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Michael H. Shiue, B Jessen, S Raber, R A. Schachar, J Shah, D Arenson; Nonclinical Assessment of the Effect of Taprenepag Isopropyl (PF-04217329) Formulated With and Without Benzylkonium Chloride (BAC) and Xalatan® on Intraocular Exposure of the Active Metabolites of Taprenepag (CP-544326) and Xalatan® (Latanoprost Acid). Invest. Ophthalmol. Vis. Sci. 2011;52(14):1520.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate potential additive effects of taprenepag (with and without BAC) and Xalatan® on intraocular exposures of CP-544326 and latanoprost acid during mono and combination applications of the drugs. The results would clarify if the increase in side effects seen in the FIH Phase 2 clinical trial of topical taprenepag alone and in an unfixed combination with Xalatan® in ocular hypertensive and primary open angle subjects was due to the combination effect of preservative from both formulations.
Dutch belted pigmented rabbits (N=100) were topically dosed with taprenepag formulated in the presence and absence of BAC and/or Xalatan® in various sequence and durations. The rabbits were sacrificed at predetermined time points and the exposure levels of CP-544326 and/or latanoprost acid were measured in cornea, aqueous humor, and plasma. The collected samples were analyzed by LC-MS/MS methods. All rabbit studies were conducted in accordance with the guidelines of the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.
Neither CP-544326 nor latanoprost acid exposures were significantly affected by taprenepag containing or not containing BAC, the order of the combination treatment, or multiday dosing. The concentration of CP-544326 and latanoprost acid in plasma samples from all treatment conditions were below the limits of quantitation of 0.2 and 0.1 ng/mL, respectively.
The current investigation suggests that ocular surface exposure to taprenepag formulated in the presence or absence of BAC and/or Xalatan® does not increase the intraocular exposure of CP-544326 or latanoprost acid. Therefore, it is unlikely that the observed clinical AEs were due to elevated absorption of the metabolites of the prodrugs.
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