Multiple-Dose Pharmacokinetics, Pharmacodynamics, and Safety of the Urotensin-II Receptor Antagonist Palosuran in Healthy Male Subjects.

PURPOSE: To investigate the multiple-dose pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of palosuran, a selective, potent antagonist of the human UT receptor. METHODS: This was a double-blind, randomized, placebo-controlled study. Three dose levels were investigated for PKs, PDs, and safety in sequential groups of 8 subjects each. RESULTS: The plasma concentration-time profile is characterized by rapid absorption and 2 peaks after drug administration. The apparent terminal half-life was approximately 25 h. Steady-state concentrations were reached after 4-5 days of dosing. The accumulation factor was approximately 2.5. With increasing doses, a more than dose proportional increase in AUCτ and Cmax was observed. Urinary excretion of unchanged palosuran was below 3%. No consistent effect was found on any of the PD variables. Palosuran was well tolerated in multiple doses up to 500 mg b.i.d. CONCLUSION: Palosuran after multiple-dosing is a well-tolerated drug in healthy subjects, but this finding warrants further investigation in patients.

Comorbidities and pharmacotherapies in patients with Gaucher disease type 1: The potential for drug-drug interactions.

PURPOSE: Clinical care for patients with rare diseases may be complicated by comorbidities. Administration of medications to treat comorbidities may elicit potentially harmful drug-drug interactions (DDIs). Genetic background may also influence DDI occurrence. We investigated the range of comorbid conditions in patients with Gaucher disease type I (GD1), the pharmacotherapies prescribed and the potential for DDI with enzyme replacement and substrate reduction therapies and additional medications, specifically cytochrome P450 (CYP) metabolizing medications. METHODS: A literature review examined comorbid conditions and pharmacotherapies reported in GD1. Analysis of two national databases reported real-world prescription practices in patients with GD1 (Germany, N=87; US, N=374). Prescribed drugs were assessed for known interactions with isoenzymes from the hepatic CYP enzyme family. RESULTS: The literature reported GD1 symptomatology and comorbid conditions in broad agreement with the known clinical picture. German patients received 86 different medications whereas US patients received 329 different medications. An average of 3.2 medications (Germany) and 7 medications (US) per patient were prescribed. Moderate/strong inhibitors of CYP isoenzymes were prescribed to 20% and 57% of patients in the US and Germany, respectively. CONCLUSION: This study describes the extensive number of comorbid conditions and drugs prescribed to patients with GD1, and the importance of determining CYP isoenzyme interaction to reduce DDI risk.

Investigation of mutual pharmacokinetic interactions between macitentan, a novel endothelin receptor antagonist, and sildenafil in healthy subjects.

AIM: To study the mutual pharmacokinetic interactions between macitentan, an endothelin receptor antagonist, and sildenafil in healthy male subjects. METHODS: In this open-label, randomized, three way crossover study, 12 healthy male subjects received the following oral treatments: A) a loading dose of 30 mg macitentan on day 1 followed by 10 mg once daily for 3 days, B) sildenafil 20 mg three times a day for 3 days and a single 20 mg dose on day 4 and C) both treatments A and B concomitantly. Plasma concentration-time profiles of macitentan and its active metabolite ACT-132577 (treatments A and C) and sildenafil and its N-desmethyl metabolite (treatments B and C) were determined on day 4 and analyzed non-compartmentally. RESULTS: The pharmacokinetics of macitentan were not affected by sildenafil. In the presence of sildenafil Cmax and AUCτ of the metabolite ACT-132577 decreased with geometric mean ratios (90% confidence interval (CI)) of 0.82 (0.76, 0.89) and 0.85 (90% CI 0.80, 0.91), respectively. In the presence of macitentan, plasma concentrations of sildenafil were higher than during treatment with sildenafil alone, resulting in increased Cmax and AUCτ values. The respective geometric mean ratios were 1.26 (90% CI 1.07, 1.48) and 1.15 (90% CI 0.94, 1.41). The pharmacokinetics of N-desmethylsildenafil were not affected by macitentan. All treatments were well tolerated. CONCLUSION: A minor, not clinically relevant, pharmacokinetic interaction was observed between macitentan and sildenafil. Based on these results, no dose adjustment of either compound appears necessary during concomitant treatment with macitentan and sildenafil.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple-dose study in healthy subjects.

