Simultaneous modelling of flosequinan and its metabolite.

DESIGN: A randomised, double-blind, prospective, placebo-controlled four-way study of the pharmacokinetics of single oral doses of flosequinan. We do not report the placebo data in this paper. Flosequinan was given at doses of 50, 100 and 150 mg, with a 2-week wash-out between periods. Blood samples were taken at a series of times up to 96 h after dosing. SETTING: Clinical pharmacology unit in a pharmaceutical company. PARTICIPANTS: Eighteen healthy volunteers of both genders, aged from 18 years to 55 years. MAIN OUTCOME MEASURES: Plasma concentrations of flosequinan and of its metabolite, flosequinoxan. RESULTS: We demonstrate that it is possible to model parent and metabolite concentration time profiles simultaneously and, in doing so, to estimate the first-pass effect using data from an oral administration. In our modelling approach, we propose a reasonably wide class of statistical models, allowing for left censoring. CONCLUSIONS: A parent-metabolite model that ignores the first-pass results in misleading predictions in a case where significant first-pass metabolism occurs. Thus, in phase-I studies, the new approach described in this paper can provide additional knowledge that may be useful in future formal studies.

Sibutramine pharmacokinetics in young and elderly healthy subjects.

OBJECTIVE: To investigate the pharmacokinetics of the pharmacologically active metabolites of sibutramine (metabolites 1 and 2) in healthy young and elderly volunteers following a single oral dose of sibutramine. METHODS: This was an open, parallel-group study completed by 12 young (six male, six female; mean age 24.0 years) and 12 elderly (six male, six female; mean age 70.3 years) healthy volunteers. Blood samples were taken at intervals up to 48 h post-dose. Plasma concentrations of metabolites were determined using HPLC-MS. Model-independent pharmacokinetic parameters of the two metabolites were compared for the two age groups. RESULTS: The similarity of the plasma profiles of the two desmethyl metabolites showed that despite the possibility of reduced hepatic function due to age, the rate and extent of formation of these was the same in both young and elderly, i.e. sibutramine metabolism was not impaired in elderly subjects. There were also no significant differences in elimination of metabolite 2 between groups, although the elderly group showed a slight trend for a reduction in k(el). CONCLUSIONS: The pharmacokinetics of the two pharmacologically active metabolites of sibutramine (metabolites 1 and 2) were not significantly different between the young and elderly groups in this study. Based on this information, a similar dosing regimen would be appropriate for both the young and elderly.

Pharmacokinetics of flosequinan in patients with heart failure.

OBJECTIVE: The pharmacokinetics of flosequinan were studied in a group of 18 patients with chronic cardiac failure. RESULTS: After a single dose of 100 mg, Cmax of the parent compound (2.52 mg.l-1) was recorded at 1.4 h, and of the sulphone metabolite flosequinoxan at 21.7 h. The plasma elimination half lives of the parent compound (6.4 h) and of the metabolite (54.3 h) were prolonged compared to previous studies in normal volunteers. After repeated dose administration for 36 days, the kinetics of the parent compound and metabolite remained essentially unchanged with an expected significant accumulation of metabolite (Cmax 8.4 vs 3.21 mg.l-1). No adverse effects were observed. CONCLUSION: It is possible that altered drug kinetics in patients with heart failure, probably related to altered hepatic blood flow, could contribute to drug toxicity.

Effects of concurrent administration of flosequinan and digoxin on the pharmacokinetics of each drug.

The pharmacokinetic and pharmacodynamic effects of co-administration of flosequinan (BTS 49465, CAS 76568-02-0) and digoxin (CAS 20830-75-5) were investigated in 12 healthy volunteers. A 4-day, open, lead-in phase established the pharmacokinetics of flosequinan (100 mg on the first day and 50 mg for the next 3 days) and was followed by a 24-day open interaction phase. Digoxin was administered alone (0.75 mg for the first 3 days and 0.5 mg for the next 4 days) to establish steady-state pharmacokinetics and in combination with flosequinan (100 mg on the 8th day and 50 mg for the next 14 days with 0.5 mg digoxin daily), and finally digoxin alone (0.5 mg for the remaining 3 days). No statistically significant differences were observed for any of the pharmacokinetic parameters for flosequinan, its major metabolite BTS 53554, or digoxin when flosequinan and digoxin were administered alone or concomitantly, but the confidence intervals for differences were relatively wide. Overall diastolic blood pressure was significantly lowered by 10% with concomitant treatment compared with flosequinan monotherapy. There were no significant effects on overall heart rate or systolic blood pressure, although pre-dose heart rate was increased by 6% during concomitant administration compared with digoxin alone, and remained high and digoxin alone. Adverse events (headache, nausea and vomiting) were reported by 2 volunteers on digoxin and 5 on concomitant therapy. One volunteer was withdrawn during concomitant therapy because of severe headache and vomiting. The results from this study indicate that no pharmacokinetic interaction occurred during concomitant administration of flosequinan and digoxin in healthy volunteers.

Pharmacokinetics, safety, and tolerability of flosequinan in patients with hepatic dysfunction.

