Letter to the Editor

Abstract

The recently published article by Gonzalez et al1 reports the results of a study comparing the stability, efficacy, and adverse effect profile of an innovator formulation, latanoprost (Xalatan) ophthalmic solution 0.005%, with that of a new formulation of a latanoprost ophthalmic solution containing cyclodextrins. Although the stability data for the innovator formulation presented in the study do support the labeled storage recommendations (before usage, the bottle should be stored at temperatures ranging from 2 to 8°C; after opening, the bottle can be stored at temperatures up to 25°C for 6 weeks), the article also contains both questionable and misleading data interpretations. We do not believe the authors’ conclusions are substantiated by the data presented. Standard stability study requirements set forth by the Food and Drug Administration2 and the International Committee on Harmonization (ICH)3 specify the use of a set of storage conditions (eg, temperatures, humidity levels, and minimum study duration), as well as the numbers and types of analytical procedures required (ie, physical, chemical, and biological), and they take into consideration the type of packaging (container), its closure system, and the presence of preservatives. The authors describe their use of a new assay method for latanoprost developed in their laboratory, but no reference is provided as to whether the new assay method has been accepted as a legitimate, validated stability assay in accordance with the ICH in any registration dossier. Also, the article does not provide any information about the new formulation's potential latanoprost degradation or the type of packaging used. In addition, the authors failed to assay or even to discuss the potential for reduction in the efficacy of the preservative benzalkonium chloride. Cyclodextrins by nature have the potential to complex with aromatic preservatives.4,5 This complexation between preservatives and other pharmaceutical ingredients has been reported to affect the antimicrobial activity. The authors state that latanoprost is unstable I n aqueous solution at temperatures greater than 4°C. Their own study results, however, contradict this statement and demonstrate that the innovator formulation maintains adequate concentrations of latanoprost for as long as 2 months at temperatures up to 30°C. Similarly, the authors claim that degradation of the innovator formulation was observed after storage at temperatures of 25°C or higher. This reduction in concentration was observed at the 3-month time point; there was no loss of concentration of the innovator formulation after 2 months of storage at temperatures reaching 30°C. These findings are inconsistent with data on file at Pfizer that indicate no significant loss of concentration of the innovator formulation over 12 months of storage at 25°C, as confirmed by the US package insert for samples.6 The authors also state that baseline concentrations of the innovator formulation were low in their in vitro studies and suggest that this may have reflected a slight degradation of the active agent owing to unfavorable storage conditions. In support of this argument, they reference an article by Varma et al.7 In fact, Varma and colleagues analyzed the concentration of the innovator formulation in bottles returned after usage by numerous patients from a clinic during the summer months in a desert region of Southern California and found that there was no significant loss of concentration in this real-world setting. Furthermore, the authors misrepresent the facts when they state that the innovator formulation must be stored under refrigeration to avoid a decrease in clinical efficacy when the only evidence they cite is an in vitro study by Morgan et al.8 There are no published data that show any loss of clinical efficacy due to inappropriate storage or handling of the innovator formulation. The authors conclude that the 2 formulations of latanoprost yield comparable efficacy and adverse effect outcomes, another inference that does not appear to be supported by study design or the data presented. Their efficacy analysis result was based on an equivalence test, but equivalence margin was not mentioned. More important, the clinical study provided no a priori power analysis and included too few patients for a true equivalency study. Furthermore, final intraocular pressure (IOP) values that would permit an independent statistical analysis were not provided. The most serious concern, however, is the claim of comparable adverse event profiles for the innovator formulation and the new formulation. This claim is not supported by sufficient data because only 1 adverse event was recognized and measured. Because cyclodextrin is believed to enhance penetration, there is a possibility that more latanoprost (or formulation excipients) could enter the anterior chamber, leading to other dose-related adverse events.9 Before claims of stability, equivalent efficacy, and safety of the 2 formulations can be made, better controlled, longer term studies with larger numbers of patients should be conducted and results appropriately presented.