Next Rosa Impact webinar: Physiological based modeling for ocular drug delivery

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. The purpose of the "Impact" series is to foster the use of M&S activities in all phases of drug development by illustrating the advantages and enhancing the applicability of M&S in product discovery, development, and marketing programs. The series is intended for drug development project team members from discovery to phase 4 clinical trials. This includes pharmacologists, ADME scientists, PK/PD modelers, clinical pharmacologists, clinical development team members, regulatory affairs specialists, and other interested professionals. Register for this free webinar at www.rosaandco.com/webinar. After registering you will receive a confirmation email containing information about joining the webinar. More information about the webinar series, an archive of past webinars, and a list of future webinar speakers may be found at www.rosaandco.com/webinar. Please allow 5-10 minutes for a Java applet to be installed on your computer prior to joining our webinar series for the first time. Toufigh Gordi, PhD President PK/PD and Clinical Pharmacology Services Rosa & Co. LLC 751 Laurel St., Ste. 127, San Carlos, CA 94070 408-480-7314 <mailto:[email protected]> [email protected] http://www.rosaandco.com/ www.rosaandco.com The information contained in this e-mail message, e-mail message sequence, and/or any enclosures is confidential, and it may be privileged and protected from unauthorized use and/or disclosure. If you are not the intended recipient, any use, dissemination, distribution, or copying is strictly prohibited. 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