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

doi:10.3390/pharmaceutics14071317

Pharmaceutics (Jun 2022)

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

DOI: https://doi.org/10.3390/pharmaceutics14071317
Journal volume & issue: Vol. 14, no. 7
p. 1317

Abstract

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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.

Published in Pharmaceutics

ISSN: 1999-4923 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine: Pharmacy and materia medica
Website: http://www.mdpi.com/journal/pharmaceutics/

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