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


METHODS
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.


RESULTS
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.


CONCLUSIONS
A significant extent of pERK inhibition was achieved for a single dose that was considered to be safe and well tolerated in healthy volunteers.
Lee
Lucy
L
Clinical Pharmacology, Hoffman-La Roche, Nutley, New Jersey 07110, USA. lucy.lee@roche.com
Niu
Huifeng
H
Rueger
Ruediger
R
Igawa
Yuriko
Y
Deutsch
Jonathan
J
Ishii
Nobuya
N
Mu
Song
S
Sakamoto
Yuuichiro
Y
Busse-Reid
Rachel
R
Gimmi
Claude
C
Goelzer
Petra
P
De Schepper
Stefanie
S
Yoshimura
Yashushi
Y
Barrett
Joanne
J
Ishikawa
Yuji
Y
Weissgerber
Georges
G
Peck
Richard
R
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents; D019540:Area Under Curve; D015415:Biomarkers / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D009368:Neoplasm Transplantation; D010919:Placebos
D000970:Antineoplastic Agents; D015415:Biomarkers; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D010919:Placebos