Population pharmacokinetics of PF-05280014 (a trastuzumab biosimilar) and reference trastuzumab (Herceptin®) in patients with HER2-positive metastatic breast cancer

Abstract

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.

Keywords: Biosimilar; Human epidermal growth factor receptor-2-positive metastatic breast cancer; NONMEM; Pharmacokinetics; Population pharmacokinetics; Trastuzumab.

Fig. 1

Diagnostic plots for final models of a PF-05280014 and b trastuzumab-EU groups. CWRES conditional weighted residuals, LOWESS locally weighted scatterplot smoothing trend line, trastuzumab-EU trastuzumab sourced from the European Union. In the scatter plots of observations versus predictions, the solid line and dashed line show the reference line (diagonal line) and linear regression line based on the individual data points, respectively. In the scatter plots of residuals, the solid line and dashed line show reference line (y = 0) and LOWESS, respectively. Observed concentrations and individual predictions were log-transformed

Fig. 2

Visual predictive check for the final a PF-05280014 and b trastuzumab-EU models. Trastuzumab-EU trastuzumab sourced from the European Union. Blue circles represent the observed data and the red lines represent the median (solid line), 2.5th percentile (dashed line), and 97.5th percentile (dashed line) of the observed data. For 1000 simulated trials, the median, 2.5th percentile and 97.5th percentile of simulated concentrations were calculated for each time bin and are presented by black lines. The 95% confidence intervals for the simulated median and each percentile are shown by light pink and light blue shaded areas

Fig. 3

Simulated concentrations for PF-05280014 and trastuzumab-EU using the final models. Trastuzumab-EU trastuzumab sourced from the European Union. The nominal time points for simulation were plotted on the x-axis. The notation “CxDyT” stands for “Cycle x Day y Trough” and “CxDyP” stands for “Cycle x Day y Peak”. The trough concentration is the simulated pre-dose concentration; the peak concentration is the simulated concentration at 1 h after the end of infusion

Fig. 4

Observed concentrations in Japanese patients vs. visual predictive check in all patients, stratified by a PF-05280014 and b trastuzumab-EU treatment groups. Trastuzumab-EU trastuzumab sourced from the European Union. The black dots represent the observed concentration in Japanese patients. The black lines represent the median (solid line), 2.5th percentile (dashed line) and 97.5th percentile (dashed line) of the simulated concentrations from 1000 simulated trials