ABSTRACT
PURPOSE: To develop a mechanism based translational pharmacokinetic-pharmacodynamic (PKPD) model in preclinical species and to predict the intraocular pressure (IOP) following drug treatment in patients with glaucoma or ocular hypertension (OHT). METHODS: Baseline diurnal IOP of normotensive albino rabbits, beagle dogs and patients with glaucoma or OHT was collected from literature. In addition, diurnal IOP of patients treated with brimonidine or Xalatan® were also obtained from literature. Healthy normotensive New Zealand rabbits were topically treated with a single drop of 0.15% brimonidine tartrate and normotensive beagle dogs were treated with a single drop of Xalatan®. At pre-determined time intervals, IOP was measured and aqueous humor samples were obtained from a satellite group of animals. Population based PKPD modeling was performed to describe the IOP data and the chosen model was extended to predict the IOP in patients. RESULTS: Baseline IOP clearly depicts a distinctive circadian rhythm in rabbits versus human. An aqueous humor dynamics based physiological model was developed to describe the baseline diurnal IOP across species. Model was extended to incorporate the effect of drug administration on baseline IOP in rabbits and dogs. The translational model with substituted human aqueous humor dynamic parameters predicted IOP in patients following drug treatment. CONCLUSIONS: A physiology based mechanistic PKPD model was developed to describe the baseline and post-treatment IOP in animals. The preclinical PKPD model was successfully translated to predict IOP in patients with glaucoma or OHT and can be applied in assisting dose and treatment selection and predicting outcome of glaucoma clinical trials.
Subject(s)
Antihypertensive Agents/pharmacokinetics , Antihypertensive Agents/therapeutic use , Glaucoma/metabolism , Intraocular Pressure/drug effects , Models, Biological , Ocular Hypertension/metabolism , Animals , Brimonidine Tartrate , Dogs , Female , Forecasting , Glaucoma/drug therapy , Humans , Intraocular Pressure/physiology , Latanoprost , Male , Ocular Hypertension/drug therapy , Prostaglandins F, Synthetic/pharmacokinetics , Prostaglandins F, Synthetic/therapeutic use , Quinoxalines/pharmacokinetics , Quinoxalines/therapeutic use , Rabbits , Translational Research, Biomedical/methods , Treatment OutcomeABSTRACT
A series of carboxylate bioisosteres of structures related to gabapentin 1 have been prepared. When the carboxylate was replaced by a tetrazole, this group was recognized by the alpha2-delta protein. Further characterization of alpha2-delta binding compounds 14a and 14b revealed a similar pattern of functional in vitro and in vivo activity to gabapentin 1.
