title: Pharmacokinetics and pharmacodynamics of the ETA-selective endothelin receptor antagonist SPP301 in healthy human subjects.
abstract: 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.
authors.affiliation: Drug Disposition Consultants, Loerrach, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Dieterle
authors.forename: Jessica
authors.initials: J
authors.lastname: Mann
authors.forename: Klaus
authors.initials: K
authors.lastname: Kutz
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D001794:Blood Pressure; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D005215:Fasting; D006207:Half-Life; D006339:Heart Rate; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D011725:Pyridines / Q000493:pharmacokinetics* / Q000494:pharmacology; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D011743:Pyrimidines; C484919:Avosentan