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Ocular Pharmacokinetics of 0.45% Ketorolac Tromethamine

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Ocular Pharmacokinetics of 0.45% Ketorolac Tromethamine Clinical Ophthalmology Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Ocular pharmacokinetics of 0.45% ketorolac tromethamine Mayssa Attar1 Purpose: A new carboxymethylcellulose (CMC)-containing ophthalmic formulation of 0.45% Rhett Schiffman2 ketorolac, pH 6.8 (Acuvail®) was recently developed for treatment of inflammation and pain Lisa Borbridge3 after cataract surgery. This study compared pharmacokinetics of the new formulation with that Quinn Farnes4 of a prior formulation, 0.4% ketorolac, pH 7.4 (Acular LS®). Devin Welty1 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 1Departments of Pharmacokinetics points, and ketorolac was quantified using liquid chromatography-tandem mass spectrometry. and Drug Metabolism, 2Global Production Enhancement, Results: In aqueous humor, the peak concentration (Cmax) and area under the concentration-time 3Bioanalytical Sciences, 4Product curve (AUC ) of ketorolac were, respectively, 389 ng/mL and 939 ng·h/mL following admin- Formulation Development, Allergan 0–t Inc., Irvine, CA, USA istration 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–τ 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 Introduction Ketorolac is a nonsteroidal anti-inflammatory drug with analgesic and anti- inflammatory properties.1 Currently available ophthalmic formulations of ketorolac include a 0.5% solution (Acular®; Allergan Inc., Irvine, CA), indicated for treatments of inflammation following cataract extraction and ocular itching due to seasonal allergic conjunctivitis, and a 0.4% solution, (Acular LS®; Allergan Inc.), indicated Correspondence: Mayssa Attar for treatment of pain and burning/stinging after corneal refractive surgery.2,3 Both of Departments of Pharmacokinetics these ketorolac formulations are indicated for instillation 4 times daily. and Drug Development, Allergan Inc., Irvine, CA, USA Several clinical studies have demonstrated the safety and efficacy of the 0.5% Tel +1 (714) 246-4322 and 0.4% ketorolac formulations for the alleviation of ocular inflammation and Fax +1 (714) 246-5850 Email [email protected] pain, prevention and treatment of cystoid macular edema, and/or prevention of submit your manuscript | www.dovepress.com Clinical Ophthalmology 2010:4 1403–1408 1403 Dovepress © 2010 Attar et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article DOI: 10.2147/OPTH.S15146 which permits unrestricted noncommercial use, provided the original work is properly cited. Attar et al Dovepress intraoperative miosis in ocular surgery patients.4–10 With Vision and Ophthalmology Statement for Use of Animals in 20% less active ingredient, the 0.4% ketorolac was Ophthalmic and Vision Research. demonstrated to be equivalent in potency to the 0.5% ketorolac in animal and human studies.8,11 Both the 0.4% and Ketorolac extraction and quantification 0.5% ketorolac solutions, however, contain the preservative Ketorolac concentrations in aqueous humor and iris- benzalkonium chloride (BAK), the surfactant octoxynol-40, ciliary body were determined after liquid-liquid extraction and the metal-chelating agent sodium edetate and are by a liquid chromatography-tandem mass spectrometry associated with a high incidence of burning and stinging (LC-MS/MS). Iris-ciliary body samples were prepared for upon instillation.2,3,9 extraction by homogenization in 1 mL of 50% methanol. The formulation of ophthalmic solutions can profoundly Finasteride (500 ng/mL; 10 µL) was then added to 50 µL affect the safety, bioavailability, and tissue distribution of aliquots of aqueous humor and to 300 µL aliquots of the the active ingredients. To enhance the ocular bioavailability homogenized iris-ciliary body samples. Since stable- isotope and tolerability of ketorolac, various modifications were labeled ketorolac is not available, finasteride, which has made to the 0.4% ketorolac formulation, which included an approximately similar retention time on liquid chro- increasing the concentration of active ingredient, lowering matography, was used as an internal standard. Ketorolac formulation pH, adding carboxymethylcellulose (CMC), was extracted with methyl tert-butyl ether. The organic and excluding preservative, surfactant, and metal chelating extracts were evaporated to dryness, and the precipitates agents. The purpose of this study was to evaluate the impact were reconstituted with 40% acetonitrile for injection