scholarly journals Terminal Half-Life of Factor VIII/IX According to Age and Blood Group Based on 8550 Assessments

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-23
Author(s):  
Olav Versloot ◽  
Emma Iserman ◽  
Pierre Chelle ◽  
Federico Germini ◽  
Tushara Mathew ◽  
...  
Keyword(s):  
Factor Viii ◽  
Blood Group ◽  
Half Life ◽  
Research Funding ◽  
Linear Models ◽  
Real Life ◽  
Population Pharmacokinetic ◽  
Haemophilia A ◽  
Terminal Half Life ◽  
History Of

Introduction: Extended half-life concentrates were recently introduced and limited data have shown extended terminal half-life (THL). However, real-life data on pharmacokinetics in large cohorts of patients with haemophilia (PWH) and information on the effects of age, body composition and blood group (THL) are lacking. Aim: to assess THL for standard half-life (SHL) and extended half-life (EHL) concentrates according to age and blood group. Methods: Data on THL, age and blood group were extracted from the WAPPS (Web-Accessible Population Pharmacokinetics Service; www.wapps-hemo.org) database. WAPPS provides an on-line service of individual pharmacokinetic (PK) calculations for clinicians, based on concentrate-specific population pharmacokinetic models. Informed consent was waived by the ethical committee. THL according to age and blood group was assessed by multivariable linear modelling. Results: Infusion data (n=8550) was collected from 4832 (2222 children, 2610 adults) patients with severe haemophilia (89% haemophilia A; 34% treated with EHL concentrates, 9.7% with history of inhibitors, median age: 20 (range: 1 month - 85 years)). Details on infusions, calculated THL and results from regression models are shown in Table 1. For factor VIII, median THL was longer in EHL at 15.1 hours (interquartile range (IQR): 12.0-19.0) vs. 11.1 hours (8.8-14.2) in SHL-FVIII. Linear models identified age, type of concentrate and blood group as independent predictors of THL in FVIII. THL increased with age by 1 hour/10 years, and THL was 2.2 hours longer in patients with blood group non-O, independent of concentrate type. For FIX, median THL was considerably longer in EHL at median 106.9 (81.1-134.2) vs. 36.5 (31.2-42.6) hours in SHL. Age was only a significant predictor of THL in children using EHL-FIX concentrates: THL increased by 2,5 hours/year until adulthood for EHL concentrates (e.g.: from 77 hrs at age 4 to 112 hrs at age 18), whereas THL was stable across all ages for SHL-FIX. THL was stable across blood groups for all FIX concentrates. In PWH with a positive inhibitor history, THL was decreased by 1,3 hours for FVIII and 22 hours for FIX. Discussion: This study was the largest study describing THL according to concentrate type and patient characteristics so far. At group level, a significant extension of THL was confirmed for both FVIII-EHL and FIX-EHL. THL was associated with age and blood group for all FVIII concentrates. In contrast, THL for FIX concentrates, was only associated with age in children using EHL-FIX. THL was significantly reduced in patients with a history of inhibitors. The results support the need for individual assessment of THL, especially for patients with haemophilia A and children treated with EHL-FIX. This was a group-based study. Within the age of personalized medicine, individualized PK assessments seem more appropriate. Our next project will be to analyse the effects of switching from SHL to EHL in individual patients. Disclosures Versloot: Bayer: Research Funding. Germini:Bayer: Research Funding; Roche: Research Funding; Takeda: Research Funding; NovoNordisk: Research Funding. Iorio:CSL: Research Funding; BioMarin: Research Funding; Bayer: Research Funding; Uniqure: Research Funding; Takeda: Research Funding; Spark: Research Funding; Sanofi: Research Funding; Roche: Research Funding; Pfizer: Research Funding; Octapharma: Research Funding; NovoNordisk: Research Funding; Grifols: Research Funding; Freeline: Research Funding. Fischer:Bayer, Biogen, Pfizer, Baxter/Shire, and Novo Nordisk: Research Funding; Bayer, Baxter, Biogen, CSL Behring, Freeline, Novo Nordisk, Pfizer, Roche, and Sobi: Consultancy; Bayer, Baxter/Shire, SOBI/Biogen, CSL Behring, Octapharma, Pfizer, NovoNordisk: Research Funding.

