T. Preijers (1), H.C.A.M. Hazendonk (2), K. Fijnvandraat (3), F.W.G. Leebeek (4), M.H. Cnossen (2), R.A.A. Mathôt (1) for “OPTI-CLOT” working group.
(1) Hospital Pharmacy-Clinical Pharmacology, Academic Medical Center Amsterdam, the Netherlands. (2) Department of Pediatric Hematology, Erasmus University Medical Center - Sophia Children’s Hospital Rotterdam, the Netherlands; (3) Department of Pediatric Hematology, Academic Medical Center Amsterdam, the Netherlands; (4) Department of Hematology, Erasmus University Medical Center Rotterdam, the Netherlands.
Objectives: This in silico simulation study aims to develop limited sampling strategies (LSSs) for recombinant factor IX (rFIX) concentrate and to evaluate their predictive performance regarding the number and timing of blood samples.
Methods: A Monte Carlo (MC) simulation was performed to obtain 5000 full concentration versus time profiles using population PK parameters for rFIX from literature [1]. Eleven LSSs were developed with 1-3 samples taken in the 80-hour interval following administration of 100 IU/kg, from which four LSSs contained blood sampling within one day. The predictive performance of the LSSs was evaluated by comparing the empirical Bayesian estimates of PK parameters with the MC simulated values. The relative mean prediction error (rMPE%) and relative root mean squared prediction error (rRMSE%) were used to describe bias and precision, respectively.
Results: For each LSS bias was low for clearance (range -1.4% to +1.3%), terminal elimination half-life (range -1.7% to +0.5%) and steady-state volume of distribution (range -3.1% – +0.7%), whereas for predicted trough concentration at day 3 bias ranged from -1.6% to 11.2%. Precision of these parameters ranged from 6.5% to 12.8%, from 11.4% to 15.6%, from 9.5% to 20.7%, and from 21.1% to 53.7%, respectively. Predictive performance of the LSS with samples taken post-infusion and two samples on day 2 after administration was superior to the other LSSs.
Conclusions: This study demonstrates that LSSs can be developed by in silico simulation and evaluated for the individualized dosing of rFIX in severe hemophilia B patients. Simulations have an important additional value when designing clinical studies to evaluate LSSs in these patients.
References:
[1] Björkman S. Population pharmacokinetics of recombinant factor IX: implications for dose tailoring. Haemophilia : the official journal of the World Federation of Hemophilia. 2013; 19: 753-7.
Reference: PAGE 25 (2016) Abstr 5897 [www.page-meeting.org/?abstract=5897]
Poster: Methodology - Other topics