Pharmacokinetics and pharmacodynamics of cumulative single doses of inhaled salbutamol enantiomers in asthmatic subjects.

Objectives of this study were to compare the pharmacokinetics, pharmacodynamics and safety of single cumulative doses of active (R)-salbutamol given either as the single enantiomer or racemic mixture by inhalation to subjects with mild to moderate asthma. This was a double-blind, crossover, cumulative-dose, randomized study where all subjects received either four doses of 1.25 mg of (R)-salbutamol or 2.5 mg of racemic (RS-) salbutamol by nebulization. The pharmacokinetic parameters were determined by noncompartmental analysis and model-fitting. Changes in FEV(1), plasma potassium, plasma glucose, heart rate, and QTc interval were measured. The potassium and glucose data were fitted to indirect response pharmacodynamic models. The heart rate and QTc data were evaluated using data descriptors. No significant differences in pharmacokinetics of (R)-salbutamol given as either (R)- or (RS)-salbutamol were found with AUC values of 11.90 +/- 4.37 and 11. 47 +/- 2.88 ng.h/ml. The t(max)of about 2 h reflected serial dosing rather than delayed absorption. The t(1/2)averaged about 3.5 h. The (S)-salbutamol showed AUC of 48.46 +/- 12.11 ng.h/ml with a t(1/2)of about 5 h. The changes in FEV(1)reached a plateau after an initial increase and did not return to pre-drug values for 10 h. All pharmacodynamic parameters were similar whether (R)- or (RS)-salbutamol was given. The exposure to (R)-salbutamol was identical after inhalation of (R) -and (RS)-salbutamol by subjects with asthma. Several pharmacological responses including FEV(1)were also similar and there were no unique safety concerns with either treatment.

Pharmacokinetic and pharmacodynamic characteristics and safety of inhaled albuterol enantiomers in healthy volunteers.

The pharmacokinetics and pharmacodynamics of inhaled albuterol given as single or multiple doses of racemate (RS-) or single enantiomers (R-, S-) were determined. In an open-label, three-way crossover, parallel-dose study, 1.25 and 5 mg of (R)- and (S)-albuterol and 2.5 and 10 mg of (RS)-albuterol were given via nebulization to 15 healthy volunteers. The pharmacokinetic parameters of each enantiomer were determined by noncompartmental and model-fitting analyses. Both (R)- and (S)-albuterol showed rapid absorption and biexponential decline, with half-lives (t1/2) averaging 4 and 6 hours, respectively. There were no differences in pharmacokinetics of (R)-albuterol when administered as (R)- or (RS)-albuterol at the 5-mg dose with equivalent relative bioavailability as seen from maximum concentration (Cmax) and area under the concentration-time curve (AUC). The same was true for (S)-albuterol at the 1.25-mg and 5-mg doses. The data from 5-mg doses were considered to be more reliable due to assay sensitivity limitations, and indicated equivalent absorption and disposition of the individual enantiomers. There was no evidence of in vivo racemization, and (R)-albuterol did not interconvert to (S)-albuterol. Plasma potassium, plasma glucose, heart rate, and QTc interval were used in linear and Emax models to assess responses relating to (R)-albuterol concentrations. The Emax for potassium change was 1.32 meq/L, with an EC50 of 0.59 and 0.94 ng/mL after administration of (R)- and (RS)-albuterol, respectively. The slopes and intercepts for glucose and heart rate changes were similar after administration of (R)- and (RS)-albuterol. No concentration-effect relationships were evident for QTc interval or for (S)-albuterol. The extrapulmonary responses of (R)-albuterol and adverse effects were similar for single R-enantiomer or the racemic mixture.

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.

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.