Absolute bioavailability of bromfenac in humans.

OBJECTIVE: To estimate absolute bioavailability of bromfenac and to compare its pharmacokinetics after intravenous and oral administration. DESIGN: This was a randomized, open-label, single-dose, crossover study conducted under fasting conditions with a washout period of at least 48 hours between doses. Each subject received a 50-mg dose of bromfenac both intravenously and orally followed by collection of blood samples at specified time intervals. Bromfenac plasma concentrations were measured by using a validated HPLC method with ultraviolet detection. SETTING: The study was conducted at the Drug Evaluation Unit. Hennepin County Medical Center, Minneapolis, MN. SUBJECTS: The participants consisted of 12 healthy subjects between 18 and 45 years of age and within +/-15% of ideal body weight. RESULTS: The mean +/- SD absolute bioavailability of bromfenac was 67% +/- 20%. CONCLUSIONS: The pharmacokinetic parameters of bromfenac were similar after intravenous and oral administration, suggesting that the prototype oral dosage form is optimal and that the observed intersubject variability is due to bromfenac itself, not the type of dosage form.

Effects of age and gender on the pharmacokinetics of bromfenac in healthy volunteers.

OBJECTIVE: To compare the pharmacokinetic parameters of bromfenac, a nonsteroidal antiinflammatory drug under development, in healthy volunteers of various ages and either gender, after single and multiple doses. DESIGN: Open-label, single- and multiple-dose, nonrandomized, parallel study. PARTICIPANTS: Twenty young (18-45 y), 12 young-elderly (65-74 y), and 12 elderly (75-85 y) subjects were studied. Half of the subjects in each group were women. INTERVENTIONS: Bromfenac was given as a single 50-mg dose and then as 50-mg doses every 12 hours for 3 additional days. Twelve blood samples were collected for 12 hours after the first and last doses. MAIN OUTCOME MEASURES: Bromfenac concentrations were measured by using an HPLC procedure with ultraviolet detection. Unbound bromfenac concentrations were measured by equilibrium dialysis. Pharmacokinetic analysis was performed by noncompartmental techniques. RESULTS: No significant differences related to gender were detected. Significant differences were observed in half-life (t1/2), AUC, clearance, and apparent volume of distribution when the elderly group was compared with the young group and in t1/2 when the elderly group was compared with the young-elderly group, although substantial overlap among groups was observed. CONCLUSIONS: Administration of bromfenac to young-elderly or elderly subjects of either gender does not require a dosage adjustment in acute settings. Consideration should be made to titrating dosages in patients over 75 years of age who require repeated doses.

Evaluation of pharmacokinetic interaction between bromfenac and phenytoin in healthy males.

An open-label, nonrandomized, multiple-dose, inpatient study was conducted in healthy male volunteers to compare the pharmacokinetics of bromfenac and phenytoin when the drugs are given individually and concomitantly. Twelve men received multiple oral doses of bromfenac for 4 days and then oral phenytoin for up to 14 days followed by concomitant administration of bromfenac and phenytoin for 8 days. Concomitant administration of the two drugs caused an approximate 40% decrease in the mean peak plasma concentration (Cmax) and the interdose area under the concentration-time curve (AUC) of bromfenac. The oral clearance (Clpo) of bromfenac doubled and the volume of distribution increased by 77%. For phenytoin, the mean peak serum concentration and the AUC increased by 9% and 11%, respectively, in the presence of bromfenac. The only change in unbound phenytoin was a 16% increase in the AUC. Although statistically significant, the changes in the pharmacokinetic parameters of phenytoin and unbound phenytoin were small. Adjustments in the dose of phenytoin should not be required during concomitant administration of bromfenac, although each patient's clinical status should be evaluated individually.

Lack of interaction between bromfenac and methotrexate in patients with rheumatoid arthritis.

OBJECTIVE: To compare the pharmacokinetics of methotrexate (MTX) and bromfenac administered separately or coadministered in patients with rheumatoid arthritis (RA). METHODS: Patients received their usual weekly oral dose of MTX on Days 1 and 8 and bromfenac 50 mg every 8 h from Days 4 to 9. On Days 1 and 8 serial blood and urine samples were collected to study the pharmacokinetics of MTX and 7-hydroxymethotrexate (7-OHMTX). Bromfenac pharmacokinetics were studied on Days 7 and 8. Concentrations of the analytes were assayed using validated high performance liquid chromatography methods. RESULTS: Nine patients, 5 women and 4 men, completed the study. No statistically significant changes were observed in any of the pharmacokinetic variables evaluated for bromfenac with or without MTX. Bromfenac also did not alter the pharmacokinetics of low dose MTX. However, some significant changes were observed in the pharmacokinetics of 7-hydroxymethotrexate: a 30% increase in dose normalized area under the serum concentration time curve (mean +/- SD) to 3102 +/- 1397 micrograms.h/l and a 16% decrease in renal clearance to 10.0 +/- 6.7 ml/h/kg. Eight patients had mild or moderate adverse events: most were considered unrelated to the study drug by the investigator. One patient did not complete the study because of moderate hypertension. No patient had clinically important abnormal laboratory test results. CONCLUSION: No clinically significant changes in MTX pharmacokinetics were detected in patients with RA when bromfenac was added to MTX therapy. Although 7-OHMTX concentrations were elevated, the changes were small and unlikely to be of clinical significance. MTX did not alter the pharmacokinetics of bromfenac.