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- Title
Population Pharmacokinetics of Palbociclib and Its Correlation with Clinical Efficacy and Safety in Patients with Advanced Breast Cancer.
- Authors
Courlet, Perrine; Cardoso, Evelina; Bandiera, Carole; Stravodimou, Athina; Zurcher, Jean-Philippe; Chtioui, Haithem; Locatelli, Isabella; Decosterd, Laurent Arthur; Darnaud, Léa; Blanchet, Benoit; Alexandre, Jérôme; Wagner, Anna Dorothea; Zaman, Khalil; Schneider, Marie Paule; Guidi, Monia; Csajka, Chantal
- Abstract
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.
- Subjects
CANCER patients; METASTATIC breast cancer; PATIENT safety; PROPORTIONAL hazards models; TERMINATION of treatment; FASTING; CD4 lymphocyte count
- Publication
Pharmaceutics, 2022, Vol 14, Issue 7, pN.PAG
- ISSN
1999-4923
- Publication type
Article
- DOI
10.3390/pharmaceutics14071317