Population Pharmacokinetics of Palbociclib and Its Correlation with Clinical Efficacy and Safety in Patients with Advanced Breast Cancer
Perrine Courlet,
Evelina Cardoso,
Carole Bandiera,
Athina Stravodimou,
Jean-Philippe Zurcher,
Haithem Chtioui,
Isabella Locatelli,
Laurent Arthur Decosterd,
Léa Darnaud,
Benoit Blanchet,
Jérôme Alexandre,
Anna Dorothea Wagner,
Khalil Zaman,
Marie Paule Schneider,
Monia Guidi,
Chantal Csajka
Affiliations
Perrine Courlet
Centre for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
Evelina Cardoso
School of Pharmaceutical Sciences, University of Geneva, 1206 Geneva, Switzerland
Carole Bandiera
School of Pharmaceutical Sciences, University of Geneva, 1206 Geneva, Switzerland
Athina Stravodimou
Breast Center, Department of Oncology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
Jean-Philippe Zurcher
Breast Center, Department of Oncology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
Haithem Chtioui
Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
Isabella Locatelli
Center for Primary Care and Public Health (Unisanté), University of Lausanne, 1011 Lausanne, Switzerland
Laurent Arthur Decosterd
Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
Léa Darnaud
Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, AP-HP, CARPEM, AP-HP, CARPEM, 75014 Paris, France
Benoit Blanchet
Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, AP-HP, CARPEM, AP-HP, CARPEM, 75014 Paris, France
Jérôme Alexandre
Department of Medical Oncology, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France
Anna Dorothea Wagner
Breast Center, Department of Oncology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
Khalil Zaman
Breast Center, Department of Oncology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
Marie Paule Schneider
School of Pharmaceutical Sciences, University of Geneva, 1206 Geneva, Switzerland
Monia Guidi
Centre for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
Chantal Csajka
Centre for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
Neutropenia is the most frequent dose-limiting toxicity reported in patients with metastatic breast cancer receiving palbociclib. The objective of this study was to investigate the pharmacokinetic–pharmacodynamic (PK/PD) relationships for toxicity (i.e., absolute neutrophil count, ANC) and efficacy (i.e., progression-free survival, PFS). A semi-mechanistic PK/PD model was used to predict neutrophils’ time course using a population approach (NONMEM). Influence of demographic and clinical characteristics was evaluated. Cox proportional hazards models were developed to evaluate the influence of palbociclib PK on PFS. A two-compartment model with first-order absorption and a lag time adequately described the 255 palbociclib concentrations provided by 44 patients. The effect of the co-administration of proton-pump inhibitors in fasting conditions increased palbociclib clearance by 56%. None of the tested covariates affected the PD parameters. Model-based simulations confirmed the concentration-dependent and non-cumulative properties of palbociclib-induced neutropenia, reversible after treatment withdrawal. The ANC nadir occurred approximately at day 24 of each cycle. Cox analyses revealed a trend for better PFS with increasing palbociclib exposure in older patients. By characterizing palbociclib-induced neutropenia, this model offers support to clinicians to rationally optimize treatment management through patient-individualized strategies.
