title: Mechanism - based translational pharmacokinetic - pharmacodynamic model to predict intraocular pressure lowering effect of drugs in patients with glaucoma or ocular hypertension.
abstract: OBJECTIVE
  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.
authors.affiliation: Pharmacokinetics and Drug Disposition, Allergan, Inc., Irvine, California, USA, Chandra.Durairaj@Alkermes.com.
authors.forename: Chandrasekar
authors.initials: C
authors.lastname: Durairaj
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Madhu
authors.initials: M
authors.lastname: Cherukury
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000068438:Brimonidine Tartrate; D004285:Dogs; D005260:Female; D005544:Forecasting; D005901:Glaucoma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects* / Q000502:physiology; D000077338:Latanoprost; D008297:Male; D008954:Models, Biological; D009798:Ocular Hypertension / Q000188:drug therapy / Q000378:metabolism*; D011461:Prostaglandins F, Synthetic / Q000493:pharmacokinetics / Q000627:therapeutic use; D011810:Quinoxalines / Q000493:pharmacokinetics / Q000627:therapeutic use; D011817:Rabbits; D057170:Translational Research, Biomedical / Q000379:methods; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D011461:Prostaglandins F, Synthetic; D011810:Quinoxalines; D000068438:Brimonidine Tartrate; D000077338:Latanoprost