Arg1126Trp, p.Arg1329His, p.Leu1481Pro, and p.Ala1610Ser resulted in decreased FVIII:C values that may explain mild HA phenotypes.

Absence of Inhibitors in Previously Untreated Patients with Severe Haemophilia A after Exposure to a Single Intermediate Purity Factor VIII Product

1997 ◽  
Vol 78 (03) ◽  
pp. 1027-1029 ◽  
Author(s):  
T T Yee ◽  
M D Williams ◽  
F G H Hill ◽  
C A Lee ◽  
K J Pasi
Keyword(s):  
Factor Viii ◽  
High Purity ◽  
Specific Activity ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
True Incidence ◽  
Conventional Fractionation ◽  
Heat Treated ◽  
Recombinant Fviii ◽  
Von Willebrand

SummaryUse of high purity and recombinant factor VIII (FVIII) concentrates has been thought to be associated with an increased incidence of FVIII inhibitors in patients with severe haemophilia A. Comparison with comparable historical control groups has suggested that the true incidence of inhibitors in patients with severe haemophilia A was ~20-25%, similar to the incidence seen with new high purity and recombinant FVIII products.We have conducted a study of inhibitor development in a cohort of 37 boys with severe haemophilia A (VIII: C <2 u/dl) exposed only to a single FVIII concentrate (BPL 8Y) with no previous blood or blood product exposure. This factor VIII concentrate is an intermediate purity product with a specific activity of ~2 IU/mg protein and contains well preserved von Willebrand factor multimers. It is manufactured by conventional fractionation technologies and terminally dry heat treated at 80° C for 72 h.

Case Report on a Female Patient with Congenital Haemophilia a and An Acquired Type-2 Inhibitor to FVIII

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4525-4525
Author(s):  
Karin Kurnik ◽  
Christoph Bidlingmaier
Keyword(s):  
Half Life ◽  
Female Child ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Hormonal Change ◽  
Fviii Inhibitor ◽  
Intron 22 Inversion ◽  
Depth Analysis ◽  
Recombinant Fviii

Abstract Only rare cases of female haemophilia have been reported. Moreover, no case of congenital haemophilia A associated with an acquired type-2 inhibitor to FVIII in a female child has been described in literature yet. We report the case of a 15-year old girl, diagnosed with severe haemophilia A (FVIII:C &lt;1%) at the age of 13 months. Her father suffered from severe haemophilia A (FVIII:C &lt;1%) due to an intron 22 inversion. In the girl both an intron 22 inversion and a non-random X-inactivation were found. At 3 years the girl received prophylactic treatment, and recombinant FVIII (3 × 40 IU/kg/week) from 6 years of age. Bleeding episodes were rare. Aged 13 she developed two large spontaneous haematomas. In-depth analysis confirmed decreased FVIII-recovery, –half-life and an inhibitor titre of 7.6 BU following type-2 kinetics (haemophilic autoantibodies). All of the few reported children with an aquired FVIII inhibitor presented with other autoimmune diseases or had used penicillin. Our patient showed none of this, but interestingly experienced menarche 4 weeks after inhibitor detection. This lets us speculate that the ethiology of the inhibitor formation in our patient at the time of hormonal change might be similar to that in pregnant or postpartum women. Taking into account the recommendations of Ma et al. (2006) regarding inhibitor development during pregnancy in healthy women, we initiated a modified ITI with 75 IU/kg rFVIII concentrate (4,000 IU per infusion) every other day without additional immunosuppressive therapy. After 6 weeks of ITI, inhibitor titres declined and became negative after 8 months, resulting in a normal FVIII half-life till now.

Cross-evaluation of Pharmacokinetic-Guided Dosing Tools for Factor VIII

2018 ◽  
Vol 118 (03) ◽  
pp. 514-525 ◽  
Author(s):  
T. Preijers ◽  
I. van Moort ◽  
K. Fijnvandraat ◽  
F. Leebeek ◽  
M. Cnossen ◽  
...  
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Trough Level ◽  
Patient Characteristics ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Haemophilia A ◽  
Blood Samples ◽  
Fviii Activity ◽  
Recombinant Fviii

Background Patients with severe and moderate haemophilia A are treated prophylactically with factor VIII (FVIII) concentrate. Individualization of prophylaxis can be achieved by pharmacokinetic (PK)-guided dosing. Aim In this study, the performance of three PK tools (myPKFiT, Web-Accessible Population Pharmacokinetic Service-Hemophilia [WAPPS] and NONMEM) is compared. Methods In 39 patients, with severe or moderate haemophilia A, blood samples were collected 4, 24 and 48 hours after administration of 50 IU kg−1 of recombinant FVIII (Advate [n = 30] or Kogenate [n = 9]). FVIII dose, FVIII activity and patient characteristics were entered into the three PK tools. Obtained PK parameters and dosing advises were compared. Results myPKFiT provided PK parameters for 24 of 30 patients receiving Advate, whereas WAPPS and NONMEM provided estimates for all patients. Half-life was different among the three methods: medians were 12.6 hours (n = 24), 11.2 hours (n = 30) and 13.0 hours (n = 30) for myPKFiT, WAPPS and NONMEM (p < 0.001), respectively. To maintain a FVIII trough level of 0.01 IU mL−1 after 48 hours, doses for myPKFiT and NONMEM were 15.1 and 11.0 IU kg−1 (p < 0.01, n = 11) and for WAPPS and NONMEM were 9.0 and 8.0 IU kg−1 (p < 0.01, n = 23), respectively. In nine patients receiving Kogenate, WAPPS and NONMEM produced different PK-parameter estimates; half-life was 15.0 and 12.3 hours and time to 0.05 IU mL−1 was 69.2 and 60.8 hours, respectively (p < 0.01, n = 9). However, recommended doses to obtain these levels were not different. Conclusion The three evaluated PK tools produced different PK parameters and doses for recombinant FVIII. Haematologists should be aware that recommended doses may be influenced by the choice of PK tool.

Sign in / Sign up

Export Citation Format

Share Document