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 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 t(max), of 2 hours. Disposition appeared to be biphasic with a terminal elimination t(1/2) of 5 to 9 hours. The variability was moderate to high, ranging from 38% to 62% for C(max) and 41% to 69% AUC. Within the dose range tested, pERK inhibition was relatively modest with a mean maximal pERK suppression of 55%.
Lee
Lucy
L
Clinical Pharmacology, Hoffman-La Roche, Inc, 340 Kingsland Street, Nutley, NJ 07110, USA. lucy.lee@roche.com
Niu
Huifeng
H
Goelzer
Petra
P
Rueger
Ruediger
R
Deutsch
Jonathan
J
Busse-Reid
Rachel
R
DeSchepper
Stefanie
S
Blotner
Steve
S
Barrett
Joanne
J
Weissgerber
Georges
G
Peck
Richard
R
D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D048289:Imidazolidines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity*; D007408:Intestinal Absorption; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D008954:Models, Biological; D010654:Phenylbutyrates / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity*; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D055815:Young Adult
C547875:2-(4-(4-(2,3-dihydroxy-propoxy)phenyl)-2,5-dioxo-imidazolidin-1-yl)-N-(2-fluoro-4-iodo-phenyl)-3-phenylbutyramide; D015415:Biomarkers; D048289:Imidazolidines; D010654:Phenylbutyrates; D047428:Protein Kinase Inhibitors; C016658:phorbolol myristate acetate; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D013755:Tetradecanoylphorbol Acetate