onto of these modifications on the ocular pharmacokinetics (PK) the LC-MS/MS system utilizing an atmospheric-pressure of ketorolac. chemical ionization heated nebulizer source. Ketorolac quantification was conducted in the positive ion multiple Methods reaction–monitoring mode. Ketorolac formulations The ophthalmic solution of 0.4% ketorolac (Acular LS) Data analysis TM contains 0.006% BAK, sodium chloride, 0.015% edetate Thermo Electron Watson (Thermo Electron Corporation, disodium, octoxynol-40, purified water, and hydrochlo- Waltham, MA) software was used for PK calculations. All ric acid and/or sodium hydroxide to adjust the pH to samples were analyzed for peak concentrations (Cmax), time 2 approximately 7.4. For the formulations tested here: a) the to Cmax (Tmax), and area under the concentration-time curve preservative BAK, the metal-chelating agent edetate diso- from time 0 to the sampling time (AUC0-t) using the random dium, and the surfactant octoxynol-40 were omitted; b) CMC method for nonsequential sampling. Relative bioavailability was added as a viscosity agent; and c) the concentration of (relative %F) was expressed as the percentage of the AUC0-t ketorolac was increased to 0.45%. The pH was adjusted by of the 0.4% ketorolac following a single ocular instillation the addition of hydrochloric acid or sodium hydroxide. (35 µL). PK simulations were performed using WinNonlin Enterprise (Pharsight, Mountain View, CA). PK sampling A 35 µL aliquot of test formulations or 0.4% ketorolac was Statistical analysis topically administered to each eye of female New Zealand Between-group differences in iris-ciliary body Cmax were White rabbits (Covance Research Products Inc., Denver, PA). evaluated by one-way analysis of variance (ANOVA) and Samples from aqueous humor (n = 6 eyes of 3 rabbits/ Dunett’s multiple comparison test. P , 0.05 was considered timepoint) were collected at 1, 2, and 4 hours postdose. a statistically significant difference. Samples from iris-ciliary body (n = 4 eyes of 2 rabbits/ timepoint) were collected at 1, 2, 4, and 8 hours postdose. Results Animals were euthanized with an intravenous injection Effects of CMC and pH on ketorolac of sodium pentobarbital. All protocols were reviewed PK in aqueous humor and approved by the Institutional Animal Care and Use The PK of the CMC-containing test formulations at dif- Committee, and the study conformed to the principles of ferent pH were compared to that of the 0.4% ketorolac animal use set forth by the Association for Research in (Acular LS) (Table 1). At pH = 7.4, the inclusion of CMC 1404 submit your manuscript | www.dovepress.com Clinical Ophthalmology 2010:4 Dovepress Dovepress Ocular PK of 0.45% ketorolac tromethamine Table 1 Aqueous Humor pharmacokinetics of ketorolac following administration of the 0.4% ketorolac, pH 7.4 (Acular LS), and the CMC-containing 0.45% ketorolac, pH 6.8 (Acuvail), formulations at varying pH Ketorolac CMC pH Tmax Cmax AUC0–4 Relative %F (%w/v) (hour) (ng/mL [SD]) (ng.h/mL [SEM]) 0.40 - 7.4 1.0 211 (106) 465 (65) 100 0.45 + 7.4 2.0 265 (71) 627 (51) 135 0.45 + 7.2 1.0 240 (84) 619 (50) 133 0.45 + 7.0 1.0 268 (125) 658 (73) 142 0.45 + 6.8 2.0 389 (258) 939 (163) 202 Abbreviations: AUC0–4, area under the concentration-time curve from time 0 to 4 hours; CMC, carboxymethylcellulose; Cmax, peak concentration; relative %F, percentage of the AUC0–4 value compared to that of the 0.4% ketorolac; SEM, standard error of the mean; SD, standard deviation; Tmax, time to Cmax. as well as a 12.5% increase in ketorolac concentration ketorolac, pH 6.8, compared to 725 ng·h/g for 4 times daily enhanced ketorolac bioavailability in aqueous humor 0.4% ketorolac, pH 7.4 (Figure 2). by 35% compared to ketorolac 0.4% (AUC0–4 [SEM] of 627 ± 51 ng·h/mL versus 465 ± 65 ng·h/mL, respectively). Discussion Decreasing the pH from 7.4 to 6.8 in combination with Ketorolac ophthalmic formulations have been used success- the addition of CMC enhanced ketorolac bioavailability in fully since 1997 for the control of inflammation after cataract aqueous humor by 2-fold compared to ketorolac exposure surgery and the reduction of pain after refractive surgery. following the 0.4% ketorolac administration (AUC0–4 However, both the 0.4% ketorolac solution (Acular LS) and [SEM] of 939 ± 163 ng·h/mL versus 465 ± 65 ng·h/mL, respectively) (Table 1). Temporal kinetics of aqueous A ketorolac concentrations following instillation of the CMC- 1000 containing 0.45% ketorolac, pH 6.8, or the 0.4% ketorolac, pH 7.4, are presented in Figure 1a.
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