Population pharmacokinetics of PF-05280014 (a trastuzumab biosimilar) and reference trastuzumab (Herceptin®) in patients with HER2-positive metastatic breast cancer.
PURPOSE
PF-05280014 is a biosimilar to trastuzumab (Herceptin®). Following demonstration of pharmacokinetic (PK) similarity in healthy volunteers, a comparative clinical study in patients with HER2-positive metastatic breast cancer (mBC) compared the efficacy, safety and immunogenicity of PF-05280014 and trastuzumab sourced from the EU (trastuzumab-EU), both with paclitaxel.


METHODS
Population PK of PF-05280014 and trastuzumab-EU was evaluated.


RESULTS
Overall, 702 patients were treated: PF-05280014 (n = 349) and trastuzumab-EU (n = 353). Peak-and-trough serum drug concentration samples were collected (selected doses) following repeated intravenous administration of PF-05280014 or trastuzumab-EU. Population PK analysis was performed with drug concentration-time data to cycle 17 for each compound, using nonlinear mixed effect modeling. Potential baseline covariates (circulating HER2 concentrations, body weight, Japanese race, Eastern Cooperative Oncology Group status, number of metastatic sites and antidrug antibody status) were evaluated. Concentration-time data of PF-05280014 and trastuzumab-EU were adequately described by a two-compartment model with first-order elimination, with inter-individual variability (IIV) on clearance (CL), volumes of distribution in central compartment (V1) and peripheral compartments, and intercompartment clearance. Similar estimated PK parameters and IIV were obtained for both treatments. For PF-05280014 and trastuzumab-EU, baseline body weight was an influential covariate on CL and V1; the magnitude was comparable between treatments. PK was consistent between the limited number of Japanese and non-Japanese patients for both compounds.


CONCLUSIONS
PF-05280014 and trastuzumab-EU had similar PK parameters and influential PK covariates in patients with HER2-positive mBC. These results provided further evidence in patients for PK similarity between PF-05280014 and trastuzumab-EU.


CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, NCT01989676.
['Chen|Xiaoying|X|', 'Li|Cheryl|C|', 'Ewesuedo|Reginald|R|', 'Yin|Donghua|D|']
D061605:Administration, Intravenous D061067:Antibodies, Monoclonal, Humanized D000074322:Antineoplastic Agents, Immunological D059451:Biosimilar Pharmaceuticals D001943:Breast Neoplasms D004311:Double-Blind Method D005260:Female D006801:Humans D008954:Models, Biological D017711:Nonlinear Dynamics D017239:Paclitaxel D018719:Receptor, ErbB-2 D000068878:Trastuzumab
Population pharmacokinetics Pharmacokinetics Trastuzumab Biosimilar Human epidermal growth factor receptor-2-positive metastatic breast cancer NONMEM