scholarly journals A Method for Deriving Pharmacokinetic Constants for Factor VIII and IX from Limited Blood Sampling

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3501-3501 ◽  
Author(s):  
Miguel Antonio Escobar ◽  
Daniel Preston Bond ◽  
Madeline Cantini ◽  
Krishna Cannon
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Research Funding ◽  
Decay Constant ◽  
Hemophilia A ◽  
Health Science ◽  
Blood Sampling ◽  
Population Pharmacokinetic ◽  
Viii And Ix ◽  
Trough Levels

Abstract Introduction The treatment of hemophilia A and B is based on the replacement of the deficient factor dosed by weight. However, dosing for hemophilia treatment has been arrived at by empiric assessment, essentially "trial and error" based on the pharmacokinetics (PK) of the factors and the characteristics of the replacement product. In the last decade clinical pharmacokinetics has gained popularity in hemophilia so that factor dosage can be adjusted according to the requirement of the individual patient. Factor-specific population pharmacokinetic models have been developed for individualized treatment of patients with hemophilia A and B. The math modeling technique presented in this project relies on minimal blood sampling to derive the constants necessary to predict the peak and trough levels within the commonly excepted error bounds. Methods Data that included FVIII, FIX levels and weight were obtained retrospectively from severe hemophilia A and B adult patients and approved by the ethics committee of the University of Texas Health Science Center. A single compartment decay model equation was used in both a custom iOS application and an Excel spreadsheet to calculate the decay constant between any 2 points on a decay curve. Using this local constant as the half-life in the standard decay equation allowed the calculation of the peak at time = 0. This peak combined with dosing information and the subject's weight allowed the calculation of the Recovery. These 2 constants in the equation: Level=(dose*Recovery/weight)*0.5^(time/half-life) allowed the calculation of the level at any point on the curve. Using this method on several example datasets showed that the model is reasonably able to predict peak and trough levels for both factor VIII and IX. Because of the time dependent nature of the local decay constant, better results are obtained using data points after the first half of the expected half-life. This method can also be used to predict steady state levels, peaks and troughs for any prophylaxis schedule. Conclusion Appropriate dosing of factor VIII or IX is at best an approximate calculation. The method described in this publication generates a math model that is generally as accurate as a multiple sample PK study with far fewer blood samples taken. Clinical applications of this model can be utilized to predict factor levels after a single infusion of factor VIII/IX in adults that are treated on-demand or prophylaxis. It can also be utilized in individuals that are infusing extended half-life products or in the surgical setting. Disclosures Escobar: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bond:Pfizer: Consultancy, Research Funding. Cantini:Pfizer: Research Funding. Cannon:Pfizer: Research Funding.

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.

The natural history of the immune response to exogenous factor VIII in severe haemophilia A

Haemophilia ◽  
1998 ◽  
Vol 4 (4) ◽  
pp. 546-551 ◽  
Author(s):  
C. A. Lee ◽  
C. M. Kessler ◽  
D. Varon ◽  
U. Martinowitz ◽  
M. Heim ◽  
...  
Keyword(s):  
Immune Response ◽  
Natural History ◽  
Factor Viii ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Exogenous Factor ◽  
History Of

Continuous infusion of extended half-life factor VIII (efmoroctocog alpha) for surgery in severe haemophilia A

Haemophilia ◽  
2018 ◽  
Vol 24 (4) ◽  
pp. e280-e283
Author(s):  
I. C. L. Kremer Hovinga ◽  
R. E. G. Schutgens ◽  
P. R. van der Valk ◽  
L. F. D. van Vulpen ◽  
E. P. Mauser-Bunschoten ◽  
...  
Keyword(s):  
Factor Viii ◽  
Continuous Infusion ◽  
Half Life ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Life Factor

scholarly journals Influence of blood group, von Willebrand factor levels, and age on factor VIII levels in non‐severe haemophilia A

