@article{oai:nagasaki-u.repo.nii.ac.jp:00018222,
 author = {Sakanaka, Koji and Kawazu, Kouichi and Tomonari, Masahide and Kitahara, Takashi and Nakashima, Mikiro and Nishida, Koyo and Nakamura, Junzo and Sasaki, Hitoshi and Higuchi, Shun},
 issue = {8},
 journal = {Biological and Pharmaceutical Bulletin},
 month = {May},
 note = {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., Biological and Pharmaceutical Bulletin, 31(8), pp.1590-1595; 2008},
 pages = {1590--1595},
 title = {Ocular Pharmacokinetic/Pharmacodynamic Modeling for Multiple Anti-glaucoma Drugs},
 volume = {31},
 year = {2008}
}