This multiple-ascending-dose study investigated safety, tolerability, pharmacokinetics, and pharmacodynamics, of macitentan, a new endothelin receptor antagonist (ERA) with sustained receptor binding and enhanced tissue penetration properties compared to other ERAs. Healthy male subjects (n = 32) received once daily oral doses of macitentan (1 - 30 mg) or placebo for 10 days. Administration of macitentan was safe and well tolerated. Macitentan had no effect on bile salts, suggesting an improved liver safety profile. The multiple-dose pharmacokinetics of macitentan were dose-proportional and were characterized by a median tmax and apparent elimination half-life varying from 6.0 to 8.5 and 14.3 to 18.5 hours, respectively, for the different doses and minimal accumulation. ACT-132577, a metabolite with lower potency than macitentan, had a half-life of about 48 hours and accumulated approximately 8.5-fold. Compared to placebo, administration of macitentan caused a dose-dependent increase in plasma ET-1 with maximum effects attained at 10 mg. A small dose-dependent increase in the 6ß-hydroxycortisol/cortisol urinary excretion ratio was observed, although there were no statistically significant differences between treatments including placebo. Effects of macitentan on cytochrome P450 enzyme 3A4 should be further evaluated in dedicated studies. The present results support investigation of macitentan in the management of pulmonary arterial hypertension and ET-1-dependent pathologies.

First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials.

AIMS: To assess the safety and pharmacokinetics of a new synthetic ozonide antimalarial, OZ439, in a first-in-man, double-blind study in healthy volunteers. METHODS: OZ439 was administered as single oral daily doses of a capsule formulation (50-1200 mg) or an oral dispersion (400-1600 mg, fed and fasted states) and for up to 3 days as an oral dispersion (200-800 mg day(-1)). Plasma concentrations of OZ439 and its metabolites were measured by LC-MS. RESULTS: The pharmacokinetic (PK) profile of OZ439 was characterized by a t(max) of around 3 h, followed by a multiphasic profile with a terminal half-life of 25-30 h. The PK parameters were approximately dose proportional for each group and profiles of the metabolites followed a similar pattern to that of the parent compound. Following dosing for 3 days, accumulation was less than two-fold but steady-state was not achieved. In the presence of food, no effect was observed on the t(1/2) of OZ439 while the exposure was increased by 3 to 4.5-fold. Exposure was higher and inter-subject variability was reduced when OZ439 was administered as an oral dispersion compared with a capsule. The urinary clearance of OZ439 and its metabolites was found to be negligible and OZ439 did not induce CYP3A4. The antimalarial activity profiles of a subset of serum samples suggested that the major antimalarial activity originated from OZ439 rather than from any of the metabolites. CONCLUSION: The safety and pharmacokinetic profile of OZ439 merits progression to phase 2a proof of concept studies in the target population of acute uncomplicated malaria.

Hemodynamics and pharmacokinetics of tezosentan, a dual endothelin receptor antagonist, in patients with cirrhosis.

