Tong Lu (1), Lu Xu (2), Jennifer Visich (1), Amita Joshi (1), David Z. D’Argenio (3)
(1) Clinical Pharmacology, Genentech, Inc.; (2) Formerly Early Development PKPD, Genentech, Inc.; (3) Biomedical Engineering, University of Southern California
Objectives: The aim of this study was to develop a population based model to describe the disease progression of the wet form of age related macular degeneration (wet-AMD) and the therapeutic effect of ranibizumab.
Methods: Visual acuity (VA) data from two randomized Phase 3 studies were utilized in model development. First, the natural progression of wet-AMD was modeled as a dynamic process [1] using the data from sham arms. The disease progression model assumed that VA will approach a steady-state untreated value which was estimated as the percent of decrease in VA (Pdelta) from baseline. The effect of ranibizumab was then modeled using data from treatment arms by assuming the same disease progression (mean value of Pdelta) and allowing the drug concentration in the vitreous to alter the steady-state of VA via an Emax model. All parameters in the model were assumed to follow a log-normal distribution, and an additive residual error model was adopted. Model development was conducted using the MLEM population module in APADT 5.
Results: The VA profiles were well described by the disease progression model for patients in the sham arms, and by the drug effect model for patients treated with ranibizumab. The mean value of Pdelta was 52.8%, indicating that the VA in untreated patients will decrease by half on average. Estimated baseline VA for both models was around 57 letters with similar CV (26%). The population mean value of EC50 for VA was 0.01 mg/ml, and was below the average trough concentration of ranibizumab in the vitreous following the FDA approved 0.5 mg per eye monthly regimen. The inter-individual variability of EC50 was large (264%), and was attributed to the following a) large difference in the sensitivity to ranibizumab among patients; b) the use of population mean value [3] to simulate the concentration-time profile of ranibizumab in the vitrous for all treated patients; c) the use of population mean disease progression parameter (Pdelta) in the modeling of treatment effect (information regarding the pre-treatment disease progression were not available).
Conclusions: A population based semi-mechanistic model was developed to describe the disease progression of wet-AMD and the therapeutic effect of ranibizumab. Key model parameters were estimated and evaluated for their physiological and clinical relevance. This model could be used to access the effects of varied dosing scenarios and PK/PD properties on the disease progression of VA.
References:
[1] Post TM, Freijer JI, DeJongh J, Danhof M. Disease system analysis: basic disease progression models in degenerative disease. Pharm Res. 2005; 22(7):1038-49
[2] D'Argenio, D.Z., A. Schumitzky and X. Wang. ADAPT 5 User's Guide: Pharmacokinetic /Pharmacodynamic Systems Analysis Software. Biomedical Simulations Resource, Los Angeles, 2009.
[3] Xu L, Jumbe N, Eppler S, Lu J, Damico L, Joshi A. Population pharmacokinetics of ranibizumab in patients with age-related macular degeneration. [Abstract] AAPS Meeting, 2006, San Antonio, TX, USA.
Reference: PAGE 21 (2012) Abstr 2641 [www.page-meeting.org/?abstract=2641]
Poster: Other Drug/Disease Modelling