Repurposing and reformulation of adefovir dipivoxil for improved topical treatment of herpes simplex virus infection of the eye - PROJECT SUMMARY Herpes simplex virus (HSV) keratitis is the leading cause of corneal ulcers and infection-associated blindness in the United States. The existing antiviral therapies for the topical management of ocular herpes infections include nucleoside analogs such as ganciclovir and trifluridine which need to be administered 5-8 times a day to control the infection. Hence, current topical therapies have patient adherence issues which impact therapeutic outcomes. In addition to the limited topical bioavailability, the emergence of drug resistance to acyclic nucleosides has necessitated the development of long-acting antiviral therapies for the topical treatment of ocular herpes infections. Our preliminary data show that adefovir dipivoxil (ADV), an off-patent, FDA-approved hepatitis B virus DNA polymerase inhibitor, is well tolerated by the human corneal epithelial cells and is significantly more active against HSV-1 and HSV-2 when compared to acyclovir, other acyclic nucleoside phosphonates such as tenofovir, cidofovir, and their prodrugs. Our preliminary data further showed that thrice daily topical administration of 1% ADV solution has a robust antiviral effect in a murine ocular herpes model compared to once daily 1% ADV solution and thrice daily 0.15% ADV solution. Thus, strategies are needed to reduce the dosing frequency of ADV to further improve ocular herpes therapy and patient compliance. We previously demonstrated that hydrophilic ionizable antibiotics such as moxifloxacin can be converted to hydrophobic moxifloxacin salt and its subsequent formulation into a mucoinert nanosuspension augmented the topical delivery and reduced the administration frequency. Here, we extend this approach to improve ocular delivery of hydrophilic ionizable antiviral drug, ADV. We hypothesize that the development of hydrophobic salts of ADV and their transformation into mucoinert nanosuspensions (NS) will improve ocular delivery and prolong the release of ADV with a concomitant reduction in dosing frequency. Aim 1 will focus on the evaluation of ADV solution compared to currently approved topical anti-herpetic drugs, ganciclovir, and trifluridine using ex-vivo ocular permeability studies, ocular PK in rabbits, and in vivo efficacy in a mouse model of ocular herpes. Aim 2 will focus on the development and characterization of NS of various ADV hydrophobic salts followed by evaluation of their in vitro cytocompatibility, in vitro antiviral activity, ex vivo corneal permeability, ocular PK in rabbits and in vivo efficacy in a rabbit model of ocular herpes. We have already generated NS of ADV pamoate, a hydrophobic salt of ADV. Our preliminary data show that once-daily topical ADV pamoate NS was significantly more effective than once daily 1% ADV solution but equally effective as thrice daily 1% ADV solution in a murine model of ocular herpes infection. We will evaluate selected nanoformulations of ADV hydrophobic salt in the rabbit model of ocular herpes infection. Finally, we will evaluate the long-term safety of ADV solution and ADV nanoformulation in rabbits. The successful completion of this project will lead to the development of clinically viable, patient-friendly long-acting topical nanomedicine for the effective management of ocular herpes infections.
