title: Ocular pharmacokinetic/pharmacodynamic modeling for timolol in rabbits using a telemetry system.
abstract: We have established an ocular pharmacokinetic/pharmacodynamic (PK/PD) model for a beta-adrenergic antagonist, timolol, after instillation into rabbits. Timolol concentrations were determined by HPLC in the tear fluid, aqueous humor, cornea, and iris-ciliary body after instillation or ocular injection into the anterior chamber of the eye in rabbits. In addition, intraocular pressure (IOP) measurement was performed after instillation of timolol by a telemetry system, which was able to obtain detailed IOP data automatically. The PK/PD parameters were estimated by fitting the concentration-time profiles and the ocular hypotensive effect-time profiles using MULTI (RUNGE) program. The PK model consisted of six compartments and the PD model included aqueous humor dynamics based on an action mechanism of timolol, which causes lowering of IOP by suppressing aqueous humor production. The PK/PD model described well the concentration-time profiles and the ocular hypotensive effect-time profiles after instillation of timolol. This study is the first trial to develop an ocular PK/PD model for timolol after instillation. This model can predict both the drug concentrations in various ocular tissues and the ocular hypotensive effect after instillation of timolol.
authors.affiliation: Santen Pharmaceutical Co., Ltd., Nara Research and Development Center, 8916-16 Takayama-cho, Ikoma 630-0101, Japan. koji.sakanaka@santen.co.jp
authors.forename: Koji
authors.initials: K
authors.lastname: Sakanaka
authors.forename: Kouichi
authors.initials: K
authors.lastname: Kawazu
authors.forename: Masahide
authors.initials: M
authors.lastname: Tomonari
authors.forename: Takashi
authors.initials: T
authors.lastname: Kitahara
authors.forename: Mikiro
authors.initials: M
authors.lastname: Nakashima
authors.forename: Koyo
authors.initials: K
authors.lastname: Nishida
authors.forename: Junzo
authors.initials: J
authors.lastname: Nakamura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sasaki
authors.forename: Shun
authors.initials: S
authors.lastname: Higuchi
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000465:Algorithms; D000818:Animals; D005123:Eye / Q000378:metabolism*; D007267:Injections; D007429:Intraocular Pressure / Q000187:drug effects; D008297:Male; D011817:Rabbits; D013686:Telemetry; D013999:Timolol / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000319:Adrenergic beta-Antagonists; D013999:Timolol