title: Population pharmacokinetic-pharmacodynamic analysis of trastuzumab-associated cardiotoxicity.
abstract: Trastuzumab treatment is associated with cardiac dysfunction. The aim of this study was to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model for the relationship between left ventricular ejection fraction (LVEF) and trastuzumab exposure and to identify associated clinically relevant covariates. Data from an unselected cohort of patients with early and advanced HER2-positive breast cancer receiving treatment with trastuzumab were analyzed using a nonlinear mixed-effects modeling approach. LVEF values from 240 patients were available. The data were best described by an effect-compartment model. The population LVEF recovery half-life after trastuzumab treatment (T(½rec)) was estimated at 49.7 days. The cumulative anthracycline dose was a significant determinant of the half maximal effect concentration (EC₅₀), causing a 45.9% increase in sensitivity (decrease in EC₅₀) at the maximum cumulative anthracycline dose. The developed population PK-PD model may be used to establish optimal treatment and cardiac monitoring strategies for trastuzumab.
authors.affiliation: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. coenvanhasselt@gmail.com
authors.forename: J G C
authors.initials: JG
authors.lastname: van Hasselt
authors.forename: A H
authors.initials: AH
authors.lastname: Boekhout
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: J H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: A D R
authors.initials: AD
authors.lastname: Huitema
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D018943:Anthracyclines / Q000009:adverse effects; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D003627:Data Interpretation, Statistical; D004347:Drug Interactions; D005260:Female; D018734:Genes, erbB-2 / Q000235:genetics; D017408:Guidelines as Topic; D006207:Half-Life; D006331:Heart Diseases / Q000139:chemically induced* / Q000453:epidemiology*; D006801:Humans; D008875:Middle Aged; D015233:Models, Statistical; D011153:Population; D011446:Prospective Studies; D015203:Reproducibility of Results; D013318:Stroke Volume / Q000187:drug effects; D043823:Taxoids / Q000009:adverse effects; D000068878:Trastuzumab; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D018943:Anthracyclines; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D043823:Taxoids; D000068878:Trastuzumab