Biomedical subjects

Jasper Dingemanse

Publications and source records attributed to Jasper Dingemanse.

At least 19 recordsLinked to original sources

PubMed2006

Tolerability, pharmacokinetics, and pharmacodynamics of clazosentan, a parenteral endothelin receptor antagonist.

OBJECTIVE: The purpose of this study was to investigate in healthy male subjects the tolerability, pharmacokinetics, and pharmacodynamics of ascending doses of clazosentan, an intravenous endothelin receptor antagonist. METHODS: Clazosentan was infused at doses of 3-60 mg/h for 3 h, 60 mg/h for 6 h and at 30 mg/h for 12 h. Each dose was given to a separate group of subjects, six of whom received clazosentan and two placebo. Vital signs, ECG, adverse events, and clinical laboratory variables were monitored to assess tolerability. Blood and urine samples were collected frequently for pharmacokinetic and pharmacodynamic determinations. RESULTS: Infusion of clazosentan up to doses of 30 mg/h for 3 h was well tolerated. A dose of 60 mg/h and longer infusions were less well tolerated and three subjects did not complete the 12-h infusion of 30 mg/h due to adverse events. Headache was the most commonly reported adverse event followed by nausea, vomiting, and nasal congestion. The pharmacokinetics of clazosentan were dose proportional in the dose range investigated. Values (mean and 95% confidence intervals) for clearance and volume of distribution at a dose of 10 mg/h for 3 h were 42.2 (36.6, 48.7) l/h and 32.4 (27.0, 38.8) l, respectively. Both variables were independent of dose. The elimination of clazosentan was characterized by a very rapid disposition phase with a half-life of 6-10 min. Compared to baseline, endothelin-1 concentrations increased approximately 2-fold after infusion of clazosentan but no dose-dependent relationship could be discerned for this effect. CONCLUSION: The observed tolerability, pharmacokinetic, and pharmacodynamic profile warrant further clinical development of clazosentan at lower doses.

Adult↗

PubMed2006

Pharmacodynamics and pharmacokinetics of the urotensin II receptor antagonist palosuran in macroalbuminuric, diabetic patients.

OBJECTIVE: In patients with renal disease increased urotensin II plasma levels have been observed. We have investigated whether palosuran, a potent, selective, and competitive antagonist of the urotensin II receptor, has effects in patients who are prone to the development of renal disease. METHODS: Macroalbuminuric, diabetic patients, categorized by renal function, were treated with oral doses of 125 mg palosuran twice daily for 13.5 days in addition to treatment with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. The 24-hour urinary albumin excretion rate was determined twice at baseline and after 13.5 days of treatment. Plasma concentrations of palosuran were determined for 12 hours after the first and last drug intake. Renal hemodynamics was measured before and after 12.5 days of treatment. Tolerability and safety parameters were monitored. RESULTS: An overall clinically significant reduction of 24.3% (geometric mean) (95% confidence interval, 4.1 to 45.0) in the 24-hour urinary albumin excretion rate was observed (P = .014). No effect was observed on renal hemodynamic parameters. Palosuran was rapidly absorbed with maximum plasma concentrations at 1 hour after drug administration. The accumulation factor was 1.7 (geometric mean) (95% confidence interval, 1.3 to 2.1). Palosuran was well tolerated. CONCLUSIONS: The good tolerability profile and the decrease in the 24-hour urinary albumin excretion rate may benefit diabetic patients with renal failure with regard to their disease progression. Larger placebo-controlled trials in this patient population are needed to investigate whether urotensin II receptor antagonists, given as monotherapy or combination therapy, may improve the current treatment of diabetic nephropathy.

Aged↗

PubMed2006

Comparison of the pharmacokinetics, pharmacodynamics and tolerability of tezosentan between caucasian and Japanese subjects.

