Biomedical subjects

Jasper Dingemanse

Publications and source records attributed to Jasper Dingemanse.

23 records · Page 2Linked to original sources

PubMed2002

Single- and multiple-dose pharmacokinetics of bosentan and its interaction with ketoconazole.

AIMS: The present study was conducted to characterize the single- and multiple-dose pharmacokinetics of bosentan, a dual endothelin receptor antagonist, and to investigate a possible pharmacokinetic interaction with ketoconazole. METHODS: In a randomized, two-way crossover study, 10 healthy male subjects received treatments A and B. Treatment A consisted of a single dose of 62.5 mg bosentan on day 1 followed by 62.5 mg twice daily for 5.5 days. Treatment B consisted of bosentan (62.5 mg twice daily) for 5.5 days plus concomitant ketoconazole (200 mg once daily) for 6 days. Plasma concentrations of bosentan and its three metabolites were measured on days 1 and 7 of treatment A and on day 6 of treatment B. RESULTS: Bosentan was absorbed and eliminated with a tmax of 4.5 h (range 3.5-6.0 h) and a t(1/2) of 5.4 h (95% CI; 4.5, 6.6). Upon multiple dosing, the exposure to bosentan was reduced by 33% without change in tmax and t(1/2). Concomitant administration of ketoconazole increased the Cmax and AUC of bosentan 2.1- (95% CI; 1.5, 2.7) and 2.3-fold (95% CI; 1.8, 2.9), respectively. Exposure to the metabolites was low and represented less than 25% of that to bosentan both after single and multiple doses. In the presence of ketoconazole, formation of the metabolites was inhibited. DISCUSSION: The multiple-dose pharmacokinetics of bosentan are consistent with the phenomenon of auto-induction. In the presence of CYP3A4 inhibitors, bosentan concentrations may be increased 2-fold.

Adult↗

PubMed2002

In vivo and in vitro studies exploring the pharmacokinetic interaction between bosentan, a dual endothelin receptor antagonist, and glyburide.

BACKGROUND: In a clinical trial with patients with chronic heart failure, a higher incidence of elevated levels of liver transaminases was observed during concomitant treatment with bosentan, a dual endothelin receptor antagonist, and glyburide (INN, glibenclamide), a sulfonylurea-type antidiabetic drug, than with treatment with bosentan alone. This study was conducted to investigate a possible pharmacokinetic interaction between bosentan and glyburide. METHODS: In a randomized, 2-way crossover study, 12 healthy volunteers received treatments A and B. Treatment A consisted of 125 mg bosentan twice a day for 10 days plus concomitant 2.5 mg glyburide twice a day on days 6 to 10. Treatment B consisted of 2.5 mg glyburide twice a day for 10 days plus concomitant 125 mg bosentan twice a day on days 6 to 10. Plasma concentrations of bosentan and its metabolites and of glyburide were measured on days 5 and 10 of treatment A and treatment B, respectively. RESULTS: Bosentan reduced the area under the concentration-versus-time curve of glyburide approximately 40% (P <.05). Glyburide decreased the area under the concentration-versus-time curve of bosentan and its metabolites 20% to 30% (P <.05). Results of in vitro experiments showed that glyburide is metabolized by cytochrome P450 (CYP) 2C9, 2C19, and 3A4. No interaction was observed on the level of serum protein binding. CONCLUSIONS: The plasma levels of both bosentan and glyburide were reduced after concomitant administration. This finding is consistent with a CYP3A4-inducing potential of both drugs. The observed pharmacodynamic interaction between bosentan and glyburide in patients with chronic heart failure cannot be explained by a pharmacokinetic interaction.

Adolescent↗

PubMed2002

Entry-into-humans study with tezosentan, an intravenous dual endothelin receptor antagonist.

The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of ascending doses of tezosentan, an IV dual endothelin receptor antagonist, during first administration in humans. Tezosentan infused at doses of 5, 20, 50, 100, 200, 400, and 600 mg for 1 h was administered to sequential groups of six male subjects in a randomized, placebo-controlled, double-blind design. Recording of vital signs, electrocardiogram, adverse events, and clinical laboratory parameters monitored tolerability and safety. Blood samples were collected frequently for pharmacokinetic determinations and measurement of plasma endothelin-1 concentrations. Tezosentan was well tolerated at all dose levels. Headache was the most frequently reported adverse event and occurred at a higher incidence than with placebo at doses of > or = 100 mg. No clinically relevant changes in vital signs, electrocardiographic, or clinical laboratory parameters occurred. Plasma concentrations of tezosentan rapidly approached steady state and could be described by a two-compartment model. The volume of distribution at steady state (approximately 16 l) and the clearance (approximately 30 l/h) were considered independent of dose, in view of the wide dose range explored. A pronounced and rapid disposition phase (half-life 6 min), accounting for the major part of the elimination, was followed by a slower phase (half-life 3 h), probably caused by distribution from tissues. Endothelin-1 concentrations increased in a dose- and concentration-dependent fashion and returned slowly to baseline after termination of the infusion. Tezosentan warrants further clinical development in view of its tolerability and pharmacokinetic profile, which appears advantageous for application in emergency situations.

Adult↗

PubMed2002

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.

Adult↗

PubMedDate not supplied

Multiple-dose pharmacokinetics of intranasally administered IS-159 in healthy subjects.

This study was designed to investigate the multiple-dose pharmacokinetics of a range of intransal doses of IS-159, a serotonin 1B/1D receptor agonist. Intranasal doses of 1, 2, 4 and 6 mg of IS-159 were administered twice at an interval of 4 hours to 17 healthy male and female subjects in a two-way crossover study. Plasma concentrations of IS-159 were determined from blood samples taken at regular intervals up to 24 hours after the first administration during both treatment periods. IS-159 was rapidly absorbed and eliminated with a t(max) of approximately 15 min and a t(1/2) of approximately 1.6 hours. With increasing dose, the exposure increased dose-proportionally, and IS-159 pharmacokinetics appear not to be influenced by gender and food intake. The results showed dose-proportional pharmacokinetics of IS-159 in the dose range tested and a low propensity for drug accumulation.

Administration, Intranasal↗