Ocular pharmacokinetics of 0.45% ketorolac tromethamine
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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