Recurrent events modelling of haemophilia bleeding events

Abstract A pharmacokinetic–pharmacodynamic (PK-PD) approach is developed for modelling the recurrent bleeding events in patients with severe haemophilia to investigate relationship between factor VIII plasma activity level and instantaneous risk of a bleed. The model incorporates patient-level pharmacokinetic (PK) information obtained through measurements taken prior study which are used fit non-linear mixed-effects two-compartment PK model. Dosing times within combined provide estimated all patients, as time-dependent covariate Methods correct attenuation effects that would otherwise arise due discrepancy true VIII. In contrast existing methods proposed such data, count data regression or time-to-event analysis, new method allows be current performance estimators assessed via simulation found outperform naive estimator, treats levels if they were measured without error, both terms bias mean squared error.