Differential Pharmacokinetics of Ganitumab in Patients With Metastatic Pancreatic Cancer Versus Other Advanced Solid Cancers.
Ganitumab is an investigational, fully human monoclonal antibody antagonist of the insulin-like growth factor-1 receptor (IGF1R) that has shown trends towards improved progression-free survival and overall survival in a phase 2 pancreatic cancer clinical trial. To characterize ganitumab pharmacokinetics (PK) and identify factors affecting PK, ganitumab serum concentration data from three clinical trials were analyzed. The PK of ganitumab as monotherapy and in combination with gemcitabine in patients with pancreatic or non-pancreatic cancer were assessed with a non-linear mixed-effect model. We found that ganitumab exhibited linear and time-invariant kinetics. A two-compartment model adequately described data over a dose range of 1-20 mg/kg with good predictive capability. Typical clearance and central volume of distribution values were 1.7- and 1.3-fold higher, respectively, in patients with pancreatic cancer than in patients with other advanced solid cancers, resulting in lower ganitumab exposure. Covariate analysis was used to evaluate effects of cancer type, gemcitabine coadministration, clinical study, demographics, and laboratory values on ganitumab PK. Pancreatic cancer type was the most significant covariate on clearance along with weight, albumin, and serum creatinine. Gemcitabine coadministration did not affect ganitumab clearance. Thus, disease state can significantly affect PK and should be considered when selecting the clinically effective dose.
Amgen Inc., Thousand Oaks, CA, USA.
Min
M
Zhu
Pharsight-A Certara Company, Montreal, QC, Canada.
Nathalie H
NH
Gosselin
Amgen Inc., Thousand Oaks, CA, USA.
Mita
M
Kuchimanchi
Amgen Inc., Thousand Oaks, CA, USA.
Jessica
J
Johnson
Amgen Inc., Thousand Oaks, CA, USA.
Ian
I
McCaffery
Pharsight-A Certara Company, Montreal, QC, Canada.
Mohamad-Samer
MS
Mouksassi
Amgen Inc., Thousand Oaks, CA, USA.
Elwyn
E
Loh
Amgen Inc., Thousand Oaks, CA, USA.
Jian-Feng
JF
Lu
IGF1R; ganitumab (AMG 479); monoclonal antibody; pancreatic cancer; pharmacokinetics