scholarly journals Measurement of extended half‐life recombinant factor IX products in clinical practice

2018 ◽  
Vol 41 (2) ◽  
pp. e46-e49 ◽  
Author(s):  
Annette E. Bowyer ◽  
M. Fiona Shepherd ◽  
Steve Kitchen ◽  
Rhona M. Maclean ◽  
Mike Makris
Keyword(s):  
Clinical Practice ◽  
Half Life ◽  
Factor Ix ◽  
Recombinant Factor Ix

A Pharmacokinetic Study of the Plasma-Derived Factor IX AlphaNine® and Its Comparison with the Recombinant Factor IX BeneFIX®, in Previously Treated Patients with Severe Hereditary Hemophilia B.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3955-3955
Author(s):  
Vicente R. Cortina ◽  
T. Lissichkov ◽  
K. Zavilska ◽  
M. Matysiak ◽  
L. Gercheva ◽  
...  
Keyword(s):  
Half Life ◽  
Factor Ix ◽  
Hemophilia B ◽  
Severe Haemophilia ◽  
Open Label ◽  
Recombinant Factor Ix ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
In Vivo Recovery

Abstract Objectives The objective of the present study was two fold: first, to determine the pharmacokinetic (PK) profile of the plasma-derived FIX concentrate AlphaNine® in patients with congenital severe haemophilia B (FIX:C 2%). To do this, two PK studies were carried out one six months after the first. The second objective was a comparison of the Alphanine® PK profile with the recombinant Factor IX, BeneFIX®. Patients and methods The first study was a prospective, five-center, open-label, comparative, PK study carried out in 25 severe hemophilia B patients who received 2 single doses of 65–75 IU/kg of AlphaNine® within 6 months (t=0 and t=6). The following parameters were assessed: in vivo recovery, half-life, AUC, mean residence time and clearance. As an extension of the study, a single dose of 65–75 IU/kg of BeneFIX® was administered in 9 out of 25 patients, after a wash-out period of 7–15 days. Results Table 1 summarizes the results obtained when comparing AlphaNine® within a period of time of 6 months (PK1 vs PK2) in 25 patients. Table 2 shows the results obtained when comparing the in vivo recovery of AlphaNine ® vs BeneFIX ® in the 9 patients studied. Conclusions These results confirm that AlphaNine® PK has similar profile as other plasma derived FIX products presently available to treat Hemophilia B patients. In addition, our results show that the recombinant FIX studied, BeneFIX® has a reduced in vivo recovery when is compared to AlphaNine®. Table 1 Parameter AlphaNine® (PK1) t=0 m AlphaNine® (PK2) t=6 m Results are expressed as Mean (SD) In vivo recovery (IU/dl:IU/kg) 1.0 (0.2) 1.2 (0.4) Half-life (h) 34.5 (6.2) 33.7 (5.4) Clearance (ml/min) 0.07 (0.01) 0.07 (0.01) AUC0-inf (IUxh/dl) 1602 (312) 1644 (360) MRT0-inf (h) 35.8 (5.4) 34.6 (5.2) Table 2 Parameter AlphaNine® (PK2) BeneFIX® Results are expressed as Mean (SD); * p<0.05 for the comparison of the in vivo recovery for the BeneFIX® group with the AlphaNine® PK2 In vivo recovery (IU/dl:IU/kg) 1.3 (0.5) 0.8 (0.2)*

Pharmacokinetic Behavior of IB1001, An Investigational Recombinant Factor IX, in Patients with Hemophilia B: Repeat Pharmacokinetic Study and Subgroup Analysis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2267-2267
Author(s):  
Uri Martinowitz ◽  
Amy D. Shapiro ◽  
Doris V. Quon ◽  
Miguel Antonio Escobar ◽  
Christine L Kempton ◽  
...  
Keyword(s):  
Subgroup Analysis ◽  
Half Life ◽  
Biological Variation ◽  
Factor Ix ◽  
Hemophilia B ◽  
Maximum Plasma ◽  
Recombinant Factor Ix ◽  
The Stability ◽  
Over Time ◽  
Group 1

