Population pharmacokinetic analysis from phase I and phase II studies of the humanized monovalent antibody, onartuzumab (MetMAb), in patients with advanced solid tumors.
Onartuzumab is a unique, humanized, monovalent (one-armed) monoclonal antibody (mAb) against the MET receptor. The intravenous (IV) pharmacokinetics (PK) of onartuzumab were investigated in a phase I study and a phase II study in recurrent non-small cell lung cancer (NSCLC) patients. The potential for drug-drug interaction (DDI) was assessed during co-administration of IV onartuzumab with oral erlotinib, by measuring the PK of both drugs. The concentration-time profiles of onartuzumab were adequately described using a two-compartment model with linear clearance (CL) at doses between 4 and 30 mg/kg. The estimates for CL, central compartment volume (V1 ), and median terminal half-life were 0.439 L/day, 2.77 L, and 13.4 days, respectively. Statistically significant covariates included creatinine clearance (CrCL) on clearance, weight and gender on V1 , and weight on peripheral compartment volume (V2 ), but the clinical relevance of these covariates needs to be further evaluated. The current analysis did not indicate obvious DDI between onartuzumab and erlotinib. MET diagnostic status did not impact the exposure of either agent. Despite the slightly faster clearance compared with typical bivalent mAbs, the PK of onartuzumab support dosing regimens of 15 mg/kg every 3 weeks or doses equivalent to achieve the target minimum tumoristatic concentration in patients.
Genentech, Inc., South San Francisco, CA, USA.
Yan
Y
Xin
Denise
D
Jin
Stephen
S
Eppler
Lisa A
LA
Damico-Beyer
Amita
A
Joshi
John D
JD
Davis
Surinder
S
Kaur
Ihsan
I
Nijem
John
J
Bothos
Amy
A
Peterson
Premal
P
Patel
Shuang
S
Bai
D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C584058:onartuzumab
MET; erlotinib; monovalent antibody; onartuzumab; pharmacokinetics