Physiologically Based Pharmacokinetic Model to Support Ophthalmic Suspension Product Development.

Autor: Le Merdy M; Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA., Tan ML; Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA., Babiskin A; Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA. Andrew.Babiskin@fda.hhs.gov., Zhao L; Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
Jazyk: angličtina
Zdroj: The AAPS journal [AAPS J] 2020 Jan 06; Vol. 22 (2), pp. 26. Date of Electronic Publication: 2020 Jan 06.
DOI: 10.1208/s12248-019-0408-9
Abstrakt: FDA's Orange Book lists 17 currently marketed active pharmaceutical ingredients (API) formulated within ophthalmic suspensions in which a majority has 90% or more of the API undissolved. We used an ocular physiologically based pharmacokinetic (O-PBPK) model to compare a suspension with a solution for ophthalmic products with dexamethasone (Dex) as the model drug. Simulations with a Dex suspension O-PBPK model previously verified in rabbit were used to characterize the consequences of drug clearance mechanism in the precorneal compartment on pharmacokinetic (PK) exposure and to assess the ocular and systemic PK characteristics of ophthalmic suspensions with different strengths or magnitudes of viscosity. O-PBPK-based simulations show that (1) Dex suspension 0.05% has a 2.5- and 5-fold higher AUC in aqueous humor and plasma, respectively, than the Dex saturated solution; (2) strength increase by 5- and 10-fold induces a respective 2.2- and 3.3-fold increase in aqueous humor and 4.4- and 8.6-fold increase in plasma C max and AUC; and (3) increasing formulation viscosity (from 1.6 to 75 cP) causes an overall increase in API available for absorption in the cornea resulting in a higher ocular C max and AUC with no significant impact on systemic exposure. This research demonstrates that solid particles present in a suspension can not only help to achieve a higher ocular exposure but also unfavorably raise systemic exposure. A model able to correlate formulation changes to both ocular and plasma exposure is a necessary tool to support ocular product development taking into consideration both local efficacy and systemic safety aspects.
Databáze: MEDLINE
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