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Abstract #25834 Published in IGR 12-2
Aqueous humor concentrations of bimatoprost free acid, bimatoprost and travoprost free acid in cataract surgical patients administered multiple topical ocular doses of LUMIGAN((registered trademark)) or TRAVATAN((registered trademark))
Faulkner R; Sharif NA; Orr S; Sall K; DuBiner H; Whitson JT; Moster M; Craven ER; Curtis M; Pailliotet CJournal of Ocular Pharmacology and Therapeutics 2010; 26: 147-156
Purpose: To quantify the aqueous humor (AH) concentrations of bimatoprost (amide), travoprost (isopropyl ester), and their hydrolysis products, bimatoprost free acid (BFA) and travoprost free acid (TFA), after multiple topical ocular doses of LUMIGAN((registered trademark)) and TRAVATAN((registered trademark)), respectively, in patients awaiting cataract surgery. Methods: In 2 separate open-label, sparse-sampling trials, glaucoma patients with cataracts received LUMIGAN((registered trademark)) (bimatoprost ophthalmic solution, 0.03%) or TRAVATAN((registered trademark)) (travoprost ophthalmic solution, 0.004%) bilaterally once daily for at least 21 days prior to cataract surgery. Anterior chamber paracentesis was performed at selected times up to 5 h after the last dose and an AH sample was collected. AH samples were assayed by an independent bioanalytical laboratory using a sensitive and validated tandem LC-MS/MS method. The assay lower limits of quantitation were 0.59 nM for bimatoprost, 0.29 nM for BFA, and 0.44 nM for TFA. Results: AH concentrations of BFA (17-phenyl-trinor PGF(2(alpha))) were quantifiable in all but one sample at 0.5 h. The maximum concentration achieved (C(max)) of BFA was 30.9 (plus or minus) 16.41 nM (n =5), observed at 2 h postdose. AH concentrations of bimatoprost amide were lower than BFA at all time points, with a C(max) of 6.81 (plus or minus) 1.36 nM (n = 7) at 1 h postdose. For TFA, measurable AH concentrations were obtained at all time points with a TFA C(max) of 3.91 (plus or minus) 2.27 nM (n = 5), which was observed at 3 h after the dose (all data are mean (plus or minus) SEM). Conclusions: Once daily topical ocular administration of LUMIGAN((registered trademark)) or TRAVATAN((registered trademark)) for 3 weeks resulted in significant concentrations of BFA and TFA in the AH. Quantifiable levels of bimatoprost amide were also measured. Maximum concentrations of BFA (30.9 nM) and TFA (3.91 nM) in the anterior chamber are sufficient to fully activate the FP prostanoid receptors in the target cells of the ciliary muscle and trabecular meshwork. Both bimatoprost in LUMIGAN ((registered trademark)) and travoprost in TRAVATAN((registered trademark)) are essentially prodrugs that are rapidly hydrolyzed to their respective free acids that induce the IOP-lowering effect observed with both drugs in vivo.
N. A. Sharif. Core Pharmacology and Imaging Alcon Research Ltd., 6201 S. Freeway, Fort Worth, TX 76134, United States. naj.sharif@alconlabs.com
Classification:
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
2.6.3 Compostion (Part of: 2 Anatomical structures in glaucoma > 2.6 Aqueous humor dynamics)
