Investigational combination product yields similar bioequivalence of corticosteroid

April 1, 2006

An investigational ophthalmic combination product containing tobramycin 0.3% and prednisolone acetate 1% seems to be bioequivalent to a marketed preparation of prednisolone acetate 1%, according to recently released results from a phase III trial.

The pharmacokinetics study measured concentrations of prednisolone achieved in the aqueous humor when the two products were administered prior to cataract surgery. Demonstration of bioequivalence required that the ratio of the mean area under the time-concentration curve (AUC) for prednisolone dosed in the combination product fall between 80% and 125% of the comparator with 90% confidence. That primary endpoint was fulfilled when results were analyzed from both the intent-to-treat (ITT) and per-protocol (PP) patient populations.

For the ITT analysis, the mean AUC ratio was 93% and the 90% confidence interval was between 85% and 101%. In the PP population, the mean AUC ratio was also 93% and the 90% confidence interval ranged from 86% to 100%.

"Safe and effective combination products are always appreciated because of their potential benefit for improving patient compliance, and it is also important to have a range of therapeutic choices for a given indication because there can be significant interpatient variability when it comes to product tolerance," Dr. Beahm said.

Multicenter investigation

The phase III study was a multicenter investigation undertaken at six clinical centers and enrolling 132 patients undergoing bilateral cataract surgery. According to the protocol, which was developed with FDA guidance, one eye was randomly assigned to receive a single drop of the combination product prior to surgery and the other to instillation of prednisolone acetate 1%. Aqueous humor samples were obtained at 30, 60, 90, 120, 180, or 240 minutes after administration.

Concentrations were analyzed in 124 patients who had a viable aqueous humor specimen. The PP population included data from 121 subjects. The statistical calculation of sample size determined what data would be needed from 120 patients. The patients included in the study had a mean age of 71 years, 60% were females, and the majority were white (83%).

In both the ITT and PP analyses, the investigational product also met the secondary endpoints: the mean maximum prednisolone acetate concentration (Cmax) and mean time to reach the maximum concentration (Tmax). In the ITT analysis, the mean Cmax for prednisolone was 171 ng/mL after administration of the combination product and 166 ng/mL for the reference product. The mean Tmax was 90 minutes with both products.

The phase III trial also demonstrated that the investigational combination product had a favorable safety profile. There were no treatment-related adverse events attributed to either medication.

"Prednisolone is the most commonly prescribed topical corticosteroid by ophthalmologists, and so we are pleased that the results from our phase III study indicated bioequivalence for that compound in both the intent-to-treat and per-protocol populations," stated Vicente Anido Jr., PhD, president and chief executive officer of ISTA Pharmaceuticals, Irvine, CA.

"Based on our phase III study results, we plan to submit to the FDA a New Drug Application (NDA) for our combination product in the first half of 2006," Dr. Anido said. "If approved, we believe our combination product could have a number of important advantages, including supplying prednisolone and tobramycin in a single formulation selected to provide greater patient comfort in inflamed eyes."