Towards a population pharmacokinetic/pharmacodynamic model of anti-VEGF therapy in patients with age-related macular degeneration.

ABSTRACT

PURPOSE: To develop a population pharmacokinetic/pharmacodynamic model (popPKPD) of intravitreal bevacizumab treatment for neovascular age-related macular degeneration (nAMD) patients to learn about the PK/PD relationship and utilise it for dosing regimen decisions on future nAMD patients. METHODS: The Greater Manchester Avastin for Neovascularisation (GMAN) randomised clinical trial data was retrospectively utilised, and the best-corrected visual acuity (BCVA) and central macular retinal thickness (CRT, measured by optical coherence tomography) were the PD inputs to the model. Using the nonlinear mixed-effects method, the best PKPD structural model was investigated, and the clinical significance of the two different dosing treatment regimens (as-needed versus routine) was evaluated. RESULTS: A structural model to describe the change of BCVA from the baseline of nAMD patients was successfully obtained based on the turnover PD model concept (drug stimulates the "visual acuity response production"). The popPKPD model and simulation indicate that the routine regimen protocol improves patient visual outcome compared to the as-needed protocol. For the change in CRT, the turnover structural PKPD model was too demanding to fit to the given clinical data. CONCLUSIONS: This is the first popPKPD attempt in nAMD treatment that shows the potential of this strategy to understand/inform the dosing regimen. Clinical trials with richer PD data will provide the means to build more robust models.