The Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Oral Doses of RO5068760, an MEK Inhibitor, in Healthy Volunteers: Assessment of Target Suppression

RO5068760, a substituted hydantoin, represents a new class of potent, highly selective, non‐adenosine triphosphate (ATP)–competitive MEK1/2 inhibitors. The study aimed to determine the safety/tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of RO5068760 in human healthy...

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Published in:Journal of clinical pharmacology Vol. 50; no. 12; pp. 1397 - 1405
Main Authors: Lee, Lucy, Niu, Huifeng, Goelzer, Petra, Rueger, Ruediger, Deutsch, Jonathan, Busse-Reid, Rachel, DeSchepper, Stefanie, Blotner, Steve, Barrett, Joanne, Weissgerber, Georges, Peck, Richard
Format: Journal Article
Language:English
Published: Oxford, UK Blackwell Publishing Ltd 01.12.2010
SAGE Publications
Wiley Subscription Services, Inc
Subjects:
Adolescent
Adult
Aged
Biomarkers - metabolism
clinical pharmacology
clinical trials
Colorectal cancer
Dose-Response Relationship, Drug
Double-Blind Method
Drug Evaluation, Preclinical - methods
Extracellular Signal-Regulated MAP Kinases - metabolism
Half-Life
Humans
Imidazolidines - blood
Imidazolidines - pharmacokinetics
Imidazolidines - pharmacology
Imidazolidines - toxicity
Intestinal Absorption
Leukocytes, Mononuclear - drug effects
Leukocytes, Mononuclear - metabolism
Male
MAP Kinase Signaling System - drug effects
Metabolic Clearance Rate
Middle Aged
Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors
Models, Biological
oncology
pharmacodynamics
pharmacokinetics and drug metabolism
Phenylbutyrates - blood
Phenylbutyrates - pharmacokinetics
Phenylbutyrates - pharmacology
Phenylbutyrates - toxicity
Phosphorylation - drug effects
Protein Kinase Inhibitors - blood
Protein Kinase Inhibitors - pharmacokinetics
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - toxicity
Tetradecanoylphorbol Acetate - analogs & derivatives
Tetradecanoylphorbol Acetate - pharmacology
Young Adult
ISSN:0091-2700, 1552-4604, 1552-4604
Online Access:Get full text
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Summary:RO5068760, a substituted hydantoin, represents a new class of potent, highly selective, non‐adenosine triphosphate (ATP)–competitive MEK1/2 inhibitors. The study aimed to determine the safety/tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of RO5068760 in human healthy volunteers. All participants received a single dose followed by 48 hours of pharmacokinetics, pharmacodynamics, and safety/tolerability assessments. The pharmacodynamics were measured by changes in ERK phosphorylation (pERK) in peripheral blood mononuclear cells, ex vivo stimulated by phorbol 12‐myristate 13‐acetate (PMA). Forty‐eight participants received 6 doses (50, 100, 200, 400, 600, 800 mg). RO5068760 was well tolerated up to 800 mg. There were no clinically significant safety findings, including laboratory, electrocardiogram, ophthalmological assessment, and fecal occult blood tests. Of the total 13 adverse events (n = 12), 11 were mild, 2 were moderate, and none were severe, and only 5 were considered by the investigator as possibly related to treatment. RO5068760 was absorbed with a tmax of 2 hours. Disposition appeared to be biphasic with a terminal elimination t1/2 of 5 to 9 hours. The variability was moderate to high, ranging from 38% to 62% for Cmax and 41% to 69% AUC. Within the dose range tested, pERK inhibition was relatively modest with a mean maximal pERK suppression of 55%.
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ISSN:0091-2700
1552-4604
1552-4604
DOI:10.1177/0091270010361254