63 research outputs found
Simplifying surgery in haemophilia B: Low factor IX consumption and infrequent infusions in surgical procedures with rIX-FP.
Abstract Introduction Long-acting recombinant factor IX (FIX) products may simplify the surgical treatment of haemophilia B patients. The impact of rIX-FP, a recombinant FIX fused to recombinant albumin, on FIX consumption and surgical management was assessed in patients with haemophilia B. Materials and methods Male patients, â€65 years old with severe haemophilia B (FIX activity â€2%) requiring non-emergency surgery were enrolled in the surgical substudy of PROLONG-9FP. Dosing was based on World Federation of Hemophilia guidelines and patients' pharmacokinetics. Haemostatic efficacy was assessed on a 4-point scale. rIX-FP consumption and safety were monitored throughout the perioperative period. Results This updated dataset reports on thirty (8 minor and 22 major) surgeries conducted in 21 patients. A single preoperative bolus was used in 96.7% (n = 29) of surgeries. After minor surgery, patients received a median (range) of 0 (0â3) infusions with a median (range) consumption of 0 (0â178.89) IU/kg in the 14-day postoperative period. In patients who underwent major surgery (including 15 patients undergoing joint replacement surgery), the median (range) number of infusions in the 14-day postoperative period was 5 (0â11) and median consumption was 221.7 (0â444.07) IU/kg. Haemostatic efficacy was rated as excellent or good in 87.5% (7/8) of minor surgeries and 95.5% (21/22) of major surgeries. Conclusion Surgical procedures can be performed using a single preoperative bolus of rIX-FP in nearly all patients. During postoperative care, use of rIX-FP necessitated infrequent infusions and low FIX consumption. Overall, data suggest rIX-FP simplifies perioperative care in patients with haemophilia B
Efficacy and safety of long-acting recombinant fusion protein linking factor IX with albumin in haemophilia B patients undergoing surgery.
IntroductionRecombinant factor IX fusion protein (rIXâFP) has been developed to improve the pharmacokinetic (PK) profile of factor IX (FIX), allowing maintenance of desired FIX activity between injections at extended intervals, ultimately optimizing haemophilia B treatment.AimTo determine the efficacy and safety of rIXâFP in the perioperative setting.MethodsSubjects were adult and paediatric patients with severe to moderately severe haemophilia B (FIX †2%) participating in three Phase III clinical trials and undergoing a surgical procedure. PK profiles were established prior to surgery for each patient. Haemostatic efficacy was assessed by the investigator for up to 72 h after surgery. Safety measurements during the study included adverse events and inhibitors to FIX. FIX activity was monitored during and after surgery to determine if repeat dosing was required.ResultsTwentyâone, both major and minor, surgeries were performed in 19 patients. Haemostatic efficacy was rated as excellent (n = 17) or good (n = 4) in all surgeries. A single preoperative dose maintained intraoperative haemostasis in 20 of 21 surgeries. Nine major orthopaedic surgeries were conducted in eight patients with a mean of 7 (range: 6â12) rIXâFP injections during surgery and the 14âday postoperative period. Median rIXâFP consumption for orthopaedic surgeries was 87 IU kgâ1 preoperatively and 375 IU kgâ1 overall. No subject developed inhibitors to FIX or antibodies to rIXâFP.ConclusionRecombinant factor IX fusion protein was well tolerated and effectively maintained haemostasis during and after surgery. Stable FIX activity was achieved with a prolonged dosing interval and reduced consumption compared to conventional or currently available longâacting recombinant FIX