PURPOSE: To assess the effect of tezosentan, a parenteral dual ET receptor antagonist, on splanchnic and systemic hemodynamics in patients with cirrhosis. In addition, the safety, pharmacokinetics, and pharmacodynamics of tezosentan were evaluated. METHODS: The population consisted of patients with cirrhosis with clinically significant portal hypertension. This was a randomized, double-blind, multicenter study. The patients were randomized 3:1 to tezosentan (3 mg/h for 2-3 h) or placebo. HVPG, hepatic blood flow (HBF, ICG method), and systemic arterial pressures were measured before and after tezosentan administration. Plasma concentrations of tezosentan and ET-1 were determined peripherally and in the hepatic vein. RESULTS: Eighteen patients received tezosentan and six placebo. Baseline clinical, biochemical, and hemodynamic characteristics were balanced between the two groups. There was no significant treatment effect on HVPG. The extraction ratio (0.31), the plasma clearance of ICG (280 ml/min), and the HBF (1,430 ml/min) did not show any relevant changes during the infusion of tezosentan, and there were no differences between placebo- and tezosentan-treated patients. A linear relationship was observed between the maximum-fold increase in ET-1 concentration and the steady-state tezosentan plasma concentration (r = 0.82). There was a strong correlation (r = 0.88) between plasma clearance of ICG and that of tezosentan (10.2 l/h). Arterial pressure and heart rate did not significantly change in either group. CONCLUSION: In patients with cirrhosis, a 2- to 3-h tezosentan infusion was safe and well tolerated but did not change the HVPG. Tezosentan infusion had no influence on the extraction ratio and plasma clearance of ICG and did not change HBF.

Macitentan: entry-into-humans study with a new endothelin receptor antagonist.

PURPOSE: To study the pharmacokinetics, pharmacodynamics, and tolerability of rising single doses of macitentan, an endothelin receptor antagonist, in healthy male subjects. METHODS: This double-blind, placebo-controlled study was performed in seven groups of eight healthy male subjects. Doses of 0.2, 1, 5, 25, 100, 300 and 600 mg or placebo (two subjects per group) were administered. Plasma macitentan and endothelin-1 and serum total bile salt concentrations were measured and analysed non-compartmentally. Plasma and urine were analysed qualitatively for the presence of metabolites and one of these, ACT-132577, was also measured quantitatively in plasma. Standard tolerability measurements were performed throughout the study. RESULTS: Macitentan was slowly absorbed and, at a dose of 300 mg, the t(1/2) (95% confidence interval, CI) was 17.5 h (14.1, 21.8). The dose-proportionality coefficient ß for C(max) (95% CI) was 0.83 (0.79, 0.87) indicating less than dose-proportional pharmacokinetics of macitentan. In plasma, a pharmacologically active oxidative depropyl metabolite, ACT-132577, was found whereas in urine two minor metabolites were detected. The t(1/2) of ACT-132577 (95% CI) was 65.6 h (53.1, 80.9). Macitentan dose-dependently increased endothelin-1 concentrations up to 2.2-fold (95% CI 1.4, 2.4) at a dose of 600 mg, but had no consistent effect on total bile salts. Macitentan was well tolerated up to and including a dose of 300 mg, the maximum tolerated dose. Headache, nausea and vomiting were dose-limiting adverse events. CONCLUSION: The pharmacokinetic and tolerability profile of macitentan is consistent with a once-a-day dosing regimen and warrants further investigation in clinical studies.

Mutual pharmacokinetic interactions between bosentan and lopinavir/ritonavir in healthy participants.

BACKGROUND: We aimed to investigate the extent of pharmacokinetic drug interactions between bosentan and a fixed combination of lopinavir/ritonavir. METHODS: This was a three-way crossover study in 12 healthy male participants treated with bosentan (125 mg twice daily) and lopinavir/ritonavir (400/100 mg twice daily) alone or in combination for 9.5 days. RESULTS: Combination treatment resulted in slightly lower area under the concentration-time curve during the 12 h dosing interval under steady-state conditions (AUC(tau,ss)) values of both lopinavir and ritonavir with geometric mean ratios (GMRs; 90% confidence intervals [CIs]) of 0.86 (0.74-0.99) for lopinavir and 0.83 (0.76-0.92) for ritonavir. The maximum concentration in steady state (C(max,ss)) of lopinavir and ritonavir remained unchanged with a GMR of 0.95 and 1.01, respectively, and the 90% CIs were within the range of 0.8-1.25. The observed effects of bosentan on lopinavir and ritonavir pharmacokinetics were considered to be not clinically relevant. The pharmacokinetics of bosentan were strongly affected by coadministration. Bosentan concentration increased up to 48-fold during the first 4 days of coadministration with lopinavir/ritonavir. At steady state, the GMR for AUC(tau,ss) was 5.22 (3.84-7.10) and for C(max,ss) was 6.12 (4.24-8.82). The increased exposure to bosentan was reflected in an increase in adverse events attributed to bosentan, that is, mainly headache, but not in liver enzyme abnormalities. CONCLUSIONS: Bosentan does not affect lopinavir and ritonavir exposure to a clinically relevant extent, but tolerability of bosentan should be monitored in HIV patients under antiretroviral therapy with lopinavir/ritonavir. It is anticipated that all ritonavir-boosted protease inhibitors will have a similar effect on bosentan pharmacokinetics.

