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

Abstract

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 x1 for 6 h (study A, six subjects) and at a rate of 5 mg h x1 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 x1 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 x1 .

Levosimendan: A New Inodilatory Drug for the Treatment of Decompensated Heart Failure

“…Tezosentan is an intravenous endothelin receptor A/B antagonist. It has an elimination half-life of 3.2 hours [78]. Infusions up to 72 hours have shown beneficial hemodynamic effects in healthy volunteers and in patients with advanced heart failure.…”

Clinical and Hemodynamic Effects of Bosentan Dose Optimization in Symptomatic Heart Failure Patients with Severe Systolic Dysfunction, Associated with Secondary Pulmonary Hypertension – A Multi-Center Randomized Study

“…ERA-blockade is typically accompanied by immediate endothelin overproduction resulting in up to ten-fold increase in serum levels [16, 17]. The excessive production resolves within hours of drug discontinuation.…”

Handbook of Cardiovascular Emergencies

“…The COMFORT score, the only sedation scoring tool validated in mechanically ventilated children (8), is used by only 20 -48% of survey respondents (4,7). BIS correlates with COMFORT scores and discriminates between light and deep levels of sedation (10,11). Additionally, approximately 30% of PICU patients are likely to receive paralytics (4), limiting the utility of objective scoring tools.…”

“…Additionally, approximately 30% of PICU patients are likely to receive paralytics (4), limiting the utility of objective scoring tools. The role of BIS deserves more study, particularly since BIS monitoring is hindered by motion artifact, poor correlation with fine gradations of sedation (10,11), and inadequate evaluation of analgesia (12). Unfortunately, these variables are unreliable (9).…”

“…Troponins have been reported to be elevated in several pediatric conditions such as postcardiac surgery (8), in systemic viral bronchiolitis without evidence of severe myocardial ischemia or dysfunction (9, 10), and following pediatric cardiac arrest (11). It is not yet clear.…”