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Pharmacokinetics and Pharmacodynamics of the ET A ‐Selective Endothelin Receptor Antagonist SPP301 in Healthy Human Subjects
Author(s) -
Dieterle Walter,
Mann Jessica,
Kutz Klaus
Publication year - 2004
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270003261047
Subject(s) - pharmacokinetics , cmax , pharmacodynamics , pharmacology , metabolite , medicine , active metabolite , placebo , tolerability , chemistry , adverse effect , alternative medicine , pathology
SPP301 is a competitive antagonist of ET‐1 with a high selectivity for the ET A receptor. A double‐blind, placebocontrolled 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. C max 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. C max 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 C max . Urinary excretion of SPP301 is below 0.1% of the dose administered.