Abstract Abstract 2267 Introduction IB1001 is an investigational recombinant factor IX for the treatment and prevention of bleeding in individuals with hemophilia B. A randomized cross-over pharmacokinetic (PK) study demonstrated that IB1001 (75 IU/kg) compared with nonacog alfa (BeneFIX®). was non-inferior (lower bound of the 1-sided 95% confidence interval for the area under the concentration curve [AUC0–∞] was 90%) and was well tolerated. Here we report the findings from a repeat PK assessment, in which a subset of patients underwent a second PK evaluation with IB1001 only. In addition, we present the results of an exploratory analysis of IB1001 PK parameters to assess the relationship between the degree of sialylation and the pharmacokinetics of recombinant factor IX. [Griffith MJ et al. J Thromb Haemost 5 (Suppl 1), PM–043, 2007]. Methods In the randomized PK study, patients were assigned to receive 75 ± 5 IU/kg of IB1001 or nonacog alfa following a washout period of ≥5 days. Factor IX levels were determined pre-infusion and at 30 minutes, 1, 3, 6, 9, 12, 24, 36, 48, 60, and 72 hours post-infusion. The evaluation was repeated 5–28 days later, when a 75 ± 5 IU/kg dose of the alternate therapy was administered. Factor IX levels were assessed at the same time points. The repeat PK assessment was planned to include patients who had received 3–6 months of IB1001 prophylaxis following their initial PK assessment. Calculated PK parameters were identical to those determined during the randomized PK study: half-life (β-phase t1/2, determined using a robust regression approach [Lee ML et al. XVIth ISTH Congress, Florence, Italy, 1997]), maximum plasma concentration (Cmax) and AUC(0-∞) (determined by the trapezoidal rule). To explore the association between sialylation level and the PK behavior of IB1001, patients in the randomized PK study (n=32) were allocated to one of three subgroups based on the sialylation levels of the IB1001 lots used (see Table). Results Thirty-two evaluable patients were enrolled in the randomized PK study (Feb 2009–Aug 2010). Of these, 13 underwent repeat PK assessments with IB1001 after receiving 4–18 months of prophylaxis with IB1001. The results demonstrate the stability of PK parameters following up to 18 months of exposure to IB1001. No significant reduction in factor IX recovery or elimination half-life occurred in any patients over time. The sialylation subgroup analysis revealed that the use of IB1001 lots with the lowest sialylation levels (Group 1) resulted in slightly lower AUC levels when compared with nonacog alfa (see Table). When lots with intermediate or the highest sialylation levels were used, the AUC of IB1001 appeared similar (Group 2), or slightly higher (Group 3), than the corresponding nonacog alfa values. Although Cmax of IB1001 was lower in Group 1, it appears comparable with the nonacog alfa controls in all groups, suggesting that this was not an effect of sialylation but of individual biological variation. Conclusions The stability of IB1001 PK profile during prophylactic use was demonstrated in 13 patients and supported observations of the lack of inhibitor development over this period. The continued PK stability of IB1001 over time is of interest for the prophylactic treatment of hemophilia B.Evaluation of IB1001 sialylation levels was consistent with observations from previously reported nonclinical studies [Griffith MJ et al. J Thromb Haemost 5 (Suppl 1). Although the level of sialylation resulted in slightly different PK behavior, these differences may simply reflect the biological variation between individuals. Disclosures: Gomperts: Inspiration Biopharmaceuticals Inc: Consultancy. Lee:Inspiration Biopharmaceuticals Inc: Consultancy.

IB1001, an Investigational Recombinant Factor IX, Pharmacokinetics in Pediatric Patients with Hemophilia B.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2225-2225
Author(s):  
Edward D. Gomperts ◽  
Shashikant Apte ◽  
Utpal Chaudhuri ◽  
Joseph M John ◽  
Vijay Ramanan ◽  
...  
Keyword(s):  
Half Life ◽  
Research Funding ◽  
Pediatric Patients ◽  
Robust Regression ◽  
Factor Ix ◽  
Hemophilia B ◽  
Maximum Plasma ◽  
Recombinant Factor Ix ◽  
In Vivo Recovery