AIM: To investigate the pharmacokinetics, pharmacodynamics and tolerability of the dual endothelin receptor antagonist tezosentan in caucasian and Japanese subjects. METHODS: Twelve subjects of each ethnic origin were treated in a double-blind, randomized design with sequential 3-h infusions of 2.5, 5.0, 12.5 and 25 mg h(-1), or placebo. Vital signs, ECG and adverse events were recorded and blood samples collected for determination of plasma concentrations of tezosentan and endothelin-1 (ET-1). RESULTS: Tezosentan was well tolerated in both ethnic groups with no clinically significant differences in laboratory measurements, ECG parameters and vital signs. The plasma concentration-time profiles of tezosentan were described by a three-compartment model with half-lives of approximately 5 min, 41 min and 3.6 h. Mean clearance and volume of distribution were approximately 35 l h(-1) and 20 l, respectively. Differences in the means (95% confidence intervals) between ethnic groups in these two parameters were 6.0 l h(-1) (-1.3, 13.3) and 4.3 l (-1.3, 9.9), respectively. Baseline ET-1 concentrations were similar but increases in response to tezosentan were greater in caucasian than in Japanese subjects. An indirect response model described the relationship between tezosentan and ET-1 plasma concentrations. The mean concentrations inhibiting 50% of ET-1 clearance (IC(50)) in caucasian and Japanese subjects were 243 and 227 ng ml(-1), respectively, with a difference in the means of 28.6 ng ml(-1) (-52.7, 110). CONCLUSIONS: The data in healthy subjects suggest that caucasian and Japanese patients can be treated with a similar dosing regimen of tezosentan.

Adult↗

PubMed2005

Comparative investigation of the pharmacokinetics of bosentan in Caucasian and Japanese healthy subjects.

Bosentan is a dual endothelin receptor antagonist in development for the treatment of pulmonary arterial hypertension in Japan, whereas it is registered for this indication in Europe and the United States. The present study was conducted to compare the pharmacokinetics of bosentan in Caucasian and Japanese subjects. In a double-blind, placebo-controlled, ascending single-dose, 5-way crossover study, 10 healthy Caucasian and 10 Japanese subjects (1:1 male/female ratio) received single doses of 31.25, 62.5, 125, and 250 mg of bosentan or placebo. Pharmacokinetic profiles of bosentan and its pharmacologically active hydroxy metabolite, Ro 48-5033, were determined after each dose of bosentan. The pharmacokinetics of bosentan were similar and dose proportional in both ethnic groups. However, peak plasma concentration values of Ro 48-5033 were significantly greater in Japanese subjects (P < .05). This difference could not be explained by the lower body weight of the Japanese subjects. Females in both groups tended to have higher exposure to both bosentan and Ro 48-5033 than males. The results suggest that, based on pharmacokinetic grounds, no dose adjustment of bosentan is necessary when used to treat Japanese patients in comparison to Caucasian patients.

Adult↗

PubMed2005

Effects of the endothelin receptor antagonist bosentan on hemodynamics, symptoms and functional capacity in Japanese patients with severe pulmonary hypertension.

BACKGROUND: Endothelin (ET)-1 has a pathogenic role in pulmonary arterial hypertension (PAH). Recent clinical studies carried out in Western populations showed that blockade of the ET receptors by bosentan improves pulmonary hemodynamics and exercise capacity. In the present study, the efficacy of bosentan was assessed in Japanese patients with PAH. METHOD AND RESULTS: Because the pharmacokinetics of bosentan and its metabolites are similar in Japanese and Caucasian subjects, the same dose of bosentan, 125 mg twice daily, was administered in the Japanese open-label clinical trial. In 18 patients, mean pulmonary arterial pressure decreased from 52.4+/-13.8 to 46.8+/-13.8 mmHg (p=0.003) and cardiac index increased from 2.20+/-0.74 to 2.61 +/-0.72 L.min(-1).m(-2) (p=0.002). The 6-min walking distance increased from 410+/-89.5 to 494+/-86.0 m (p<0.0001). The dyspnea index (Borg scale) decreased from 3.2+/-2.4 to 2.2+/-1.7 (p=0.02). The specific activity scale (SAS) gradually increased throughout the study period from 2.9+/-0.8 to 4.6+/-1.9 METs (p=0.0005). WHO Class improved in 10 patients. CONCLUSION: Bosentan was well tolerated and improved the hemodynamics, symptoms, exercise capacity, and quality of life of Japanese patients with PAH. Thus, bosentan can be a valuable therapeutic option in Japanese patients.

