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Pharmacokinetics and Pharmacodynamics of the ET_A-Selective Endothelin Receptor Antagonist SPP301 in Healthy Human Subjects

From Drug Disposition Consultants, Loerrach, Germany (Dr. Dieterle); Clinical Research & Development, Speedel Development AG, Basle, Switzerland (Dr. Mann); and AccelPharm, Basle, Switzerland (Dr. Kutz).

SPP301 is a competitive antagonist of ET-1 with a high selectivity for the ET_A 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. 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.

Key Words: Endothelin-1 • SPP301 • ET_A-selective endothelin receptor antagonist • tolerability • pharmacokinetics • pharmacodynamics

Address for reprints: Dr. Jessica Mann, Speedel Development AG, Department of Clinical Research & Development, Hirschgüsslein 11, CH-4051 Basel, Switzerland.

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