Sustained i.v.t. delivery was achieved in a dose-dependent fashion after the i.v.t. injection of a proprietary sirolimus depot-forming ocular formulation. Across the tolerability and safety studies, no significant findings were observed for systemic and ocular tolerability. The human WB levels were well below the daily trough systemic blood level range required for systemic immunosuppression. An i.v.t. injection of sirolimus has a PK and safety profile that is favorable for treating inflammatory conditions of the eye, such as non-infectious uveitis, and warrants further investigation in humans.

No abstract

A reactive oxygen species (ROS) assay was previously developed for photosafety evaluation of pharmaceuticals, and the present multi-center study aimed to establish and validate a standard protocol for ROS assay. In three participating laboratories, two standards and 42 coded chemicals, including 23 phototoxins and 19 nonphototoxic drugs/chemicals, were assessed by the ROS assay according to the standardized protocol. Most phototoxins tended to generate singlet oxygen and/or superoxide under UV-vis exposure, but nonphototoxic chemicals were less photoreactive. In the ROS assay on quinine (200 µm), a typical phototoxic drug, the intra- and inter-day precisions (coefficient of variation; CV) were found to be 1.5-7.4% and 1.7-9.3%, respectively. The inter-laboratory CV for quinine averaged 15.4% for singlet oxygen and 17.0% for superoxide. The ROS assay on 42 coded chemicals (200 µm) provided no false negative predictions upon previously defined criteria as compared with the in vitro/in vivo phototoxicity, although several false positives appeared. Outcomes from the validation study were indicative of satisfactory transferability, intra- and inter-laboratory variability, and predictive capacity of the ROS assay.

Drug-induced phototoxicity is elicited after exposure of the skin and/or eyes to topically or systemically administered pharmaceutical substances, followed by exposure to sunlight. This undesirable side effect is one of the impediments in drug discovery and development, and substantial efforts have been made to avoid drug-induced phototoxic reactions. To evaluate the phototoxic potential of compounds, effective methodologies have been developed over the past few years, and screening strategies have also been proposed for predicting in vivo phototoxic reactions. European and American regulatory agencies have published guidelines for predicting and avoiding drug-induced phototoxicity in an early phase of drug discovery. The guidelines have indicated the requirements for assessing the photosafety of chemicals on the basis of their photochemical behaviors and have recommended some phototoxic assessment tools for aiding new drug development. A number of phototoxic screening systems have also been proposed on the basis of the pathogenesis of drug-induced phototoxicity, and some of them have already been applied to the phototoxic evaluation of new drug entities in drug discovery and development. The present review aims to summarize the current status of research tools, screening strategy and regulations for evaluating the photosafety of new drug candidates and to introduce our thoughts on the phototoxic risk assessments of compounds.

Levofloxacin, the L-isomer of ofloxacin and a potent quinolone with a broad spectrum of antibacterial activity, was evaluated in a series of toxicology studies including acute and chronic dosing in rabbits and primates with intact and injured eyes. No evidence of ocular toxicity was observed in rabbits with intact eyes that were topically instilled with levofloxacin ophthalmic solutions under various treatment regimens, including Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by University of California San Francisco on 03/31/15For personal use only. ORDER REPRINTSmultiple dosing (four to six times daily) for up to 26 weeks at levofloxacin concentrations from 0.3% to 3%. When rabbits were repetitively instilled (10 times at 30 minute intervals) with 0.3%, 1%, or 3% levofloxacin ophthalmic solutions over a single day, they exhibited no increase in ocular irritation scores, whereas dosing with 10% and 25% levofloxacin produced dose-dependent increases in ocular discharge, conjunctival injection and edema, corneal edema/fluorescein staining, iridic congestion, and behavioral abnormalities. Healing of 7.5 mm diameter epithelial wounds in rabbit eyes was not delayed by dosing four times daily (QID) with 0.5% or 1.5% levofloxacin in four different vehicles, with complete healing after 48 hours. The QID dosing with 3% or 6% levofloxacin retarded healing at 24 hours, but healing was complete in eyes treated with 3% levofloxacin by 72 hours after injury, and nearly complete in eyes treated with 6% levofloxacin by 96 hours. Using a similar model in primates, QID treatment with 1.5% levofloxacin produced no delay in healing of epithelial wounds or increased corneal thickness compared to glycerin vehicle, while QID treatment with 3% levofloxacin delayed healing at 24 and 48 hours after injury and increased corneal thickness for 11 days. Histological evaluation of the eyes confirmed that there was no detrimental effect to the corneal endothelium as a result of treatment with 1.5% levofloxacin. In conclusion, the results of these studies support the ocular safety of concentrations of levofloxacin up to 1.5% when administered topically to the intact or wounded eye.