Ocular pharmacokinetics of a novel tetrahydroquinoline analog in rabbit: Compartmental analysis and PK-PD evaluation

The elimination kinetics of the pharmacologically active compound 1-ethyl-6-fluoro-1,2,3,4-tetrahydroquinoline (MC4) were characterized along with pharmacodynamic (PD) measurements. Four compartmental models based on ocular anatomy, physiology, and possible absorption and disposition pathways were proposed to model the pharmacokinetic (PK) data in WinNonlin and the best model was chosen based on statistical and goodnessoffit criteria. A threecompartment physiologic-based PK model with a bidirectional transfer between cornea and aqueous humor and a unidirectional transfer between aqueous humor and irisciliary body best described the data. The ocular PD parameters, maximum effect attributed to drug (Emax) and drug concentration which produces 50% of maximum effect (EC50), were estimated with change in intraocular pressure (Delta IOP) as the effect (PD response) in the effect compartment model (PKPD link model) using aqueous humor concentrationtime and Delta IOPtime profiles. The link model better described the effect compartment concentrations than a simple Emax model that used irisciliary body concentrationtime data, indicating that there is an apparent temporal displacement between aqueous humor concentration (plasma/central compartment equivalent) and pharmacological effect. A physiologically plausible value of 0.0159min-1 was obtained for the drug elimination rate constant (keo) from the effect site to account for equilibration time in the biophase. Hysteresis was observed for the irisciliary body, aqueous humor drug concentrations, and effect data, further confirming the utility of the link model to describe the PD of MC4. (c) 2011 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:414-423, 2012