2020 ◽  
Vol 18 (5) ◽  
pp. 1081-1086
Author(s):  
Judit Rejtő ◽  
Oliver Königsbrügge ◽  
Ella Grilz ◽  
Stefanie Hofer ◽  
Lisa‐Marie Mauracher ◽  
...  
Keyword(s):  
Factor Viii ◽  
Blood Group ◽  
Von Willebrand Factor ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Von Willebrand ◽  
Willebrand Factor

scholarly journals Real Life Population Pharmacokinetics Modelling of Eight Factors VIII in Patients with Severe Haemophilia A: Is It Always Relevant to Switch to an Extended Half-Life?

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 380 ◽  
Author(s):  
Quentin Allard ◽  
Zoubir Djerada ◽  
Claire Pouplard ◽  
Yohann Repessé ◽  
Dominique Desprez ◽  
...  
Keyword(s):  
Half Life ◽  
Random Effect ◽  
Real Life ◽  
Compartment Model ◽  
Central Compartment ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Severe Haemophilia ◽  
Fviii Activity ◽  
Data Files

We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.

Target Joint Bleeding in Pediatric Patients with Hemophilia Α Receiving Twice Weekly Prophylaxis with a Pegylated Full-Length Recombinant Factor VIII with Extended Half-Life

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3778-3778
Author(s):  
Amy L. Dunn ◽  
Alexis A. Thompson ◽  
Werner Engl ◽  
Marlies Sharkhawy ◽  
Brigitt E. Abbuehl
Keyword(s):  
Factor Viii ◽  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Pediatric Patients ◽  
Hemophilia A ◽  
Point Estimate ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
The Mean

Abstract Introduction: Patients with hemophilia A are at risk for acute bleeding which may affect muscles and other soft tissues but characteristically involves joints. Prophylaxis with factor VIII (FVIII) is the optimal treatment to prevent bleeding into joints and, when begun at a young age, may prevent arthropathy. BAX 8551, a polyethylene glycol (peg)ylated, full-length, recombinant FVIII built on ADVATE2, demonstrated extended half-life, efficacy, and safety for prophylaxis and treatment of bleeding in patients with severe hemophilia A. Methods: A phase 3, prospective, uncontrolled, multicenter study was performed in pediatric patients with severe hemophilia A without history of inhibitors. To be eligible, patients aged <6 years had to have ≥50, those aged 6 to <12 years ≥150 previous exposure days (EDs) to FVIII. Patients received twice weekly infusions of 50 ±10 IU/kg of BAX 855 over a period of 6 months or ≥50 EDs. The prevalence of target joints, defined as a single joint with ≥3 spontaneous bleeding episodes in any consecutive 6-month period, was assessed at baseline. Annualized rates of target joint bleeds and the course of target joints were evaluated by age (<6 and 6 to <12 years). The study was performed in accordance with the principles of the Declaration of Helsinki of the World Medical Association. Results:Sixty-six patients were treated with a mean (SD) BAX 855 dose of 51.1 (5.5) IU/kg at a mean (SD) frequency of 1.8 (0.2) infusions/week. Fourteen of 66 patients (21.2%), 3/32 (9.4%) in the younger and 11/34 (32.4%) in the older cohort, had a total of 23 target joints at screening. The number of target joint bleeds decreased during a mean (SD) of 48.5 (7.7; median: 49.0) prophylactic EDs/patient. Five of 66 (7.6%) patients had at least 1 target joint bleed, 1/32 (3.1%) in the younger and 4/34 (11.8%) in the older cohort. The point estimate for the mean (95% CI) annualized rate of target joint bleeds was 0 (0 - infinity; median: 0) compared to an annualized rate of all joint bleeds of 1.1 (0.6 - 1.9; median: 0) and an annualized rate of all bleeds of 3.0 (2.2 - 4.2; median: 2.0) (Table 1). The point estimate for the mean (95% CI) annualized bleeding rate (ABR) in 52 patients without target joints was 2.9 (2.0 - 4.2; median: 2.0) and was similar in 14 patients with target joints at screening at 3.5 (1.9 - 6.6; median: 2.1). In the younger cohort, the ABR was lower in patients with than those without target joints. However, the number of patients <6 years with target joints (N = 3) was too small to draw any conclusions (Table 1). During BAX 855 prophylaxis, no new target joints developed in any patient. Ten of 14 patients had at least 1 target joint revert to a non-target joint. In 8 of these 10 patients, 4 with 1 and 4 with 2 target joints, all target joints resolved. Conclusions:These results suggest that twice weekly infusion of BAX 855 is effective in the prevention of bleeding into target joints and may revert target to non-target joints in pediatric patients with severe hemophilia A. 1BAX 855 (Baxalta US Inc., now part of Shire) is licensed in the US and Japan under the trade name ADYNOVATE. 2ADVATE is a trade mark of Baxalta US Inc., now part of Shire. Disclosures Dunn: NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Research Funding; Pfizer: Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta (now part of Shire): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Research Funding. Thompson:Eli Lily: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; bluebird bio: Consultancy, Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mast: Research Funding; Amgen: Research Funding; Baxalta (now part of Shire): Research Funding. Engl:Shire: Employment, Equity Ownership. Sharkhawy:Baxalta (now part of Shire): Employment. Abbuehl:Baxalta (now part of Shire): Employment.

