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Ghrelin Agonist (TZP‐101): Safety, Pharmacokinetics and Pharmacodynamic Evaluation in Healthy Volunteers: A Phase I, First‐in‐Human Study
Author(s) -
Lasseter Kenneth C.,
Shaughnessy Laura,
Cummings David,
Pezzullo John C.,
Wargin William,
Gag Rene,
Oliva Jesus,
Kosutic Gordana
Publication year - 2008
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 - 10.1177/0091270007310380
Subject(s) - medicine , pharmacokinetics , pharmacodynamics , tolerability , anesthesia , adverse effect , placebo , volume of distribution , heart rate , orthostatic vital signs , bradycardia , crossover study , pharmacology , blood pressure , alternative medicine , pathology
The authors evaluate the human safety, tolerability, pharmacokinetics, and pharmacodynamics of TZP‐101, an agonist of the hGHS‐R1a (ghrelin) receptor. Healthy subjects were randomized to either single‐dose TZP‐101 (20–600 μg/kg) or placebo by 30‐minute intravenous infusion. Subjects underwent continuous cardiac monitoring, 12‐lead electrocardiograms, and assessment for orthostatic hypotension, injection site tolerability, vital signs, and adverse events during the 24‐hour postdose period. Blood and urine samples were collected for pharmacokinetic/pharmacodynamic assessment for 24 hours. Forty‐eight subjects randomly received 1 of 6 TZP‐101 doses or placebo. TZP‐101 was well tolerated, with single episodes each of headache, lower abdominal pain, diarrhea, and dizziness. At the highest dose, 2 subjects experienced bradycardia. All events were self‐limited. Mean arterial blood pressure and heart rate decreased from baseline approximately 45 to 60 minutes after infusion start at higher doses. No other significant changes were observed. Pharmacokinetic analysis revealed less than dose‐proportional behavior of drug with low clearance (≅7 mL/h/kg), small volume of distribution (≅114 mL/kg), and half‐life values of ≅13 hours, which were independent of dose. Pharmacodynamic analyses suggested TZP‐101, at doses as low as 40 μg/kg, expressed activity at the receptor. TZP‐101 displayed a promising pharmacokinetic, pharmacodynamic, and safety profile for use in gastrointestinal motility disorders.