Physiological based modeling for ocular drug delivery
by
Valeriu Damian-Iordache
Director Pharmacokinetics and Translational Biology, GlaxoSmithKline
July 20, 2012
1:00 - 2:00 pm EDT
Delivering drugs to the eye - in particular to the back of the eye is quite
challenging. The retina and the choroid - one of the main targets for back
of the eye diseases are protected by several kinds of ocular barriers:
permeation barriers like the cornea, sclera and the Bruch's membrane; flow
barriers like the tear flow and aqueous humor flow that are meant to keep
the eye structure clean and nourished clear out any foreign substances and
also the blood retinal barrier. Given a drug molecule finding the best
delivery method, the optimal dosing schedule based on preclinical data is a
daunting task. Typical pharmacokinetic approaches do not always apply for
ocular delivery - the shape of the ocular tissues play a significant role in
the way drugs distribute in the eye. In addition, physiological differences
between the eyes of various species make extrapolation quite difficult.
We present a detailed physiological based finite element model for drug
delivery to the eye that accounts for:
. the detailed three dimensional geometry of the ocular structures
for humans and several preclinical species (rat, mouse, rabbit, monkey)
. ocular flows (tear flow and humor flow and drainage pathways)
accounting for physiological differences between species (e.g. rabbits don't
blink)
. permeation and diffusion through all ocular tissues
. non-specific binding and melanin binding kinetics of the drug
accounting for the species dependent melanin content of each ocular
structure
. systemic drug absorption from the nasolacrimal duct, nose, and
gut as well as various clearance mechanisms
. drug and formulation characteristics
. various drug delivery methods: topical, oral, IV, intravitreal
and periocular injections
The physiology information used in the model was gathered from extensive
literature searches.
The model was calibrated based on the measured physicochemical properties of
pazopanib, plasma PK and rabbit ocular PK. Pazopanib (GW786034), a
multi-targeted tyrosine kinase inhibitor, is under clinical development by
GlaxoSmithKline (GSK) for the treatment of ophthalmic disorders such as
age-related macular degeneration (AMD). Tissue distribution following eye
drop administration revealed that potential pharmacologically active levels
reached the target ocular tissues, the retina and choroid in preclinical
studies. Results from rabbit PK study using 14C-pazopanib support the
hypothesis that the major route of drug transit to the choroid/retina is via
the transconjunctival/scleral route, as only minor amounts of pazopanib were
detected in the aqueous and vitreous fluids. There is also evidence for some
transfer of drug into the circulation following eye drop administration of
14C-pazopanib.
All of these findings were explained by the model which shows in a
cross-section of the eye, the time dependent concentration of the compound
in all ocular tissues. A qualitatively similar picture was obtained using
microradiography.
With proper calibration this modeling approach is applicable to any drug and
has shown quite good predictive capabilities particularly when extrapolating
between species and delivery routes.
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Toufigh Gordi, PhD
President PK/PD and Clinical Pharmacology Services
Rosa & Co. LLC
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San Carlos, CA 94070
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