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

Non-compartmental estimation of pharmacokinetic parameters in serial sampling designs.

Pharmacokinetic studies are commonly analyzed using a two-stage approach where the first stage involves estimation of pharmacokinetic parameters for each subject separately and the second stage uses the individual parameter estimates for statistical inference. This two-stage approach is not applicable in sparse sampling situations where only one sample is available per subject. Nonlinear models are often applied to analyze pharmacokinetic data assessed in such serial sampling designs. Modelling approaches are suitable provided that the form of the true model is known, which is rarely the case in early stages of drug development. This paper presents an alternative approach to estimate pharmacokinetic parameters based on non-compartmental and asymptotic theory in the case of serial sampling when a drug is given as an intravenous bolus. The statistical properties of the estimators of the pharmacokinetic parameters are investigated and evaluated using Monte Carlo simulations