The pharmacokinetics of flosequinan and its active metabolite, flosequinoxan, were investigated following a single 100-mg oral dose in 10 patients with compromised hepatic function. Plasma and urine samples were collected for up to 144 h postdose and analyzed by HPLC. All 10 patients provided analyzable data even though one patient withdrew before the 144-h sample because of an adverse event unrelated to the study medication. Interpatient variability was appreciable for the plasma and urine concentrations was well as for the calculated pharmacokinetic parameters. Relative to a comparative cohort of normal subjects, flosequinan concentrations in the study patients were elevated, showing increases in mean AUC0-t (62.8 +/- 49.4 vs 3.4 +/- 1.5 micrograms.h/mL), AUC0-infinity (70.2 +/- 58.3 vs 3.8 +/- 1.6 micrograms.h/m:), Cmax (2.43 +/- 0.56 vs 1.30 +/- 0.39 micrograms/mL), and t1/2 (20.7 +/- 16.8 vs 1.7 +/- 0.5 h). The mean systemic clearance decreased (47.3 +/- 46.5 vs 544 +/- 279 mL/min), along with the elimination rate constant (0.066 +/- 0.069 vs 0.44 +/- 0.13 h-1). Mean flosequinoxan AUC0-t and AUC0-infinity values were unaffected by hepatic dysfunction. The mean time to peak was longer (36.4 +/- 27.4 vs 7.0 +/- 3.1 h) and Cmax was less (0.98 +/- 0.52 vs 1.84 +/- 0.26 micrograms/mL) than in normal subjects. These findings are consistent with a decrease in the rate of flosequinan metabolism to flosequinoxan. Five patients reported adverse events, which included headache (three patients) and syncope (one patient).(ABSTRACT TRUNCATED AT 250 WORDS)

A multiple dose pharmacokinetic and tolerance study of once daily 200 mg sustained-release flurbiprofen capsules in young and very elderly patients.

The pharmacokinetic profile of 200 mg sustained-release flurbiprofen capsules was compared in nine elderly (mean age 84.2 years) and 10 young (mean age 38.1 years) patients with arthritis. After a single capsule, a 48 h plasma concentration profile was performed. The patients then took 1 capsule daily for a further 13 days with plasma levels of the drug being measured pre-dose on alternate days. Following ingestion of the last capsule, a further 48 hour plasma concentration profile was performed. These results were compared with each other and with computer predicted data obtained from dosing with 200 mg conventional flurbiprofen (as 100 mg b.d.). In both young and elderly patients, the two 48 h plasma concentration profiles confirmed the sustained-release characteristics of the capsule. There was no evidence of dose-dumping, although, in one elderly patient with a partial gastrectomy, higher plasma concentrations were observed. Inter- and intra-patient variability was acceptable. A steady-state was achieved within the predicted four days in both groups and there was no evidence of accumulation with the daily dosing interval. A mean steady-state level of approximately 6 micrograms/ml was achieved for both populations. Computer predicted data for 200 mg conventional flurbiprofen (as 100 mg b.d.) showed a pre-dose/peak range of 1-12 micrograms/ml. The pre-dose/peak ranges for the young and old patients were 4-10 micrograms/ml and 4-8 micrograms/ml respectively. One young patient developed a hypersensitivity reaction of moderate severity; one young and four elderly patients developed a low haemoglobin concentration during the study. No other changes in haematological or biochemical parameters were seen.

The pharmacokinetics and haemodynamics of BTS 49 465 and its major metabolite in healthy volunteers.

The pharmacokinetic and haemodynamic effects of a 200 mg oral dose of BTS 49 465 (7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) were investigated in a double-blind placebo controlled study. BTS 49 465 was rapidly absorbed and cleared from the systemic circulation with a half-life of 1.6 h by oxidation to the sulphone metabolite. The metabolite was cleared with a half-life of 37.6 h. Saliva concentrations of both BTS 49 465 and its metabolite correlated well with the plasma concentrations. Compared to placebo, BTS 49 465 produced statistically significant reductions in blood pressure and increases in heart rate both supine and after a 60 degrees head up tilt. The time course of the haemodynamic changes suggested that the sulphone metabolite contributed to the overall hypotensive response. Plasma Renin Activity was only marginally elevated and there was no evidence of acute fluid retention. BTS 49 465 was well tolerated in terms of haematological and biochemical parameters and subjective side-effects.

Pharmacokinetics of oral and rectal flurbiprofen in children.

Eight subjects, aged 6-12 years and weighing 18.8-36.7 kg, received single doses of flurbiprofen 50 or 75 mg (corresponding to 1.4-2.7 mg/kg) as syrup and suppository in a Latin square design. Half-life (2.7-3.2 h), elimination constant (0.22-0.26 h-1), area under the plasma level curve (72.4-77.3 micrograms X h X ml-1) and time to reach the concentration peak (1-0.75 h) were similar after the syrup and suppository. Flurbiprofen showed equivalent bioavailability after oral and rectal administration and the same pharmacokinetic profile was confirmed in children as observed in adults.

The effect of flurbiprofen on the responses to frusemide in healthy volunteers.

Ten subjects participated in a four-way, open, crossover study to investigate the effect of frusemide, flurbiprofen, flurbiprofen plus frusemide, and placebo on urinary volume, sodium, and potassium. Compared with placebo, flurbiprofen was shown to significantly reduce all three parameters. The diuretic effect of frusemide was reduced by the addition of flurbiprofen but not to a statistically significant degree. The reduction was less than in previous reports using indomethacin. As flurbiprofen is a more potent inhibitor of prostaglandin synthesis than indomethacin, these data cast doubt on the theory that nonsteroidal anti-inflammatory drugs antagonize the action of diuretics by prostaglandin synthetase inhibition. The methods for assaying the two drugs are described. A pharmacokinetic explanation of the reduction of the diuretic effects of frusemide by flurbiprofen was sought but not found.