Safety and efficacy of a glycoPEGylated rFVIII (turoctocog alpha pegol, N8-GP) in paediatric patients with severe haemophilia A

2017 ◽  
Vol 117 (09) ◽  
pp. 1705-1713 ◽  
Author(s):  
Sandrine Meunier ◽  
Jayanthi Alamelu ◽  
Silke Ehrenforth ◽  
Hideji Hanabusa ◽  
Faraizah Abdul Karim ◽  
...  
Keyword(s):  
Half Life ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Older Children ◽  
Open Label ◽  
Paediatric Patients ◽  
Effective Prophylaxis ◽  
History Of ◽  
Previously Treated Patients ◽  
Previously Treated

SummaryTuroctocog alfa pegol (N8-GP, Novo Nordisk, Bagsværd, Denmark), an extended half-life glycoPEGylated recombinant factor VIII (rFVIII), is being developed for prophylaxis and treatment of bleeds in haemophilia A patients. pathfinder™5 is a multinational, open-label, single-arm trial to assess safety, efficacy and pharmacokinetics of N8-GP in paediatric (<12 years), previously treated patients. Boys with severe haemophilia A (<1 % FVIII), no history of inhibitors and previously treated with FVIII products (>50 exposure days [ED] for patients aged 0–5 years [younger cohort]; >150 ED for patients aged 6–11 years [older cohort]) were included. For prophylaxis, N8-GP was dosed at 50–75 IU/kg twice weekly; bleeds were treated with 20–75 IU/kg. Half-life was estimated for the patients’ previous FVIII product and for N8-GP. Sixty-eight patients received N8-GP; none developed inhibitors and no other concerns were identified. Median annualised bleeding rate was 1.95 (1.94 and 1.97 in the younger and older cohorts, respectively). Twenty-nine patients (42.6 %; 15 younger and 14 older children, respectively) did not report any bleeding while on N8-GP prophylaxis; 39 patients (57.4 %; 19 younger and 20 older children, respectively) reported 70 bleeds (all mild/moderate). N8-GP treatment was successful for 78.6 % of bleeds in all patients, 80.0 % in younger and 77.5 % in older patients. Most bleeds (80.0 %) were treated with ≤2 injections. Half-life ratio between N8-GP and the patients’ previous FVIII product was 1.85. N8-GP was well tolerated and provided effective prophylaxis and treatment of bleeds in paediatric patients with severe haemophilia A.Trial registered at www.clinicaltrials.gov (NCT01731600).Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals Immune Tolerance Induction with Simoctocog Alfa (Nuwiq®) in Six Patients with Severe Haemophilia a and FVIII Inhibitors

