pharmacokinetics of herceptin

[Lani]

AS this is a question which comes up frequently I am posting the abstract of the definitive article published by Genentech as well as their references, eg original articles on giving it every three weeks vs every week

Note that the interpatient variability in half-life of Herceptin (how long it takes half of it to leave your body and not be available to do its job) is 43%! Also note that they looked at serum her2neu ECD levels of metastatic breast cancer patients on herceptin. In the complete article the words are long and technical, but hopefully you can get the gist of it from this and look up any of the reference articles that interest you.

Population pharmacokinetics of trastuzumab in patients With HER2+ metastatic breast cancer
Journal Cancer Chemotherapy and Pharmacology
Publisher Springer Berlin / Heidelberg
ISSN 0344-5704 (Print) 1432-0843 (Online)
Subject Medicine
Issue Volume 56, Number 4 / October, 2005
Category Original Article
DOI 10.1007/s00280-005-1026-z
Pages 361-369
Online Date Monday, May 02, 2005
Rene Bruno1, Carla B. Washington1, Jian-Feng Lu1 , Grazyna Lieberman2, Ludger Banken4 and Pamela Klein3

(1) Pharmacokinetic and Pharmacodynamic Sciences, MS 70 Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
(2) Departments of Biostatistics, Genentech Inc, South San Francisco, CA, USA
(3) Oncology Departments, Genentech Inc, South San Francisco, CA, USA
(4) Biostatistics Department, , Roche, Basel, Switzerland
Received: 26 October 2004 Accepted: 12 January 2005 Published online: 3 May 2005

Abstract Purpose: To characterize the population pharmacokinetics of trastuzumab in patients with metastatic breast cancer. Methods: A nonlinear mixed effect model was based on pharmacokinetic data from phase I, II, and III studies of 476 patients. The phase I study enrolled patients with advanced solid tumors. The phase II and III studies enrolled patients with HER2-positive metastatic breast cancer. Patients in the pivotal phase II and III studies were treated with a 4 mg/kg loading dose of trastuzumab followed by 2 mg/kg weekly for up to 840 days. The model adequately predicted observed trastuzumab concentrations. Model stability and performance were verified using bootstrap simulations. Percentiles, mean, and standard deviation of observed levels were compared with their distributions from 100 replicates of datasets simulated under the model. Results: A two-compartment linear pharmacokinetic model best described the data and accounted for the long-term accumulation observed following weekly administration of trastuzumab. Population estimates from the base model for clearance (CL) and volume of distribution of the central compartment (V1) of trastuzumab were 0.225 L/day, and 2.95 L, respectively. Estimated terminal halflife (t1/2) based on the population estimate was 28.5 days. Interpatient variabilities in clearance and volume were 43 and 29%, respectively. The number of metastatic sites, plasma level of extracellular domain of the HER2 receptor, and patient weight were significant baseline covariates for clearance, volume, or both (P<0.005). However, these covariate effects on trastuzumab exposure were modest and not clinically important in comparison with the large inter-patient variability of CL. Concomitant chemotherapy (anthracycline plus cyclophosphamide, or paclitaxel) did not appear to influence clearance. Conclusion: This population pharmacokinetic model can predict trastuzumab exposure in the long-term treatment of patients with metastatic breast cancer and provide comparison of alternative dosage regimens via simulation.
Keywords Pharmacokinetics - Trastuzumab - Metastatic breast cancer - HER2

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