Abstract Abstract 2225 Introduction IB1001 is a recombinant factor IX product being investigated for the treatment and prevention of bleeding in individuals with hemophilia B. Pharmacokinetics (PK) in adults (>12 years) demonstrated that IB1001 had results similar to the currently available recombinant FIX with respect to parameters such as terminal phase half-life and incremental recovery. We report the interim findings from a PK assessment in children <12 years, with severe hemophilia B (FIX <2%), >50 prior exposure days to FIX, and no history of or currently detectable inhibitor to FIX. Methods Non-randomized, open-label PK study with patients receiving 75±5 IU/kg of IB1001 following a washout period of ≥4 days from a previous FIX infusion. Factor IX levels were determined pre-infusion and at 15–30 minutes, 4–6, 24–26, and 68–72 hours post-infusion. Additional samples could be drawn at 1–3 and 10–14 hours. Calculated PK parameters were: half-life (β-phase t1/2, determined using a robust regression approach [Lee ML et al. XVIth ISTH Congress, Florence, Italy, 1997]) but generally assuming a single compartmental model because of the small number of points, maximum plasma concentration (Cmax), in vivo recovery (IVR) and AUC(0-∞) (determined by the trapezoidal rule). In addition, the AUC(0-t) and mean residence time (MRT) were calculated. Results When compared to the findings previously reported with IB1001 in adult (≥12 years of age) subjects (Martinowitz U et al. Haemophilia, 18, 2012), the results in pediatric patients demonstrate a more rapid metabolism of factor IX as is indicated by the shorter terminal half-life (mean±SD of 19.3±7.8 h versus 29.6±18.2 h in adults) and the smaller AUC0-∞ (mean±SD of 1059±264 versus 1668±598 in adults). In addition, the in vivo recovery was lower (mean±SD of 0.69±0.21) versus that seen in adults (mean±SD of 0.98±0.22). These results are similar to those reported by Berntorp et al (Haemophilia, 7, 2001) with nonacog alfa. Conclusions The pharmacokinetics of IB1001 has previously been shown to be non-inferior to nonacog alfa, another recombinant factor IX, in hemophilia B individuals >12 years of age. The current study is intended to provide information on children <12 and, particularly, <6 years of age. IB1001 is metabolized faster and has a lower recovery than the comparable findings in patients >12 years of age. Although the study is ongoing, these may represent important implications for the potential use of IB1001 in pediatric patients. Disclosures: Gomperts: Inspiration Biopharmaceuticals Inc: Consultancy. Apte:Inspiration Biopharmacauticals Inc: Research Funding. Chaudhuri:Inspiration Biopharmaceuticals Inc: Research Funding. John:Inspiration Biopharmaceuticals Inc: Research Funding. Ramanan:Inspiration Biopharmaceuticals Inc: Research Funding. Liesner:Inspiration Biopharmaceuticals Inc: Research Funding. Shapiro:Inspiration Biopharmaceuticals Inc: Honoraria, Research Funding. Mills:Inspiration Biopharmaceuticals Inc: Employment. Lee:Inspiration Biopharmaceuticals Inc: Employment.

Pharmacokinetics of Idelvion (rIX-FP) in a Patient with Renal Failure

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4957-4957
Author(s):  
Adam S. Kotowski ◽  
Shilpa Jain ◽  
Steven John Ambrusko ◽  
Linda Belling ◽  
Karen Kovach
Keyword(s):  
Renal Failure ◽  
Renal Disease ◽  
End Stage Renal Disease ◽  
Half Life ◽  
Factor Ix ◽  
Hemophilia B ◽  
Activity Levels ◽  
Recombinant Factor Ix ◽  
Stage Renal Disease ◽  
End Stage

