Abstract
Purpose :
Perform composite parameter sensitivity analysis, elucidate relative contribution of two parallel drug penetration pathways into eye from topically applied drops, towards establishing an oBCS and refining its framework.
Methods :
Experimentally determined intrinsic solubility values of drug substances found in commercially available eye drops were compiled. A subset of forty drugs with available in vitro corneal (Cr) and conjunctival (Cj) tissue permeability (Papp) data, expressed as CrPapp/CjPapp, were used to plot sensitivity surfaces as a function of total topical ophthalmic dose (Do). Extent of aqueous humor (AqH), iris-ciliary body (ICB) and systemic exposure was calculated 0-20 minutes (e.g. AUC0-20min) using OCAT™ simulated topical ophthalmic dosing as a function of corneal vs. conjunctival penetration access, and nasolacrimal drainage. Do and CrPapp/CjPapp parameter sensitivity analysis (PSA) were performed on 40 drugs to assess influence of corneal/conjunctival permeability, dose/solubility ratios on extent of absorption into eye vs. systemic.
Results :
Contribution of the corneal route of absorption was dominant at nearly 90% fraction of dose reaching AqH for all compounds, while relatively low corneal permeability ones displayed up to 90% dependence of their ICB exposure on conjunctival access. Similarly, Do displayed up to 40% dependence on ICB access via conjunctival absorption, however was insensitive towards AqH access via corneal route of penetration. Contribution of nasolacrimal drainage towards systemic exposure displayed up to 15% dependence specifically on compounds with corneal penetration route preference as a function of increasing Do, while the opposite was true for compounds with conjunctival penetration route preference.
Conclusions :
A oBCS is proposed in FIGURE. Pragmatic limitations in ocular bioanalysis result in challenges for bioequivalence establishment between different topical ophthalmic formulations of the same drug substance. There is potential value for computational model integrated biopharmaceutics in formulation design, optimization, and performance prediction.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.