In vivo pharmacokinetics and in vitro pharmacodynamics of nepafenac, amfenac, ketorolac, and bromfenac.
OBJECTIVE
To evaluate the aqueous humor concentrations and cyclooxygenase (COX) inhibitory activities of nepafenac, amfenac, ketorolac, and bromfenac after topical ocular administration of Nevanac (nepafenac 0.1%), Acular LS (ketorolac 0.4%), or Xibrom (bromfenac 0.09%).


METHODS
Five private ophthalmology practices throughout the United States.


METHODS
Patients requiring cataract extraction were randomized to 1 of 3 treatment groups: Nevanac, Acular LS, or Xibrom. Patients were administered 1 drop of the test drug 30, 60, 120, 180, or 240 minutes before cataract surgery. At the time of paracentesis, an aqueous humor sample was collected and later analyzed for drug concentration. In addition, COX-1 (homeostatic) and COX-2 (inducible) inhibitory activities of nepafenac, amfenac, ketorolac, and bromfenac were determined via the in vitro measurement of prostaglandin E(2) (PGE(2)) inhibition.


RESULTS
Seventy-five patients participated in the study. The prodrug nepafenac had the shortest time to peak concentration and the greatest peak aqueous humor concentration (C(max)). The C(max) of nepafenac was significantly higher than that of the other drugs (P<.05), including the higher-concentration ketorolac (0.4%). The area under the curve (AUC) of nepafenac was significantly higher (P<.05) than the AUCs of amfenac, ketorolac, and bromfenac. The combined AUCs of nepafenac and amfenac were the highest of all drugs tested (P<.05). Ketorolac showed the most potent COX-1 inhibition, whereas amfenac was the most potent COX-2 inhibitor. The PGE(2) aqueous humor levels of each study medication were highly variable; as a result, meaningful interpretation of the data was not possible.


CONCLUSIONS
Nepafenac showed significantly greater ocular bioavailability and amfenac demonstrated greater potency at COX-2 inhibition than ketorolac or bromfenac.
Walters
Tom
T
Keystone Research, Department of Ophthalmology, 1020 West 34th Street, Austin, Texas 78705, USA. twalters@austin.rr.com
Raizman
Michael
M
Ernest
Paul
P
Gayton
Johnny
J
Lehmann
Robert
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001082:Aqueous Humor / Q000378:metabolism*; D019540:Area Under Curve; D044482:Benzeneacetamides / Q000493:pharmacokinetics / Q000494:pharmacology; D001577:Benzophenones / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001969:Bromobenzenes / Q000493:pharmacokinetics / Q000494:pharmacology; D002387:Cataract Extraction; D002851:Chromatography, High Pressure Liquid; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D020910:Ketorolac / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010648:Phenylacetates / Q000493:pharmacokinetics / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D044482:Benzeneacetamides; D001577:Benzophenones; D001969:Bromobenzenes; D016861:Cyclooxygenase Inhibitors; D010648:Phenylacetates; C414203:nepafenac; C014285:amfenac; C053083:bromfenac; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D020910:Ketorolac