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5037-5037
Author(s):  
Neha Bhatnagar ◽  
Kate Khair ◽  
Ri Liesner ◽  
Alice Wilkinson ◽  
Larisa Belyanskaya
Keyword(s):  
Immune Tolerance ◽  
Half Life ◽  
Research Funding ◽  
Poor Prognosis ◽  
Case Series ◽  
Tolerance Induction ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Immune Tolerance Induction ◽  
Inhibitor Titre

Abstract Introduction and Objective: Inhibitors to coagulation factor VIII (FVIII) are the most serious complication of haemophilia A treatment. Previously untreated patients (PUPs) are at the greatest risk of inhibitors, which generally occur within the first 20 exposure days (ED) to FVIII. Immune tolerance induction (ITI) is the only clinically proven strategy for eradication of inhibitors. We present a case series of six PUPs with severe haemophilia A and inhibitors who underwent ITI with simoctocog alfa (Nuwiq®), a 4th generation human cell-line-derived recombinant FVIII approved for treatment of haemophilia A. Materials and Methods: Six male PUPs with severe haemophilia A who developed FVIII inhibitors after treatment with simoctocog alfa were started on ITI with simoctocog alfa. Primarily, we assessed the success of simoctocog alfa in patients with inhibitors. Success of ITI was determined based on undetectable inhibitor titre (< 0.6 BU/ml), FVIII recovery ≥ 66% and half-life ≥ 6 hours. Secondary objectives were to assess bleeding rate, tolerability and safety in patients with inhibitors treated with simoctocog alfa ITI. Results: The age of the patients at the start of ITI ranged from 8 to 186 months. Four of the patients were Caucasian, and two were African. All patients had a F8 mutation associated with high risk of ITI failure and two patients had an additional risk factor for ITI failure. The number of EDs prior to inhibitor development ranged from 9 to 33, and the peak inhibitor titre ranged from 0.9 to 114 BU. For ITI, five patients were treated with 100 IU/kg simoctocog alfa daily, and one with 90 IU/kg every other day. One patient achieved complete tolerisation and is now on prophylaxis at normal doses, having achieved an undetectable inhibitor titre after 9 months. This was despite an inhibitor titre ≥ 10 BU/mL at ITI start, which is considered a poor prognosis factor for ITI success. Three other patients achieved an undetectable inhibitor titre after 1, 6 and 18 months of ITI, and FVIII recovery has normalised but half-life remains short and they are on weaning doses as the half-life extends. One patient discontinued ITI with simoctocog alfa after 15 months due to an increasing inhibitor level. This patient was 15 years old at ITI start, and older age is associated with poor ITI outcome. Additionally, his haemophilia A was untreated for 15 years, during which time he developed severe arthropathy. One patient, who started ITI 3 months ago, has an ongoing inhibitor titre and continues on ITI with simoctocog alfa. Conclusions: In a case series of six patients treated with simoctocog alfa for ITI, who all had poor prognosis factors for ITI success, four patients (67%) to date have achieved an undetectable inhibitor titre. These data suggest that ITI with simoctocog alfa may be an effective treatment approach in haemophilia A patients with inhibitors. Disclosures Khair: Shire, SOBI, Pfizer, Roche, Novo Nordisk, Octapharma: Speakers Bureau; shire, SOBI, Pfizer, Roche: Research Funding. Liesner:Roche: Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Baxalta: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Octapharma: Consultancy, Other: Clinical study investigator for NuProtect Study (Octapharma sponsored), Research Funding, Speakers Bureau; Sobi: Speakers Bureau. Belyanskaya:Octapharma AG: Employment.

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