Adult↗

PubMed2004

The hemodynamic and neurohormonal effects of low doses of tezosentan (an endothelin A/B receptor antagonist) in patients with acute heart failure.

BACKGROUND: In previous studies (the RITZ project), tezosentan, an intravenous (i.v.)-balanced dual endothelin (ET-A/B) antagonist, in doses of 50 and 100 mg/h, improved the hemodynamics but not the clinical outcome of patients with acute heart failure (AHF). OBJECTIVE: To evaluate the effect of lower doses of tezosentan in patients with AHF. SUBJECTS AND METHODS: Included were 130 patients hospitalized due to AHF with dyspnea at rest, despite initial treatment, and were in need of hemodynamic monitoring with cardiac index (CI)<2.5 l/min/m(2) and wedge pressure > or = 20 mm Hg. Patients were randomized in a double-blind fashion to receive placebo or tezosentan: 0.2, 1, 5, or 25 mg/h for 24 h. RESULTS: The primary endpoint of the study, CI increase at 6 h of treatment, was significant in the 5 and 25 mg/h groups. Tezosentan induced a dose-dependent increase in CI and a decrease in wedge pressure, peaking after 3 h in the 5 and 25 mg/h groups. In the 1 mg/h group, this effect was smaller during the first 6 h and increased gradually, becoming significant at 24 h and beyond treatment discontinuation. There was no hemodynamic effect in the 0.2 mg/h arm. Type-B natriuretic peptide (BNP) decreased in the 1, 5, and 25 mg/h groups but not on placebo. Endothelin levels were significantly increased by the 5 and 25 mg/h groups but not in the lower (< or = 1 mg/h) tezosentan doses. Urine output decreased on the 25 mg/h dose. There was a trend towards improvement in patients' subjective dyspnea score and worsening heart failure events, mainly in the 1 mg/h group. CONCLUSIONS: In patients admitted with AHF, tezosentan doses of 1-25 mg/h are efficacious in improving the hemodynamics and reducing BNP. Tezosentan doses beyond 1 mg/h increased plasma endothelin levels and reduced urine output, probably limiting their clinical efficacy, as compared to tezosentan 1 mg/h.

Aged↗

PubMed2004

Influence of mild liver impairment on the pharmacokinetics of tezosentan, a drug excreted unchanged into bile.

AIMS: To investigate the effect of mild liver impairment on the pharmacokinetics of tezosentan. METHODS: Eleven patients with mild liver impairment and eight healthy subjects received an intravenous infusion of 50 mg h-1 tezosentan for 1 h. Plasma and urine concentrations were determined during and following termination of the infusion. RESULTS: The pharmacokinetic parameters presented as geometric means [95% confidence interval (CI)] for clearance, volume of distribution and terminal half-life were 30 (22, 40) and 42 (36, 48) l h-1, 28 (19, 42) and 19 (16, 23) l, and 4.5 (2.9, 7.0) and 3.6 (2.9, 4.5) h in liver patients and healthy subjects, respectively. The ratios (liver patients/healthy subjects) of these geometric means (95% CI) were 0.71 (0.47, 1.1), 1.5 (0.87, 2.6), and 1.3 (0.69, 2.3), respectively. A two-compartment model accurately fitted the concentration-time data. In both groups approximately 4% of the dose was excreted unchanged into urine. CONCLUSIONS: Although there was a slight trend towards a decreased clearance, the pharmacokinetics of tezosentan in patients with mild liver impairment were similar to those in healthy subjects. Therefore, no dose adaptation seems to be needed in this patient population.

