Population Pharmacokinetic Analysis of Trastuzumab (Herceptin®) based on Data from Three Different Dosing Regimens.
Yumi Fukushima (1), Jean-Eric Charoin (1), Michael Brewster (2), E. Niclas Jonsson (1)
(1) Clinical Pharmacology, F. Hoffmann-La Roche, Basel, Switzerland; (2) Clinical Pharmacology, Roche Products Ltd., Welwyn, UK
Objectives: Herceptin® (trastuzumab) is currently indicated for the treatment of HER2 overexpressed metastatic breast cancer (MBC) and HER2 positive early breast cancer (EBC) patients. The registered dosing regimens are i) a weekly dosing regimen; starting with a 4 mg/kg loading dose followed by 2 mg/kg maintenance for MBC and EBC, and ii) 3 weekly dosing regimen starting with a 8 mg/kg loading dose followed by 6 mg/kg as maintenance for EBC. Recently a more aggressive loading regimen, 6 mg/kg weekly for the first 3 weeks followed by 6mg/kg every 3 weeks as maintenance, was investigated in MBC patients. The aim of this analysis is to establish a comprehensive population pharmacokinetic (PK) model for Herceptin, taking data from the three dosing regimens into account, which can be used as a reference for future PK analyses in other cancer populations.
Methods: There were approximately 4000 PK observations from 265 patients from 5 studies. Integrated data from one Phase I, two Phase I/II and two Phase II studies were available for the population PK analysis. In a previous population PK analysis the best structural PK model was a two compartment model parameterized in terms of CL, k12, k21 and Vc. In this current analysis, the previous model was refined using NONMEM VI, the first-order conditional estimation method with interaction (FOCEI) instead of the first-order approximation (FO) and a parameterization that focused on the primary PK parameters, e.g. CL, Vc, Vz and Q. Automated stepwise covariate model building and case deletion diagnostics were conducted using PsN (ver. 2.2.2).
Results: The best structural population PK model in the current analysis was a two compartment model. The estimated parameter values were: CL 0.254 L/day, Vc 3.02 L, Vz 3.10 L and Q 0.452 L/day. Residual variability was 20.9 %. Based on the objective function value and precision of estimates, inter-individual variability was estimated on CL, Vc and Vz (%CVs: 42.8, 24.0 and 79.4, respectively). Goodness of fit plots indicated a good fit to the data. The long terminal half-life was estimated as approximately 3 weeks and is in line with endogenous IgG1 immunogloblin elimination (t1/2: 23 days).
Conclusions: The currently refined structural population PK model provides a solid basis for covariate analysis leading to a model which can be used as a reference for future PK analyses in other cancer populations.
References:
[1]. Charoin JE. et al. Population pharmacokinetic analysis of trastuzumab (Herceptin®) following long-term administration using different regimens. PAGE 2004.
[2]. Bruno R. et al. Population pharmacokinetics of trastuzumab in patients with HER2+ metastatic breast cancer. Cancer Chemother Pharmacol (2005) 56: 361-369.
