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.

Objective: 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.

Design: A retrospective study based on virtual populations and real patients.

Setting: A comprehensive hospital in China.

Participants: Virtual populations generated by Monte Carlo simulations and retrospectively collected real patient data.

Methods: 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). 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. PK data from three patients with severe haemophilia A were retrospectively collected to further validate the accuracy of the two methods.

Results: 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%.

Conclusion: The proposed method for estimating FVIII PK parameters and levels demonstrates high accuracy and has the potential for precision dosing.