Adult↗

PubMed2004

Treatment of secondary pulmonary hypertension with bosentan and its pharmacokinetic monitoring in ESRD.

Pulmonary hypertension (PH) is a rare disease with a very poor prognosis. Certain pharmacologic approaches, which reduce pulmonary arterial pressure (PAP) and thereby prevent end-stage cardiopulmonary failure, have been used during recent years. Endothelin-1 has been found to be involved in the pathogenesis of PH. The dual endothelin-receptor antagonist, bosentan, was recently approved for the treatment of pulmonary arterial hypertension. The drug is mainly cleared by hepatic elimination. Severe renal dysfunction does not affect the single-dose pharmacokinetics of bosentan to a clinically relevant extent. Whether renal replacement therapy, however, interferes with the pharmacokinetics of bosentan is unknown. The authors report on the use of bosentan (125 mg twice daily) and its pharmacokinetic monitoring in a 19-year-old woman with PH and end-stage renal disease secondary to scleroderma. Treatment was well tolerated without drug-specific adverse effects. After 12 months of treatment, pulmonary arterial pressure had normalized (48 mm Hg before start of treatment, 27 mm Hg at last follow-up). On the basis of analyzing samples from Genius-hemodialysis by a liquid chromatography assay with tandem mass spectrometry detection, the authors determined the bosentan dialysis clearance to be as low as 3.5 mL/min. Bosentan for the treatment of secondary PH seems to be safe as well as effective in end-stage renal disease patients and no adjustment of the bosentan dosing regimen appears necessary.

Adult↗

PubMed2004

Clinical pharmacology of bosentan, a dual endothelin receptor antagonist.

Bosentan, a dual endothelin receptor antagonist, is indicated for the treatment of patients with pulmonary arterial hypertension (PAH). Following oral administration, bosentan attains peak plasma concentrations after approximately 3 hours. The absolute bioavailability is about 50%. Food does not exert a clinically relevant effect on absorption at the recommended dose of 125 mg. Bosentan is approximately 98% bound to albumin and, during multiple-dose administration, has a volume of distribution of 30 L and a clearance of 17 L/h. The terminal half-life after oral administration is 5.4 hours and is unchanged at steady state. Steady-state concentrations are achieved within 3-5 days after multiple-dose administration, when plasma concentrations are decreased by about 50% because of a 2-fold increase in clearance, probably due to induction of metabolising enzymes. Bosentan is mainly eliminated from the body by hepatic metabolism and subsequent biliary excretion of the metabolites. Three metabolites have been identified, formed by cytochrome P450 (CYP) 2C9 and 3A4. The metabolite Ro 48-5033 may contribute 20% to the total response following administration of bosentan. The pharmacokinetics of bosentan are dose-proportional up to 600 mg (single dose) and 500 mg/day (multiple doses). The pharmacokinetics of bosentan in paediatric PAH patients are comparable to those in healthy subjects, whereas adult PAH patients show a 2-fold increased exposure. Severe renal impairment (creatinine clearance 15-30 mL/min) and mild hepatic impairment (Child-Pugh class A) do not have a clinically relevant influence on the pharmacokinetics of bosentan. No dosage adjustment in adults is required based on sex, age, ethnic origin and bodyweight. Bosentan should generally be avoided in patients with moderate or severe hepatic impairment and/or elevated liver aminotransferases. Ketoconazole approximately doubles the exposure to bosentan because of inhibition of CYP3A4. Bosentan decreases exposure to ciclosporin, glibenclamide, simvastatin (and beta-hydroxyacid simvastatin) and (R)- and (S)-warfarin by up to 50% because of induction of CYP3A4 and/or CYP2C9. Coadministration of ciclosporin and bosentan markedly increases initial bosentan trough concentrations. Concomitant treatment with glibenclamide and bosentan leads to an increase in the incidence of aminotransferase elevations. Therefore, combined use with ciclosporin and glibenclamide is contraindicated and not recommended, respectively. The possibility of reduced efficacy of CYP2C9 and 3A4 substrates should be considered when coadministered with bosentan. No clinically relevant interaction was detected with the P-glycoprotein substrate digoxin. In healthy subjects, bosentan doses >300 mg increase plasma levels of endothelin-1. The drug moderately reduces blood pressure, and its main adverse effects are headache, flushing, increased liver aminotransferases, leg oedema and anaemia. In a pharmacokinetic-pharmacodynamic study in PAH patients, the haemodynamic effects lagged the plasma concentrations of bosentan.