Abstract Life expectancy for people with hemophilia has improved and is now approaching that of the general population. This growing population will likely experience age-related co-morbidities such as cardiovascular diseases, diabetes, and chronic kidney disease. Distribution of endogenous and exogenous (plasma or recombinant) factor IX between the intravascular and extravascular spaces have not been fully elucidated. In vivo recovery and elimination half-life have been suggested to be inadequate descriptors of effective pharmacokinetics (PK) of FIX, but that differences in distribution might be clinically important (Bjorkman Haemophilia 2013). Pharmacokinetics (PK) of the long acting recombinant Factor IX albumin fusion protein (rIX-FP) with albumin demonstrated improved PK in a pivotal trial. However, no data exists in patients with end stage renal failure requiring dialysis. We present PK data for a single patient on dialysis who has received a single dose of rIX-FP, Case: 71 y/o male with moderate hemophilia B with factor IX activity levels ranging between 2-4%. He averaged 2 bleeds per year until 2013, when his creatinine increased to 1.93-2.3 (GFR approx. 30mL/min). He averaged 2-4 joint or soft tissue bleeds since 2013. His GFR dropped to 7-10 mL/min in 2015. He tested negative for HCV, HIV, and multiple myeloma. A kidney biopsy and angiogram was not performed. He had nephrotic range proteinuria. His renal ultrasound was unremarkable. Hypertensive nephrosclerosis was the working diagnosis. The patient had a central line placed and AV fistula created in April 2016, which was complicated by bleeding despite factor replacement with Benefix (Pfizer). He began hemodialysis in May 2016 using a tunneled central catheter while awaiting maturation. The patient wanted to switch to peritoneal dialysis (PD). For the PD catheter placement we recommended Idelvion for factor replacement and conducted a pharmacokinetic study. A dose of 100 IU/kg (10,879 units) was administered. Factor IX levels were drawn at 1 hour (h), 24 (h), 72 (h), 168 (h), 216 (h), and 336 (h), with factor IX activity levels of 91%, 59%, 34%, 18%, 16%, and 11% respectively. Dialysis occurred 2 (h), 4 days, 1 week, and 11 days during the 2 week PK study. Samples were analyzed with a one stage assay using a silica activator (PTT A Diagnostica Stago) on a Stago Evolution Conclusion: rIX-FP's demonstrated improved pharmacokinetic parameters in half-life, clearance and AUC in a recent study. To our knowledge, no data exist in patients with end-stage renal disease. We have presented data in a dialysis patient and show comparable PK parameters to that shown in the aforementioned study. Our patient's half-life (t1/2) was 165.2 (h) and AUC was 7663.5. It appears that dialysis and end-stage renal disease does not alter PK of rIX-FP. Further studies are needed in more hemophilia B patients with end-stage renal disease to confirm our findings. Disclosures Jain: Biogen: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria.

Hemostatic Management in an Infant With Neuroblastoma and Severe Hemophilia B With Extended Half-life Recombinant Factor IX Fusion Protein

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Franziska Cuntz ◽  
Hedwig E. Deubzer ◽  
Johannes H. Schulte ◽  
Antje Nimtz-Talaska ◽  
Angelika Eggert ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Half Life ◽  
Factor Ix ◽  
Hemophilia B ◽  
Severe Hemophilia ◽  
Recombinant Factor Ix

Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with hemophilia B

Blood ◽  
2011 ◽  
Vol 118 (10) ◽  
pp. 2695-2701 ◽  
Author(s):  
Claude Negrier ◽  
Karin Knobe ◽  
Andreas Tiede ◽  
Paul Giangrande ◽  
Judi Møss
Keyword(s):  
Half Life ◽  
Factor Ix ◽  
Hemophilia B ◽  
Recommended Treatment ◽  
Human Dose ◽  
Pharmacokinetic Properties ◽  
Recombinant Factor Ix ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Dose Trial

Abstract 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.

scholarly journals Real-World Health Care Expenditure In Hemophilia B Patients Using Standard And Extended Half-Life Recombinant Factor IX Products

2017 ◽  
Vol 20 (9) ◽  
pp. A567
Author(s):  
D Spurden ◽  
PF Fogarty ◽  
A Chhabra ◽  
BJ Tortella ◽  
J Alvir ◽  
...  
Keyword(s):  
Health Care ◽  
Real World ◽  
Half Life ◽  
Health Care Expenditure ◽  
Factor Ix ◽  
Hemophilia B ◽  
World Health ◽  
Recombinant Factor Ix

Biodistribution of the Recombinant Fusion Protein Linking the Human Factor IX to Human Albumin (rIX-FP) in Rats

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1117-1117
Author(s):  
Eva Herzog ◽  
Stephen Harris ◽  
Andrew McEwen ◽  
Ingo Pragst ◽  
Gerhard Dickneite ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fusion Protein ◽  
Half Life ◽  
Human Albumin ◽  
Factor Ix ◽  
Long Bones ◽  
Research Organisation ◽  
Recombinant Factor Ix ◽  
Plasma And Urine Samples ◽  
Commercial Research

