Sparse sampling design for characterizing individual PK of recombinant factor VIII fusion protein (rFVIIIFc) in prophylactic treatment of Hemophilia A
Kayode Ogungbenro (1), Ivan Nestorov (2) and Srividya Neelakantan (3)
(1) The University of Manchester, Manchester, United Kingdom, (2) Biogen Inc, Cambridge, USA, (3) Bioverativ, Waltham, USA
Objectives: To determine sparse sampling times for estimating individual rFVIIIFc maximum a priori (MAP) Bayesian estimates in children (<12yr) and adults/adolescents (≥12yr) and to evaluate the effectiveness of the recommended times to estimate individual pharmacokinetic (PK) parameters.
Methods: Fisher information matrix (FIM) for Bayesian MAP estimator [1] was implemented in PopDes, determinant of the FIM was optimized to derive optimal sampling times, assuming a dose of 50 IU/kg and 10 minutes intravenous infusion, and were also used to evaluate designs. Previously developed population PK model provided prior information. Robust three and two time points were proposed to estimate individual PK based on Bayesian methodology and their effectiveness was investigated using simulations. Plasma FVIII activities of 1000 random individuals were simulated using the population PK model for different designs, individual MAP Bayesian estimates and their relative errors were determined.
Results: Optimal three sampling times for children and adolescent/adults identified were all in the terminal phase due to the relatively weak prior on clearance. Despite informative prior on volume, an earlier timepoint at 0.5h was explored for the robust, practical sampling design to better estimate individual volume. Robust and practical three and two time points designs were identified for children and adults/adolescents with efficiencies relative to the optimal time points of approximately 91 and 83% for three and two time points respectively. Due to possible loss of information to data below lower limit of quantification at later timepoints for those robust sampling designs, alternative three and two time points were also derived; 0.5, 24, 48h and 0.5, 48h for children and 0.5, 48, 72h and 0.5, 72h for adults/adolescents. Relative to the optimal time points, the efficiencies of these designs were approximately 85 and 79% for three and two time points respectively. Simulation results showed adequate MAP Bayesian parameter estimation by both robust designs; mostly with relative errors within ±25 to 30% for the parameters.
Conclusions: Robust three and two sampling times for estimation of individual MAP Bayesian estimates were successfully derived and the simulations indicated that these allowed adequate estimation of individual PK of rFVIIIFc which could then subsequently be utilized for dose individualization.
References:
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