Antihypertensive Agents↗

PubMed2003

Determination of tezosentan, a parenteral endothelin receptor antagonist, in human plasma by liquid chromatography-tandem mass spectrometry.

An analytical method was developed for the quantification of tezosentan in human plasma obtained in clinical studies. The method was linear in the range 1 to 512 ng/ml. After liquid-liquid extraction, the samples were analyzed by reversed-phase HPLC with tandem mass spectrometry. The limit of quantification was 1 ng/ml and the extraction recovery was at least 88.2%. Intra- and inter-assay coefficients of variation were below 10%. Stability tests revealed that tezosentan is stable under the different conditions tested.

Chromatography, High Pressure Liquid↗

PubMed2003

Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension.

BACKGROUND: Bosentan, a dual endothelin-receptor antagonist, is registered for the treatment of pulmonary arterial hypertension. Little is known about the effects of bosentan in children. This study was conducted to investigate the pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. METHODS: In this 2-center, open-label study, 19 pediatric patients with pulmonary arterial hypertension were enrolled and stratified for body weight and epoprostenol use. Patients weighing between 10 and 20 kg, between 20 and 40 kg, or greater than 40 kg received a single dose of 31.25, 62.5, or 125 mg, respectively, on day 1, followed by 4 weeks of treatment with the initial dose. The dose was then up-titrated to the target dose (31.25, 62.5, or 125 mg twice daily). Pharmacokinetic and hemodynamic parameters were obtained at baseline and after 12 weeks of treatment. Six-minute walk distance and cardiopulmonary exercise testing results were measured at baseline and at week 12 in children aged 8 years or older. RESULTS: The variability in exposure among the 3 groups was less than 2-fold after single- and multiple-dose administration. The exposure to bosentan decreased over time in all groups. The covariates body weight, gender, age, and the use of epoprostenol had no significant effect on the pharmacokinetics of bosentan. Bosentan produced hemodynamic improvement and was well tolerated. The mean change from baseline in mean pulmonary artery pressure was -8.0 mm Hg (95% confidence interval, -12.2 to -3.7 mm Hg), and that in pulmonary vascular resistance index was -300 dyne x s x m(2)/cm(5) (95% confidence interval, -576 to -24 dyne x s x m(2)/cm(5)). CONCLUSIONS: The pharmacokinetics of bosentan in pediatric patients with pulmonary arterial hypertension and healthy adults are similar, and treatment with bosentan resulted in hemodynamic improvement. These results suggest that the applied dosing regimens may be appropriate to treat pediatric patients.

Adolescent↗

PubMed2003

Influence of mild liver impairment on the pharmacokinetics and metabolism of bosentan, a dual endothelin receptor antagonist.