Le facteur VIII porcin recombinant chez les patients atteints d'hémophilie A avec inhibiteurs
L'hĂ©mophilie A est une maladie hĂ©morragique hĂ©rĂ©ditaire rare caractĂ©risĂ©e par un dĂ©ficit en facteur VIII (FVIII) de la coagulation, pouvant se compliquer par le dĂ©veloppement d'inhibiteurs anti-FVIII. Les inhibiteurs du FVIII sont souvent moins rĂ©actifs vis-Ă -vis du FVIII porcin (FVIIIp) que du FVIII humain (FVIIIh), supposant qu'un concentrĂ© du FVIHp pourrait devenir une option thĂ©rapeutique pour les patients ayant dĂ©veloppĂ© des inhibiteurs. L'objectif Ă©tait de dĂ©terminer l'efficacitĂ© hĂ©mostatique in vitro de doses croissantes d'OBI-1, un concentrĂ© de facteur VIII (FVIII) recombinant d'origine porcine,avec dĂ©lĂ©tion du domaine B, Ă l'aide de tests globaux de l'hĂ©mostase, en se basant sur les titres des inhibiteurs anti-FVIIIhumain (anti-FVIIIh) et anti-FVIII porcin (anti-FVIIIp) et sur les Ă©pitopes ciblĂ©s par ces inhibiteurs. OBI-1 Ă©tait ajoutĂ© in vitro dans les plasmas de patients hĂ©mophiles A sĂ©vĂšres avec inhibiteurs Ă raison de 0, 2,7, 5,4 et 10,8 U mL- 1 correspondant aux doses 0, 100,200 et 400 U kg-1 , respectivement. Les inhibiteurs anti-FVIIIh et anti-FVIIIp Ă©taient considĂ©rĂ©s comme faibles, modĂ©rĂ©s et forts aprĂšs titrage par la mĂ©thode Nijmegen Ă 5-10 et> 10 UB mL-\ respectivement. Des tests globaux de l'hĂ©mostase tels que la thromboĂ©lastographie (TEG), le test de gĂ©nĂ©ration de thrombine (TGT) suivi de l'analyse par microscopie Ă©lectronique du caillot, Ă©taient rĂ©alisĂ©s pour l'ensemble des plasmas. L'Ă©pitope mapping Ă©tait rĂ©alisĂ© par ELISA directe. Nous avons utilisĂ©s des analyses statistiques de variance (ANOV A), de corrĂ©lation de Spearman et de t-test. Une valeur de p <0,05 considĂ©rĂ©e comme significative. Vingt-et-un patients atteints d'hĂ©mophilie A sĂ©vĂšres avec inhibiteurs ont Ă©tĂ© inclus dans l'Ă©tude. Respectivement, des titres faibles, modĂ©rĂ©s et forts Ă©taient retrouvĂ©s pour 6, 2 et 13, et 10, 0 et 11 des inhibiteurs anti-FVIIlh et anti-FVIIIp. Parmi 16 patients n'ayant pas reçu de traitement antĂ©rieur par FVIIIp, la rĂ©activitĂ© croisĂ©e Ă©tait de 62%. Trois paramĂštres de TGT, l'ETP, le pic de thrombine et le temps jusqu'au pic, montraient une amĂ©lioration de la capacitĂ© de gĂ©nĂ©ration de thrombine dĂ©pendante de la dose (p<O,OOO 1, p=0,0006 et p=0,0001, respectivement) et du titre des inhibiteurs anti-FVIIIp (r=-0,67; p=0,0009). Le mĂȘme effet Ă©tait retrouvĂ© pour le raccourcissement du temps de coagulation explorĂ© par TEG (p<O,OOO 1 ). Les domaines C2 et A2 reprĂ©sentaient 40 et 35% des Ă©pitopes, respectivement. Aucune relation n'apparaissait entre les Ă©pitopes et la restauration de la capacitĂ© hĂ©mostatique des plasmas contenant des inhibiteurs. 081-1 a prouvĂ© son efficacitĂ© Ă restaurer une capacitĂ© hĂ©mostatique satisfaisante dans les plasmas, dĂ©pendante de la dose et du titre des inhibiteurs anti-FVIIIp. Des Ă©tudes cliniques actuellement en cours d'investigation devraient permettre de confirmer ces rĂ©sultats in vivoLYON1-BU SantĂ© (693882101) / SudocSudocFranceF
Histoire des techniques d'hémostase de l'Antiquité à nos jours
LYON1-BU Santé (693882101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF
Transfusion Medicine 3 Coagulation factor concentrates: past, present, and future