Pharmacokinetics and pharmacodynamics of the urotensin-II receptor antagonist palosuran in healthy male subjects.

Palosuran is a new potent and specific antagonist of the human urotensin II (U-II) receptor (UT receptor). This entry-into-humans study evaluated the tolerability and safety, pharmacokinetics, and pharmacodynamics of palosuran in a double-blind, placebo-controlled, single ascending-dose design. Oral doses of 5 to 2000 mg were given to 9 sequential groups of 8 healthy young men (6 on active drug, 2 on placebo) each. At regular intervals, tolerability and safety parameters and plasma levels of palosuran and U-II were determined. Urine was collected to determine excretion of sodium, potassium, creatinine, and palosuran. In this study, palosuran was well tolerated. No serious adverse events or dose-related adverse events were reported. No treatment-related pattern was detected for vital signs, clinical laboratory parameters, or electrocardiography parameters. After rapid absorption, palosuran displayed a plasma concentration-time profile characterized by 2 peaks at approximately 1 and 4 hours after drug administration. The apparent terminal elimination half-life was approximately 20 hours. AUC and C(max) values increased proportionally with doses up to 500 mg. Excretion of unchanged palosuran in urine was limited. No consistent effect was found on any of the pharmacodynamic variables measured. The results of this entry-into-humans study warrant further investigation of the therapeutic potential of palosuran.

Pharmacokinetics, safety and tolerability of miglustat in the treatment of pediatric patients with GM2 gangliosidosis.

GM2 gangliosidosis (GM2g) is an inherited neurodegenerative disorder caused by deficiency of lysosomal beta-hexosaminidase A, resulting in accumulation of GM2 ganglioside, principally in the brain. Substrate reduction therapy is currently under investigation as a treatment. The study investigated the pharmacokinetics and safety of miglustat given as single and multiple doses in infantile and juvenile GM2g patients for 6- and 24-months, respectively. Eleven patients with infantile (n = 6) and juvenile (n = 5) GM2g received oral miglustat at 30-200 mg t.i.d. adjusted to the body surface area. Patients underwent pharmacokinetic assessments on day 1 and at month 3. The pharmacokinetics of miglustat were described by a 2-compartmental model with a lag time, median time to maximum concentration of 2.5 h, and terminal half-life of about 10 h. The pharmacokinetics were time-independent, and did not differ between infantile and juvenile cohorts. The accumulation index was 1.7. Among infantile GM2g patients, the major drug-related adverse events (DRAEs) were abdominal discomfort and flatulence. In the juvenile group, however, the major DRAEs observed were diarrhea and weight loss. One juvenile patient developed peripheral neuropathy, and others showed progression of already established neuropathy, which was judged to be part of the natural progression of the disease. Some mild laboratory abnormalities observed were either transient or attributable to concomitant medications. Miglustat showed similar pharmacokinetic parameters in all patients, with no specific difference between infantile and juvenile forms. Miglustat was shown to be a safe drug, with mild to moderate diarrhea, as an age-dependent DRAE, which was controlled by dietary modification.

