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Ocular pharmacokinetics of 0.45% ketorolac tromethamine

Authors Attar M, Schiffman RM, Borbridge L, Farnes Q, Welty D

Published 1 December 2010 Volume 2010:4 Pages 1403—1408


Review by Single-blind

Peer reviewer comments 3

Mayssa Attar1, Rhett Schiffman2, Lisa Borbridge3, Quinn Farnes4, Devin Welty1
1Departments of Pharmacokinetics and Drug Metabolism, 2Global Production Enhancement, 3Bioanalytical Sciences, 4Product Formulation Development, Allergan Inc., Irvine, CA, USA

Purpose: A new carboxymethylcellulose (CMC)-containing ophthalmic formulation of 0.45% ketorolac, pH 6.8 (Acuvail®) was recently developed for treatment of inflammation and pain after cataract surgery. This study compared pharmacokinetics of the new formulation with that of a prior formulation, 0.4% ketorolac, pH 7.4 (Acular LS®).
Methods: Ketorolac formulations were administered bilaterally (35 µL) to female New Zealand White rabbits. Samples from aqueous humor and iris-ciliary body were collected at multiple time points, and ketorolac was quantified using liquid chromatography-tandem mass spectrometry.
Results: In aqueous humor, the peak concentration (Cmax) and area under the concentration-time curve (AUC0–t) of ketorolac were, respectively, 389 ng/mL and 939 ng•h/mL following administration of the CMC-containing 0.45% ketorolac, pH 6.8, and 211 ng/mL and 465 ng•hr/mL following administration of the 0.4% ketorolac, pH 7.4. In iris-ciliary body, Cmax and AUC0–t of ketorolac were, respectively 450 ng/g and 2040 ng•h/g after administration of the CMC-containing 0.45% ketorolac, pH 6.8, and 216 ng/g and 699 ng•h/g after administration of the 0.4% ketorolac, pH 7.4. PK simulations predicted an AUC0–t of 2910 ng•h/g for twice daily, CMC-containing 0.45% ketorolac, pH 6.8, compared to 725 ng•h/g for 4 times daily, 0.4% ketorolac, pH 7.4.
Conclusions: The CMC-containing formulation of 0.45% ketorolac, pH 6.8, increased ketorolac bioavailability by 2-fold in aqueous humor and by 3-fold in iris-ciliary body in comparison to the 0.4% ketorolac, pH 7.4, allowing a reduced dosing schedule from 4 times daily to twice daily.

Keywords: Acuvail, Acular LS, inflammation, ketorolac, ocular pharmacokinetics, twice-daily dosing

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