Modeling the Ocular Pharmacokinetics and Pharmacodynamics of Ranibizumab for Improved Understanding and Data Collection Strategies in Ocular Diseases.

Abstract

Purpose: Improving our understanding of the ocular pharmacokinetics and pharmacodynamics of anti-vascular endothelial growth factor (VEGF) therapies, such as ranibizumab, is essential to enhance treatment strategies for a range of retinal diseases, and will help inform the development of novel anti-VEGF drug candidates.

Methods: In this study, we examine a two-compartment pharmacokinetic/pharmacodynamic model of an intravitreal ranibizumab injection to understand its impact on ocular VEGF suppression. We use Bayesian inference to infer the model parameters from aqueous humor data extracted from healthy cynomolgus macaques. We leverage this approach to explore various sources of uncertainty in the data, offering practical recommendations for minimizing avoidable uncertainty.

Results: The model provides a robust description of ranibizumab pharmacokinetics and pharmacodynamics, identifying the recovery region of the aqueous humor VEGF concentration-time profile as critical for the precise estimation of parameters. Our results advocate focusing on this region in future studies for optimal data collection. We consider standard data correction techniques to reduce the data uncertainty introduced by the lower limit of quantification, identifying the most preferable technique for this model and data. Using a Bayesian approach we obtain an inferred mean posterior distribution of 1459 ± 98 pM for the ranibizumab dissociation constant, a pharmacodynamic parameter with notable variability across the literature.

Conclusions: This study extends our understanding of the ocular pharmacokinetics and pharmacodynamics of ranibizumab and provides theoretical insights for enhanced data collection schemes to be considered for clinical trials and in the development of novel anti-VEGF therapies.