Population pharmacokinetic analysis of panitumumab in patients with advanced solid tumors.
Panitumumab is a fully human monoclonal antibody targeted to the extracellular domain of human epidermal growth factor receptor (EGFR). A comprehensive population pharmacokinetic model of panitumumab was developed using nonlinear mixed-effects modeling of 1200 patients with advanced solid tumors in 14 clinical studies. The disposition of panitumumab was best described with a 2-compartment model with parallel linear and nonlinear (Michaelis-Menten) elimination pathways. For a typical male patient with colorectal cancer (80 kg, 60 years old), the estimates for the linear clearance (CL), the maximum nonlinear clearance (V(max)/K(m)), the central volume of distribution (V(1)), the peripheral volume of distribution (V(2)), and the Michaelis-Menten constant (K(m)) are 0.273 L/d, 28.4 L/d, 3.95 L, 2.59 L, and 0.426 mcg/mL, respectively. Baseline covariates such as body weight, cancer type, age, sex, and race were studied for their influence on panitumumab pharmacokinetics. Body weight was found to be the most influential covariate on panitumumab exposure, affecting CL, V(max), and V(1). The administration of concomitant chemotherapy (IFL, FOLFIRI, or paclitaxel/carboplatin) or intensity of baseline tumor EGFR expression did not alter the pharmacokinetics of panitumumab. The presence of antipanitumumab antibodies in patients (immunogenicity rate 3.4%) did not appear to affect panitumumab exposure substantially (AUC difference 8%). In support of a new drug application in Japan, the model was used to assess panitumumab pharmacokinetics in Japanese patients compared to other racial groups; there were no significant differences in model-predicted steady-state panitumumab AUC, C(max), or C(min) after accounting for the effect of body weight.
Ma
Peiming
P
Department of Pharmacokinetics and Drug Metabolism, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, USA. peimingm@amgen.com
Yang
Bing-Bing
BB
Wang
Yow-Ming
YM
Peterson
Mark
M
Narayanan
Adimoolam
A
Sutjandra
Liviawati
L
Rodriguez
Rachelle
R
Chow
Andrew
A
D000367:Age Factors; D000906:Antibodies / Q000032:analysis; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000276:immunology* / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics; D044466:Asian People; D001835:Body Weight; D002986:Clinical Trials as Topic; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism; D017711:Nonlinear Dynamics; D000077544:Panitumumab; D011159:Population Surveillance; D012737:Sex Factors; D044465:White People
D000906:Antibodies; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000077544:Panitumumab; C512478:EGFR protein, human; D066246:ErbB Receptors