Influence of liver cirrhosis on the pharmacokinetics, pharmacodynamics, and safety of tezosentan.

This study investigates the pharmacokinetics, pharmacodynamics, and safety of the parenteral endothelin receptor antagonist tezosentan in patients with Child-Pugh classification B/C liver impairment. Cohorts I and II consist of 5 and 11 patients, respectively, with low serum bilirubin (

Influence of ethnic origin and sex on the pharmacokinetics of clazosentan.

This study investigated the influence of ethnic origin and, as a secondary objective, sex on the pharmacokinetics of the parenteral endothelin receptor antagonist clazosentan in healthy Caucasian and Japanese subjects. Twelve subjects of each ethnic origin (female/male ratio 1:1) were treated with sequential 4-hour infusions of 1, 5, and 15 mg/h. Blood samples were taken frequently to determine plasma levels of clazosentan. The exposure to clazosentan was approximately 16% higher in Japanese subjects compared with Caucasian subjects and 18% higher in females compared with males. These differences were mainly attributable to a difference in clearance. A 3-compartment model well described the plasma concentration-time profiles of clazosentan with disposition half-lives of approximately 6 minutes, 21 minutes, and 2.7 hours. The data suggest that Caucasian and Japanese patients can be treated with a similar dosing regimen of clazosentan. At the doses infused, administration of clazosentan was safe and well tolerated in both ethnic groups.

Effect of gender on the tolerability, safety and pharmacokinetics of clazosentan following long-term infusion.

OBJECTIVE: The purpose of this study was to investigate the effect of gender on the tolerability, safety and pharmacokinetics of clazosentan, an intravenous endothelin receptor antagonist. METHODS: Clazosentan was infused at a dosage of 0.05 mg/kg/h or 0.1 mg/kg/h for 72 hours in 8 female and 8 male healthy volunteers, respectively. Tolerability and safety were assessed via the recording of dose reductions/infusion stops, vital signs, ECG, adverse events and clinical laboratory variables. Blood samples were collected for the determination of clazosentan and endothelin-1 concentrations. RESULTS: The occurrence of adverse events such as headache, vomiting and nausea of moderate to severe intensity led either to discontinuation of the infusion or to a dose reduction in the majority of volunteers. The values (mean and 95% confidence intervals) for clearance were 37.7 (32.8, 43.4) and 35.2 (27.8, 44.5) L/h in male and female volunteers, respectively. CONCLUSION: Long-term infusion of clazosentan at the doses tested was poorly tolerated in both male and female volunteers. Gender appeared to have no influence on the pharmacokinetics of clazosentan.

Influence of food intake on the pharmacokinetics of miglustat, an inhibitor of glucosylceramide synthase.

The objective of this study was to investigate the effect of food on the pharmacokinetics of miglustat, an inhibitor of glucosylceramide synthase. Twenty-four healthy male (n = 9) and female (n = 15) subjects were treated in a randomized, 2-way crossover design with a single oral dose of 100 mg miglustat with or without food. Consumption of a standard high-fat breakfast within 30 minutes before administration of miglustat significantly reduced peak exposure but did not significantly affect the extent of systemic exposure to miglustat. The peak plasma concentration (C(max)) decreased by 36% on average following administration with food. Area under the plasma concentration-time curve (AUC(0-infinity)) showed a modest (14%) decrease with food, but the 90% confidence interval was within the acceptance limit of 80% to 125%. The median (min-max) time to C(max) (t(max)) was prolonged from 2.5 (1.0-4.0) hours in the fasted state to 4.5 (1.5-8.0) hours in the fed state, whereas the apparent terminal half-life was approximately 8 hours and not affected by food. In conclusion, the intake of food has an effect on some pharmacokinetic parameters such as C(max) and t(max) but does not affect the extent of exposure to miglustat. The observed effects of food intake on the pharmacokinetics of miglustat are not considered to be of clinical relevance.

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.

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.

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.

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.

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.

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.