The purpose of the study was to investigate the effect of mild liver impairment on the pharmacokinetics and metabolism of bosentan. Eight patients with mild liver impairment and 8 matching healthy subjects were treated with single and multiple oral 125-mg doses of bosentan. The pharmacokinetic parameters of bosentan and its metabolites were similar in both groups: geometric means for Cmax and AUC for bosentan were 2534 and 1980 ng/ml and 11,957 and 10,781 ng.h/ml after single doses and were 1831 and 1715 ng/ml and 7216 and 7838 ng.h/ml after multiple doses, respectively, in healthy subjects and patients. In both groups, the exposure to the metabolites was low when compared to that to bosentan. The decrease in exposure to bosentan after multiple dosing, indicative of autoinduction, tended to be less pronounced in patients as compared to healthy subjects. Bosentan was well tolerated in this study. In conclusion, the pharmacokinetics, metabolism, and tolerability of bosentan are similar in healthy subjects and patients with mild liver impairment.

Alanine Transaminase↗

PubMed2003

Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin.

BACKGROUND: In vitro, bosentan has been shown to be a mild inducer of cytochrome P450 (CYP) 2C9 and 3A4. PURPOSE: To investigate in vivo the mutual pharmacokinetic interactions between bosentan and simvastatin, a CYP3A4 substrate. METHODS: Nine healthy male subjects were treated in a three-period randomised crossover study with: (A) bosentan 125 mg twice daily for 5.5 days; (B) simvastatin 40 mg once daily for 6 days; and (C) bosentan 125 mg twice daily and simvastatin 40 mg once daily for 5.5 and 6 days, respectively. Plasma concentration-time profiles of bosentan and its metabolites (treatments A and C) and simvastatin and beta-hydroxyacid simvastatin (treatments B and C) were determined on day 6. RESULTS: Steady-state conditions for bosentan and its metabolites were attained on day 4 of treatment. The pharmacokinetic parameters of bosentan and its metabolites were not influenced by concomitant treatment with simvastatin: areas under the plasma concentration-time curve over one administration interval of 12 hours (AUC(tau)) [geometric mean and 95% CI] were 4586 (3719-5656) and 4928 (3945-6156) micro g * h/L. In contrast, bosentan significantly reduced exposure to simvastatin and beta-hydroxyacid simvastatin by 34 and 46%, respectively. AUC(tau) values for simvastatin were 30.5 (23.1-40.2) and 20.0 (15.9-25.1) micro g * h/L and for beta-hydroxyacid simvastatin 43.0 (32.1-57.8) and 23.4 (16.7-32.6) micro g * h/L in treatments B and C, respectively. CONCLUSIONS: Concomitant treatment with bosentan reduces the exposure to simvastatin and beta-hydroxyacid simvastatin by approximately 40%, indicating that in vivo bosentan is also a mild inducer of CYP3A4.

Adult↗

PubMed2003

Nemifitide. Innapharma.

Nemifitide is a peptide under development by Innapharma for the potential treatment of depression. By June 2001, the first phase II trial of nemifitide in moderate to severely depressed individuals had been completed and in February 2003, Innapharma anticipated that phase III trials would commence later that year.

Animals↗

PubMed2002

Bosentan, a dual endothelin receptor antagonist, activates the pregnane X nuclear receptor.

Recent clinical studies have shown that bosentan, a dual endothelin receptor antagonist, decreases the exposure to various substrates of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. The aim of the study was to investigate the effect of bosentan, its metabolites and glibenclamide on the activity of the pregnane X receptor, a nuclear receptor that regulates the transcription of CYP3A4. CV-1 monkey kidney cells were transiently transfected with a luciferase reporter plasmid containing three copies of the ER6 response element of CYP3A4 and the human or mouse pregnane X receptor. Subsequently, the cells were incubated with the test compounds and the activity of luciferase determined. Bosentan activated the human pregnane X receptor with an EC(50) of 19.9 microM, whereas rifampicin had an EC(50) value of 1.9 microM. Ro 47-8634 (4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-hydroxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzenesulfonamide), a metabolite of bosentan, and glibenclamide also activated the pregnane X receptor. The findings provide a molecular mechanism for the interactions observed between bosentan and several drugs.

Animals↗

PubMed2002

Cyclosporin increases the exposure to tezosentan, an intravenous dual endothelin receptor antagonist.

