Ocular Exposure Extrapolation Across Multiple Species Using PBPK Modeling and Simulation: Latanoprost Solution Case Study
Maxime Le Merdy, Viera Lukacova
Simulations Plus, Inc. Lancaster, California.
Objectives:
Glaucoma is a disease that damages the optic nerve, leading to vision loss. In most cases, it is caused by elevation of the intra-ocular pressure (IOP). Vision loss can be slowed or prevented by daily administration of drugs impacting the aqueous humor (AH) dynamic within the eyeball. The rabbit eye physiology is comparable to human eye physiology in most respects and is commonly used as a pharmacokinetic (PK) preclinical model to support the development of new and generic ophthalmic drug products. However, rabbits may not have the same sensitivity to ophthalmic drugs compared to humans and other preclinical species may be more relevant models to investigate drugs’ pharmacodynamics (PD). This was demonstrated for latanoprost (LAT), a prostanoid selective FP receptor agonist that is believed to reduce the IOP by increasing the outflow of AH in humans. PD endpoint studies conducted in rabbits and monkeys demonstrated LAT had an effect only in the latter. This case illustrates the need to have an alternative methodology to scale the PK and PD of ophthalmic drug products across multiple species. Ocular physiologically based PK (PBPK) models can provide insight into drug partitioning in eye tissues that are not accessible and/or are challenging to sample in humans and serve as an alternative methodology to study PK and PD of ophthalmic drugs. The purpose of this study is to demonstrate the utility of an ocular PBPK model for the translation of ocular exposure across multiple species using LAT as a case study.
Methods:
The LAT ocular PBPK model was built using GastroPlus® v9.8.3 (Simulations Plus, Inc.). A two-compartment PK model was used to describe LAT systemic distribution and clearance. Distribution and elimination parameters were fitted based on plasma concentration-time profiles following IV administration of LAT to rabbits, monkeys, and humans. The Ocular Compartmental Absorption and Transit (OCAT™) model was used to parameterize LAT ocular distribution after topical solution administration. The OCAT model accounts for nasolacrimal drainage, ocular absorption, and distribution in the eye. Permeabilities and systemic absorption rates for ocular tissue compartments were fitted to match the observed concentration-time courses in the cornea, conjunctiva, and aqueous humor, following single administration of LAT 0.005% solution in one rabbit study. External validation was performed using four additional ocular PK datasets in rabbits receiving single or multiple administrations of LAT 0.005% solution. The model was subsequently used to predict LAT exposure after topical solution administration in monkeys (three studies with single administrations of 0.06, 0.02, 0.005% solutions) and humans (three studies with single administrations of LAT 0.005% solution). For monkey and human predictions, the drug-specific parameters were used as fitted and validated in rabbit studies. The physiological parameters were adjusted to match the monkey and human ocular physiologies. The dose, dose volume, and dose administration schedules were defined to match each study protocol. Predicted monkey and human ocular PK profiles were compared with observed concentration data to assess the OCAT models’ ability to predict exposure across multiple species once validated using rabbit data.
Results:
A total of five rabbit ocular studies were collected and used to develop and validate the rabbit ocular model. OCAT model simulations for rabbits accurately described the observed concentrations in the anterior segment of the eye (cornea, conjunctiva, aqueous humor) following single or multiple administrations of LAT 0.005% topical solution. For most of the studies, simulated Cmax and AUC were within 0.8 and 1.25-fold of the observed values. Adjusting the physiological parameters of the OCAT model to describe the monkey or human eye allowed for a reasonable prediction (within 2-fold) of ocular exposure in both species following ocular administration of LAT solution at different doses and various administration schedules.
Conclusions:
The presented case study demonstrated the OCAT model’s ability to extrapolate drug ocular exposure between species. The successful PK extrapolation of LAT solutions represents an important step in establishing an extrapolation method for the prediction of human ocular PK and PD using ocular PBPK models. This method could have a significant impact on ophthalmic generic drug product development.
References:
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