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Population Pharmacokinetic Analysis of Panitumumab in Patients With Advanced Solid Tumors
Author(s) -
Ma Peiming,
Yang BingBing,
Wang YowMing,
Peterson Mark,
Narayanan Adimoolam,
Sutjandra Liviawati,
Rodriguez Rachelle,
Chow Andrew
Publication year - 2009
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270009344989
Subject(s) - panitumumab , pharmacokinetics , medicine , volume of distribution , concomitant , population , oncology , nonmem , pharmacology , cetuximab , colorectal cancer , cancer , environmental health
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 constantt (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.