Development and validation of an innovative approach to estimating FVIII levels and designing personalised doses in the prophylactic treatment of haemophilia A: based on the principle of the two-compartment model.

Abstract

To predict the level at a specified time and design personalised dosing, we proposed a method (Method 1) for estimating coagulation factor VIII (FVIII) pharmacokinetic (PK) parameters using 4 levels within 48 hours after administering a test dose. A retrospective study based on virtual populations and real patients. A comprehensive hospital in China. Virtual populations generated by Monte Carlo simulations and retrospectively collected real patient data. PK profiles of FVIII after dosing in the virtual populations were generated from a published population PK model coupled with Monte Carlo simulation. The simulated coagulation factor levels were considered as the reference (C_ref). FVIII levels at six sampling points after dosing were estimated with Method 1 and the method proposed by Lisheng Cai (Method 2) and compared with C_ref. PK data from three patients with severe haemophilia A were retrospectively collected to further validate the accuracy of the two methods. In the adult group, the maximum mean deviations for Methods 1 and 2 were 0.43% (±0.35%) and -36.31% (±6.67%), with corresponding maximum root mean square errors (RMSE) of 0.12% and 28.44%, respectively. For the paediatric group, the maximum mean deviations for Methods 1 and 2 were 0.13% (±0.25%) and -34.27% (±6.74%), with maximum RMSEs of 0.05% and 25.33%, respectively. In three actual patients, mean deviations using Method 1 were 0.32%, 1.34% and 0.24%. Mean deviations using Method 2 were 13.37%, -16.86% and 56.66%. The proposed method for estimating FVIII PK parameters and levels demonstrates high accuracy and has the potential for precision dosing.