OBJECTIVE: To investigate in 12 healthy subjects the pharmacokinetics and tolerability of tezosentan, an endothelin receptor antagonist, when given concomitantly with cyclosporin. METHODS: Tezosentan was infused at a dose of 6.25 mg/h and 25 mg/h for 6 h either alone or following a single dose of 400 mg cyclosporin. Blood and urine samples were collected for pharmacokinetic determinations. Vital signs, electrocardiogram, adverse events, and clinical laboratory parameters were monitored to assess tolerability. RESULTS: Concomitant cyclosporin resulted in a fourfold increase in the exposure to tezosentan. Tezosentan alone was well tolerated. In combination with cyclosporin, and at both doses, all subjects reported headache, hot flushes and nausea/vomiting, some of which were of severe intensity. CONCLUSION: The poor tolerability of the combination of cyclosporin and tezosentan is not correlated with the plasma concentrations of tezosentan.

Area Under Curve↗

PubMed2002

Pharmacokinetics and pharmacodynamics of tezosentan, an intravenous dual endothelin receptor antagonist, following chronic infusion in healthy subjects.

AIMS: The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of tezosentan, an intravenous dual endothelin receptor antagonist, during chronic infusions in healthy male subjects. METHODS: Tezosentan was infused at a rate of 100 mg h(-1) for 6 h (study A, six subjects) and at a rate of 5 mg h(-1) for 72 h (study B, eight subjects). Both studies had a randomized, placebo-controlled, double-blind design. Tolerability and safety were monitored by the recording of vital signs, ECG, adverse events and clinical laboratory parameters. Blood samples were collected frequently for pharmacokinetic determinations and measurement of plasma endothelin-1 concentrations. RESULTS: In both studies tezosentan was well tolerated with headache the most frequently reported adverse event (incidence of 75-100% for tezosentan and 50% for placebo). Plasma concentrations of tezosentan rapidly approached steady state (3000 and 125 ng ml(-1) in study A and B, respectively) and did not change upon prolonged infusion. A two-compartment model could describe its pharmacokinetic profile. The half-lives of the two disposition phases were approximately 0.10 and 3.2 h. Endothelin-1 concentrations increased rapidly 11- and 2-fold compared with pre-dose values in study A and B, respectively, during infusion of tezosentan and did not change during the 72 h infusion. CONCLUSIONS: On the basis of these results, dose finding studies with tezosentan in acute heart failure can be initiated in the dose range 5-100 mg h(-1).

Adolescent↗

PubMed2002

Effect of the catechol-O-methyltransferase inhibitor entacapone on the steady-state pharmacokinetics and pharmacodynamics of warfarin.

AIMS: To investigate the influence of a multiple-dose regimen with the catechol-O-methyltransferase inhibitor entacapone on the pharmacokinetics and pharmacodynamics of warfarin. METHODS: In a randomized, double-blind, two-way cross-over study, 12 healthy subjects (gender ratio 1 : 1) received treatment for 1 week with either entacapone 200 mg four times daily or placebo during individually optimized treatment with warfarin (INR 1.4-1.8). The effect of entacapone on the steady-state pharmacokinetics of both R- and S-warfarin was determined and, in addition, INR values were measured. The key pharmacokinetic variables were AUCss, Cmax and tmax. RESULTS: Entacapone increased the exposure to R-warfarin by 18% (90% CI: 111, 126%), and caused a 13% (6, 19%) increase in INR values. No effect was seen on the pharmacokinetics of the pharmacologically more potent S-enantiomer. Safety and tolerability variables did not show any difference between the treatment phases. CONCLUSIONS: In healthy subjects, entacapone displays a slight pharmacokinetic interaction with R-warfarin but, based on the lack of a clinically relevant pharmacodynamic interaction, it appears that it can also be used safely in Parkinson's disease patients who are receiving warfarin.

Adult↗