Dirk Garmann (1) Matthias Frede (2) Anita Shah (3) Bart Ploeger (4)
(1,2,4) Bayer Pharma AG, Wuppertal/Berlin, Germany (3) Bayer HealthCare, Whippany, NJ, USA
Objectives: to evaluate different dosing regimen for their clinical effectiveness through a quantitative understanding of the occurrence of repeated bleeding events after recombinant factor VIII treatment by a Repeated Time To Event (RTTE) analysis.
Methods: Bleeding data after recombinant factor VIII (FVIII) treatment were used to develop a RTTE model using non-linear mixed-effects modelling [1]. The following factors were evaluated as possible factors affecting bleeding rate: Time below a certain FVIII level/standardized to 1 week and complete FVIII activity time profiles for each subject both estimated using population PK modelling, number of target joints, reported bleedings in past year.
Results: A RTTE model assuming a decreasing repeated bleeding risk over time was chosen as a base model. Reported bleedings in the past year and the individual FVIII activity time profile were identified as significant covariates. The effect of the change in FVIII over time was highly significant (p< 0.00001) and was a better predictor compared to time below FVIII thresholds. Simulations show that the final model describes the observed occurrence of bleeding events adequately.
Conclusions: A RTTE model was established to describe bleeding events in haemophilia A. This model can be used to simulate and evaluate several clinical relevant scenarios e.g. the effect of different dosing schedules or a factor VIII exposure guided approach of keeping patients above a threshold of 1IU/dL factor VIII.
References:
[1] Holford N. A Time to Event Tutorial for Pharmacometricians. CPT: Pharmacometrics & Systems Pharmacology. 2013;2(5):e43-. doi:10.1038/psp.2013.18.
Reference: PAGE 24 (2015) Abstr 3683 [www.page-meeting.org/?abstract=3683]
Poster: Drug/Disease modeling - Other topics