Abstract
Purpose: Hemophilia B is a bleeding disorder, caused by a factor IX (FIX) deficiency. Recently, FIX concentrates with extended half-life (EHL) have become available. Prophylactic dosing of EHL-FIX concentrates can be optimized by assessment of individual pharmacokinetic (PK) parameters. To determine these parameters, limited sampling strategies (LSSs) may be applied. The study aims to establish adequate LSSs for estimating individual PK parameters of EHL-FIX concentrates using in silico evaluation. Methods: Monte Carlo simulations were performed to obtain FIX activity versus time profiles using published population PK models for N9-GP (Refixia), rFIXFc (Alprolix), and rIX-FP (Idelvion). Fourteen LSSs, containing three or four samples taken within 8 days after administration, were formulated. Bayesian analysis was applied to obtain estimates for clearance (CL), half-life (t1/2), time to 1% (Time1%), and calculated weekly dose (Dose1%). Bias and precision of these estimates were assessed to determine which LSS was adequate. Results: For all PK parameters of N9-GP, rFIXFc and rIX-FP bias was generally acceptable (range: −5% to 5%). For N9-GP, precision of all parameters for all LSSs was acceptable (< 25%). For rFIXFc, precision was acceptable for CL and Time1%, except for t1/2 (range: 27.1% to 44.7%) and Dose1% (range: 12% to 29.4%). For rIX-FP, all LSSs showed acceptable bias and precision, except for Dose1% using LSS with the last sample taken on day 3 (LSS 6 and 10). Conclusion: Best performing LSSs were LSS with samples taken at days 1, 5, 7, and 8 (N9-GP and rFIXFc) and at days 1, 4, 6, and 8 (rIX-FP), respectively.
| Original language | English |
|---|---|
| Pages (from-to) | 237-249 |
| Number of pages | 13 |
| Journal | European Journal of Clinical Pharmacology |
| Volume | 78 |
| Issue number | 2 |
| Early online date | 15 Oct 2021 |
| DOIs | |
| Publication status | Published - Feb 2022 |
Bibliographical note
Funding Information:All authors have completed the Competing interest form and have no financial or personal relationships that could inappropriately influence the study. KM reports grants and other from Bayer, grants and other from Sanquin, grants from Pfizer, other from Boehringer Ingelheim, other from BMS, other from Aspen, other from Uniqure, outside the submitted work. KF1 reports grants from CSL Behring, grants from Novo Nordisk, other from Takeda, other from Roche, other from Pfizer, outside the submitted work. KF2 reports grants and other from Bayer, grants and other from Baxter/Shire, grants and other from Novo Nordisk, other from Biotest, other from CSL Behring, other from Octapharma, grants and other from Pfizer, other from SOBI, other from Roche, outside the submitted work. FL an unrestricted research grant from CSL Behring, Shire/Takeda, and Sobi; is a consultant for uniQure, Novo Nordisk, Biomarin, and Shire/Takeda for performing the WiN study; is a consultant for uniQure, Novo Nordisk, and Shire/Takeda, the fees of which go to the institution; and has received a travel grant from Sobi. He is also a DSMB member for a study by Roche. MC has received investigator-initiated research grants over the years from the Netherlands Organisation for Scientific Research (NWO), the Netherlands Organization for Health Research and Development (ZonMw), the Dutch “Innovatiefonds Zorgverzekeraars,” Baxter/Baxalta/Shire, Pfizer, Bayer Schering Pharma, CSL Behring, Sobi Biogen, Novo Nordisk, Novartis, and Nordic Pharma, and has served as a steering board member for Roche and Bayer. All grants, awards, and fees go to the Erasmus MC as institution. RM reports grants from Bayer, grants from Shire, grants from Merck Sharpe Dome, grants from CSL Behring, other from Bayer, other from Shire, outside the submitted work. Other authors declare no competing financial interests.
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© 2021, The Author(s).