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Assessment of the Predictive Performance of a New Population Pharmacokinetic Model For Trastuzumab (Herceptin) and Simulation of Trastuzumab Steady-State Exposure During Long-Term Weekly Dosing.

Jian-Feng Lu and René Bruno

Pharmacometry Group, Clinical and Experimental Pharmacology Division, Genentech Inc. South San Francisco CA.

Purpose: To assess the predictive performance of a new population PK model for trastuzumab and to investigate inter-patient variability of trastuzumab exposure at steady-state (SS) after weekly dosing of Herceptin.

Methods: The PK of trastuzumab following long-term weekly dosing in HER2 overexpressing metastatic breast cancer patients has been reevaluated using the population approach (1). The terminal half-life was 28.5 days (95% CI, 25.5-32.8 days), longer than previous estimates (5.8 days). In addition inter-patient variability and covariate effects on trastuzumab PK parameters were estimated. The performance of the model in predicting trastuzumab exposure (trough levels) was evaluated in 416 patients who participated to trastuzumab single-agent and combination studies by using a simulation-based model checking. Several statistics of observed levels were compared to their distribution from 100 replicates of data sets simulated under the model. To assess the magnitude of inter-patient variability of SS trough levels, trough levels were simulated at SS for 1000 patients using the model (patients characteristics bootstrapped from the actual database of 416 patients). All the simulations were performed using the NONMEM program.

Results: The model adequately predicted 25th, 50th (median), 75th percentiles, mean and standard deviation of observed trough levels demonstrating the usefulness of the model in predicting trastuzumab exposure and its variability. The inter-patients variability (%CV) of SS troughs in 1000 simulated patients was 67.6%. The variability due to covariate effects (patient weight, number of metastatic sites, plasma level of extra-cellular domain of the HER2 receptor) was 28.7%. Expected trough concentrations exceeded 20 ng/mL (the efficacy threshold level) in most of the patients (92.5 %).

Conclusion: The new trastuzumab population PK model provides an operational tool to simulate trastuzumab exposure during Herceptin treatment of MBC patients, explore PK-clinical response relationships and simulate alternative dosing regimen (Q3W) for trastuzumab.

1 - Washington C.B., Lieberman G., Liu P., Fox J.A., Bruno R. A population pharmacokinetic model for trastuzumab following weekly dosing. Clin. Pharmacol. Ther., 71 (2), P12 (abstract MPI-30), 2002.