Clotting factor transfusions are vital for people with diseases such as haemophilia. In the 1970s and 1980s, transfusions with pooled plasma led to a devastatingly high number of recipients becoming infected with blood-borne pathogens such as HIV and hepatitis C. This epidemic triggered the development of virus-free factor concentrates through a combination of improved donor selection and screening, eff ective virucidal technologies, and recombinant protein expression biotechnology. There is now a wide range of recombinant factor concentrates, and an impressive safety record with respect to pathogen transmission. However, remaining therapeutic challenges include the potential threat of transmission of prions and other pathogens, the formation of inhibitory alloantibodies, and the international disparity that exists in product availability due to diff erences in licensure status as well as prohibitively high costs. In the future, it is likely that bioengineered recombinant proteins that have been modifi ed to enhance pharmacokinetic properties or reduce immunogenicity, or both, will be used increasingly in clinical practice
Phénotypage du systÚme de coagulation sanguine par la mesure de génération de thrombine (étude pré-clinique et applications cliniques innovantes)
L'exploration de l'hĂ©mostase est basĂ©e sur la mesure des temps de coagulation ou des activitĂ©s des diffĂ©rentes protĂ©ines de la coagulation. Cette approche a une faible valeur prĂ©dictive du risque individuel hĂ©morragique ou thrombotique encouru par les patients. Nous avons Ă©tudiĂ© le test de gĂ©nĂ©ration de thrombine pour le phĂ©notypage de la coagulation. Les conditions prĂ©analytiques et analytiques permettant de s'approcher le plus possible des conditions physiologiques ont Ă©tĂ© dĂ©terminĂ©es avec une bonne rĂ©pĂ©tabilitĂ©, reproductibilitĂ© du test permettant son utilisation dans des laboratoires hospitaliers. Nous avons montrĂ© que le test pouvait dĂ©tecter l'hypo- et hypercoagulabilitĂ©s liĂ©es Ă l'hĂ©mophilie et aux thromboses veineuses. Nous avons Ă©tabli une relation entre l'ETP et le risque d'Ă©vĂ©nement clinique hĂ©morragique ou thrombotique chez les hĂ©mophiles et les patients thrombotiques. Le test peut aussi ĂȘtre utilisĂ© pour la surveillance des traitements antihĂ©mophiliquesLYON1-BU.Sciences (692662101) / SudocSudocFranceF
AccessibilitĂ© aux mĂ©dicaments dans le cadre dâune maladie rare, un enjeu de pharmacie clinique : apport de la gĂ©ographie en santĂ© pour lâanalyse dâune cohorte de personnes hĂ©mophiles
International audienc
Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with hemophilia B
Replacement therapy with factor IX (FIX) concentrates is the recommended treatment for patients with hemophilia B, an X-linked bleeding disorder occurring in 1: 25 000 male births. N9-GP is a recombinant FIX molecule with a prolonged half-life which is obtained by site-directed glycoPEGylation where a 40-kDa polyethylene glycol molecule is attached to the activation peptide of FIX. This first human dose trial in patients with hemophilia B investigated the safety and pharmacokinetic properties of a single IV dose of N9-GP. Sixteen previously treated patients received one dose of their previous FIX product followed by one dose of N9-GP at the same dose level (25, 50, or 100 U/kg). None of the patients developed inhibitors. One patient developed transient hypersensitivity symptoms during administration of N9-GP and was excluded from pharmacokinetic analyses. In the remaining 15 patients, N9-GP was well-tolerated. The half-life was 93 hours, which was 5 times higher than the patient's previous product. The incremental recovery of N9-GP was 94% and 20% higher compared with recombinant and plasma-derived products, respectively. These results indicate that N9-GP has the potential to reduce dosing frequency while providing effective treatment of bleeding episodes with a single dose. The trial was registered at www.clinicaltrials.gov as NCT00956345. (Blood. 2011;118(10):2695-2701
AccessibilitĂ© aux mĂ©dicaments dans le cadre dâune maladie rare, un enjeu de pharmacie clinique : apport de la gĂ©ographie en santĂ© pour lâanalyse dâune cohorte de personnes hĂ©mophiles
International audienc
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