Pharmacokinetic properties and metabolism of idebenone.

Four phase 1 studies were conducted to assess the pharmacokinetics and metabolism of idebenone (including parent drug and inactive metabolites QS10, QS6, and QS4) and to evaluate the safety of a wide range of idebenone doses and regimens in healthy adult men. After a single oral dose of idebenone 150 mg, 750 mg, or 1050 mg in fasted or fed subjects, blood samples were taken for up to 72 hours. In one study, after a single oral dose and a 7-day washout period, subjects received repeated doses of idebenone 150 mg or 750 mg every 8 hours for 14 days. In the repeated-dose study, urine samples also were taken. Plasma and urine samples were analysed with the use of liquid chromatography with tandem mass spectrometry. Non-compartmental standard pharmacokinetic methods were used. In these studies, a total of 69 subjects ranging in age from 19 to 41 years (body weight, 57-94.6 kg) were included. Plasma concentrations of parent idebenone were low but increased in proportion to dose and increased approximately five-fold in the presence of food. Total QS4 was the main metabolite in plasma and urine. The most common adverse events were loose stool, fatigue, headache, and disturbances in attention. Idebenone was well tolerated in single oral doses up to 1050 mg and in repeated daily doses up to 2250 mg. Idebenone showed linear pharmacokinetics after single and repeated oral dosing. Administration after a meal resulted in the highest exposure to parent idebenone.

Pharmacokinetics and metabolism of idebenone in healthy male subjects.

PURPOSE: Idebenone is a synthetic analogue of ubiquinone that may be beneficial in the treatment of Friedreich's ataxia. Since in previous pharmacokinetic trials only lower doses were studied, it was the aim of this study to evaluate the pharmacokinetics of idebenone in higher doses of up to 2,250 mg/day. METHODS: In this open, randomized trial, 25 healthy male subjects received first either a single oral dose of 150 mg or 750 mg of idebenone, then the same dose given at 8-h intervals for 14 days. RESULTS: Idebenone and its metabolites appeared in the plasma quickly. Over 99% of parent idebenone was metabolized, indicating a high first-pass effect. C(max) and AUC(0-t) values for parent idebenone and its metabolites increased in a dose-proportional manner. There was virtually no accumulation of parent drug or metabolites following multiple dosing. CONCLUSIONS: Idebenone exhibited dose-dependent pharmacokinetics in daily doses up to 2,250 mg. In 6/14 subjects, adverse events of mild to moderate severity were observed.

Pharmacokinetics and pharmacodynamics of the ETA-selective endothelin receptor antagonist SPP301 in healthy human subjects.

SPP301 is a competitive antagonist of ET-1 with a high selectivity for the ETA receptor. A double-blind, placebo-controlled study was performed to investigate the tolerability, pharmacokinetics, and pharmacodynamics of SPP301 after single oral doses in male healthy subjects; doses of 5, 20, 50, 100, and 200 mg were given to different groups of 4 or 8 subjects each. The effect of food on the pharmacokinetics of SPP301 was assessed for the 50-mg dose according to a sequential design in the same subjects. At regular intervals, blood pressure and pulse rate, plasma levels of ET-1 and of SPP301 and its hydroxymethyl metabolite, and urinary excretion of the parent drug and its metabolite were determined. SPP301 was generally well tolerated. At doses >20 mg, adverse events that are typical for vasodilating agents-namely, headache, nausea and vomiting, dizziness, and postural hypotension-were observed. Maximum plasma levels of SPP301 were reached within 4.5 hours. Cmax and AUC values increased linearly with doses up to 100 mg. The apparent terminal half-life was quite constant over the whole dose range and ranged from 7.5 to 15.2 hours. Urinary excretion of SPP301 was below 0.1% of any dose. Cmax and AUC of the metabolite amounted only to about 5% of the values for SPP301. Concomitant food intake had no effect on the overall exposure but increased average peak plasma concentrations of SPP301 by around 50%. Plasma ET-1 increased nearly twofold at the 5-mg SPP301 dose, with no further relevant increase at higher doses. In conclusion, SPP301 is an active ET-1 antagonist and is well tolerated. The pharmacokinetics of the drug and its metabolite are linear up to 100 mg. Food does not affect overall exposure of SPP301 but increases Cmax. Urinary excretion of SPP301 is below 0.1% of the dose administered.

Influence of food intake and formulation on the pharmacokinetics and metabolism of bosentan, a dual endothelin receptor antagonist.

The purpose of the study was to investigate the effect of food intake on the pharmacokinetics and metabolism as well as the relative bioavailability of bosentan. Sixteen healthy male subjects were treated in a randomized, four-way, crossover design with single oral doses of 125 mg bosentan, given as one tablet (with or without food), two tablets of 62.5 mg (with food), and a suspension (without food). The pharmacokinetic parameters of bosentan (and also three of its metabolites) were very similar after the four treatments: geometric means for Cmax and AUC0-infinity, ranged from 1.3 to 1.6 microg/ml and from 7.8 to 8.9 microg x h/ml, respectively, and median t(max) from 3.0 to 4.0 hours. The bioavailability of the 125 mg tablet relative to that of the suspension, both given fasted, was 102%. In the presence of food, Cmax and AUC0-max increased by 22% and 10%, respectively, whereas the two 62.5 mg tablets were bioequivalent to the 125mg tablet, both under fed conditions. The pharmacokinetics of the metabolites was independent of the treatment administered. In conclusion, bosentan bioavailability from the newly developed 125 mg tablet formulation is similar to that of the suspension, and food intake does not influence its pharmacokinetics to a clinically relevant extent.

Phase I clinical and pharmacokinetic study of BBR 3576, a novel aza-anthrapyrazole, administered i.v. every 4 weeks in patients with advanced solid tumors: a phase I study group trial of the Central European Society of Anticancer-Drug Research (CESAR).

BBR 3576 is a novel aza-anthrapyrazole with limited potential for cardiotoxicity in preclinical models. This phase I clinical and pharmacokinetic study was performed to determine the maximum tolerated dose, the dose-limiting toxicity (DLT) and the pharmacokinetic profile of BBR 3576 administered i.v. as a 1-h infusion repeated every 4 weeks. In total, 27 patients were treated at doses starting from 1 to 150 mg/m2. The dose levels 1, 2, 4, 8, 16, 32, 64, 90, 125 and 150 mg/m2 were investigated in one, three, one, three, two, one, three, four, three and six patients, respectively. The DLT was a grade 3 stomatitis at 150 mg/m2. At this dose level as well as at 125 mg/m2, neutropenia grade 3 and 4 were frequently seen, but not reaching the criteria for DLT. Time to neutrophil nadir was about 2 weeks and recovery took place within 1 week. Other bone marrow toxicities were mild; lymphopenia was also observed. No significant drug-induced cardiotoxicity was observed. The plasma concentration versus time curves of BBR 3576 showed a biexponential profile with a linear kinetic behavior. A very large volume of distribution, a high plasma clearance and long elimination half-lives were calculated. Renal unchanged drug excretion was less than 10% and therefore a minor excretion route. No objective antitumor responses were found. On the basis of this study, the recommended dose for phase II studies is 150 mg/m2, although the maximum tolerated dose as per protocol definition was not reached. This trial showed that BBR 3576 has a manageable toxicity profile on a 4-week schedule. Phase II studies have started in patients with solid tumors, as suggested by preclinical data in different in vivo model systems.