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Ocular Pharmacokinetic/Pharmacodynamic Modeling for Multiple Anti-glaucoma Drugs


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Title: Ocular Pharmacokinetic/Pharmacodynamic Modeling for Multiple Anti-glaucoma Drugs
Authors: Sakanaka, Koji / Kawazu, Kouichi / Tomonari, Masahide / Kitahara, Takashi / Nakashima, Mikiro / Nishida, Koyo / Nakamura, Junzo / Sasaki, Hitoshi / Higuchi, Shun
Issue Date: 30-May-2008
Publisher: Pharmaceutical Society of Japan
Citation: Biological and Pharmaceutical Bulletin, 31(8), pp.1590-1595; 2008
Abstract: We have constructed a new ocular pharmacokinetic pharmacodynamic (PK/PD) model for anti-glaucoma drugs to describe ocular hypotensive effects on intraocular pressure (IOP) after instillation of a combination of an a1-adrenergic antagonist, bunazosin, and a b -adrenergic antagonist, timolol, into rabbits. This model was constructed by the combination of two ocular PK/PD models for bunazosin and timolol by including aqueous humor dynamics based on both action mechanisms. We also verified the reliability of this model by confirming the drug concentrations in aqueous humor and ocular hypotensive effects after instillation of the drug combination. The aqueous humor concentrations of timolol and bunazosin were determined by an HPLC, and ocular hypotensive effect-time profiles were measured using a telemetry system, which was able to record automatically detailed effects. The combined model could simulate the aqueous humor concentrations of both drugs and the additive IOP-lowering effect after instillation of the combination using the MULTI (RUNGE) program and PK/PD parameters which were obtained from ocular hypotensive effects after instillation of bunazosin alone or timolol alone. The theoretical concentration curves of both drugs in the aqueous humor and the theoretical ocular hypotensive effect curves almost agreed with both the observed concentrations and ocular hypotensive effects after instillation of the drug combination. These results indicate the reliability and usefulness of PK/PD modeling considering aqueous humor dynamics to predict IOP in multidrug therapy. This is the first study to develop a PK/PD model for multidrug therapy for the eye.
Keywords: timolol / bunazosin / pharmacokinetics / pharmacodynamics / aqueous humor dynamics
URI: http://hdl.handle.net/10069/19226
ISSN: 09186158
DOI: 10.1248/bpb.31.1590
Rights: (c) 2008 The Pharmaceutical Society of Japan
Type: Journal Article
Text Version: publisher
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/19226

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