The safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of CH4987655 in healthy volunteers: target suppression using a biomarker

CH4987655 (RO4987655) is an orally active and highly selective small-molecule MEK inhibitor. It potently inhibits mitogen-activated protein kinase signaling pathway activation and tumor cell growth, with an in vitro IC(50) of 5.2 nmol/L for inhibition of MEK1/2. Single-agent oral administration of C...

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Podrobná bibliografia
Vydané v:	Clinical cancer research Ročník 15; číslo 23; s. 7368
Hlavní autori:	Lee, Lucy, Niu, Huifeng, Rueger, Ruediger, Igawa, Yuriko, Deutsch, Jonathan, Ishii, Nobuya, Mu, Song, Sakamoto, Yuuichiro, Busse-Reid, Rachel, Gimmi, Claude, Goelzer, Petra, De Schepper, Stefanie, Yoshimura, Yashushi, Barrett, Joanne, Ishikawa, Yuji, Weissgerber, Georges, Peck, Richard
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 01.12.2009
Predmet:	Administration, Oral Adolescent Adult Antineoplastic Agents Area Under Curve Biomarkers - metabolism Biomarkers, Tumor - metabolism Dose-Response Relationship, Drug Double-Blind Method Enzyme Inhibitors - administration & dosage Enzyme Inhibitors - pharmacokinetics Female Humans Inhibitory Concentration 50 Male MAP Kinase Signaling System Middle Aged Neoplasm Transplantation Placebos
ISSN:	1078-0432, 1557-3265, 1557-3265
On-line prístup:	Zistit podrobnosti o prístupe
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Popis
Shrnutí:	CH4987655 (RO4987655) is an orally active and highly selective small-molecule MEK inhibitor. It potently inhibits mitogen-activated protein kinase signaling pathway activation and tumor cell growth, with an in vitro IC(50) of 5.2 nmol/L for inhibition of MEK1/2. Single-agent oral administration of CH4987655 resulted in complete tumor regressions in xenograft models. All 40 subjects received a single oral dose followed by 72 hrs of pharmacokinetic, pharmacodynamic, and safety/tolerability assessments. The pharmacodynamics were measured by changes in phosphorylated extracellular signal-regulated kinase (pERK) levels in a surrogate tissue peripheral blood mononuclear cells ex vivo stimulated by PMA. Doses of 0.5, 1, 2, 3, and 4 mg were safe and well tolerated. No clinically significant safety event was observed. A total of 26 adverse events (n = 15) were reported: 21 mild, 5 moderate, and none severe. Moderate adverse events were experienced by one subject at 1 mg (autonomic nervous system imbalance) and three subjects at 4 mg (diarrhea, abdominal pain, autonomic nervous system and acne). CH4987655 was rapidly absorbed with a t(max) of approximately 1 h. Exposures were dose proportional from 0.5 to 4 mg. The disposition was biphasic with a terminal t(1/2) of approximately 25 hr. Intersubject variability was low, 9% to 23% for C(max) and 14% to 25% for area-under-the-curve (AUC). pERK inhibition was exposure dependent and was greater than 80% inhibition at higher doses. The pharmacokinetic-pharmacodynamic relationship was characterized by an inhibitory E(max) model (E(max) approximately 100%; IC(50) 40.6 ng/mL) using nonlinear mixed-effect modeling. A significant extent of pERK inhibition was achieved for a single dose that was considered to be safe and well tolerated in healthy volunteers.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3
ISSN:	1078-0432 1557-3265 1557-3265
DOI:	10.1158/1078-0432.CCR-09-1696