Abstract Abstract 1117 The recombinant fusion protein linking the human coagulation factor IX to human albumin, rIX-FP, developed by CSL Behring GmbH, is currently undergoing investigation in clinical phase II/III trials (PROLONG - 9FP) for prophylaxis and on-demand treatment of bleeding in haemophilia B patients. The present study has been conducted to evaluate the biodistribution of rIX-FP in comparison to the marketed recombinant factor IX product BeneFIX®. Therefore, [3H]-rIX-FP or [3H]-BeneFIX®, labeled at lysine or terminal NH2 residues using the N-Succinimidyl [2,3,-3H] propionate (NSP) method, were administered intravenously to male Sprague Dawley (SD) rats at a single dose leading to a radioactive dose of 400 μCi/kg. Using whole-body autoradiography (QWBA), tissue radioactivity was determined at 0.25, 1, 3, 8, 24, 72, 120 and 240 hours following [3H]-rIX-FP, and at 0.25, 1, 3 and 24 hours following [3H]-BeneFIX® administration. In addition to full body sections, the hind limbs were separately subjected to QWBA to obtain more detailed information on the product distribution within the bone marrow, articular capsule and synovial region of the knee joints. In parallel, plasma, urine and faeces were collected at pre-dose and at several sampling points throughout the 24 and 240 hour study period, respectively, to calculate excretion balance and assess physiological elimination pathways. The radioactivity associated with the purified [3H]-labelled protein was determined by quantitative radiochemical analysis (QRA) and high performance liquid chromatography (HPLC). Biological activity of [3H]-labelled rIX-FP and BeneFIX® was confirmed using a chromogenic assay for factor IX activity. The radioactivity associated with plasma, urine and faeces samples was determined by QRA. HPLC-mass spectrometry (MS) techniques were employed to further characterize individual components identified following profiling of plasma and urine samples by size exclusion chromatography (SEC). Overall, the tissue distribution of [3H]-rIX-FP and [3H]-BeneFIX® was comparable, both penetrating predominantly into well perfused tissues and organs. Both products are also rapidly present in synovial and mineralized regions of knee joint sections and seem to mostly localize to the zone of calcified cartilage within the growth plate regions of long bones. For both, the longest retention time was observed in the bone marrow and endosteum of long bones. However, whereas [3H]-rIX-FP was detectable over 120 hours after administration, [3H]-BeneFIX® signal could only be detected until 24 hours post dosing. This is also reflected in the pharmacokinetic parameters determined based on the QRA of plasma and urine samples which suggested a terminal half life of 20.4 and 6.1 hours for [3H]-rIX-FP and [3H]-BeneFIX®, respectively, following correction for total radioactivity attributable to intact product. For both proteins, the major route of elimination was urinary. In case of [3H]-rIX-FP 73% of radioactivity was recovered in urine at 240 hours, the latest sampling point investigated. Less than 5% of radioactivity was eliminated in faeces and approximately 20% of radioactivity was present in tissues after 240 hours. Plasma profiling showed that up to 8 hours, 100% of the radioactivity could be assigned to unchanged [3H]-rIX-FP. From 24 to 240 hours, increasing levels of low molecular weight components (LMW) could be observed in plasma. Intriguingly, no high molecular protein components like [3H]-rIX-FP or albumin were detected in urine. Only LMW [3H]-components were found to be renally excreted. Such LMW components could be either be free [3H]-Lysine or bigger peptide fragments derived from [3H]-rIX-FP, which occur as a result of physiological protein catabolism. An exact identification of such renally excreted fragments is currently underway using HPLC-MS. Overall, the observed data are consistent with the hypothesis, that recycling via FcRn receptor is likely to be the physiological retention route for [3H]-rIX-FP. Consequently, this study shows that rIX-FP exhibits equal biodistribution compared to other marketed recombinant factor IX products such as BeneFIX®, but clearly distinguishes itself from BeneFIX® by its extended plasma half-life allowing a reduction in dosing frequency leading to increased therapeutic convenience and compliance. Disclosures: Herzog: CSL Behring GmbH: Employment. Harris:Quotient Bioresearch Metabolic Chemistry: Commercial Research Organisation Other. McEwen:Quotient Bioresearch Metabolic Chemistry: Commercial Research Organisation Other. Pragst:CSL Behring GmbH: Employment. Dickneite:CSl Behring GmbH: Employment. Schulte:CSL Behring GmbH: Employment. Zollner:CSL Behring GmbH: Employment.

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