In silico evaluation of limited blood sampling strategies for individualized recombinant factor IX prophylaxis in hemophilia B patients

Essentials Individual pharmacokinetic (PK) parameters can be obtained by limited sampling strategies (LSSs). Following 100 IU kg −1 rFIX, LSSs with 1 to 3 samples were evaluated in 5000 simulated subjects. For all LSSs, estimated individual PK parameters showed acceptable bias and precision. One sample between 10 min–3 h and two between 48 h–56 h showed best predictive performance.Summary Background Patients with severe hemophilia B regularly administer prophylactic intravenous doses of clotting factor IX concentrate to maintain a trough level of at least 0.01 IU mL −1 in order to prevent joint bleeds. Assessment of individual pharmacokinetic ( PK ) parameters allows individualization of the recombinant factor IX (r FIX ) dose. Aim To evaluate the predictive performance of limited sampling strategies ( LSS s) with one to three samples to estimate individual PK parameters of r FIX . Methods Monte Carlo simulations were performed to obtain 5000 concentration–time profiles by the use of population PK parameters for r FIX from literature. Eleven LSS s were developed with one, two or three samples taken within an 80‐h interval following administration of 100 IU kg −1 r FIX . Clearance ( CL ), half‐life ( t 1/2 ), time to 1% and steady‐state distribution volume ( V ss ) were estimated for each simulated individual by the use of Bayesian analysis. Results For each LSS , average bias was small for CL (range − 1.5% to 1.4%), t 1/2 (range − 4.5% to − 0.7%), time to 1% (range − 2.9% to 0%), and V ss (range − 3.7% to 0.3%). Imprecision for these parameters ranged from 6.4% to 11.9%, from 10.3% to 15.6%, from 7.3% to 10.9%, and from 9% to 20.1%, respectively. The best predictive performance was achieved with one sample taken between 10 min and 3 h and two samples taken between 48 h and 56 h after administration of r FIX . Conclusions This study demonstrates that limited sampling strategies, used for individualized dosing of r FIX in hemophilia B patients, can be developed and evaluated by in silico simulation.