Alexandre Le Marouille1, Emma Petit1, Courèche Kaderbhaï2, Isabelle Desmoulins22, Audrey Hennequin2, Didier Mayeur2, Jean-David Fumet2, Sylvain Ladoire2, Zoé Tharin2, Siavoshe Ayati2, Silvia Ilie2, Bernard Royer3, Antonin Schmitt1
1. INSERM U1231, Dijon, France
2. Oncology Department, Centre Georges-François Leclerc, Dijon, France 3. UMR 1098 INSERM/UFC/EFS, Besançon,France
Palbociclib is an oral anti-CDK4/6 indicated in HR+/HER2- advanced or metastatic breast cancer in combination with hormonotherapy. Its main toxicity is neutropenia. The aim of our study was to describe the kinetics of circulating neutrophils from real-life palbo-ciclib-treated patient.
A population pharmacokinetic (popPK) model was first constructed to describe palbociclib phar- macokinetic (PK). Individual PK parameters obtained were then used in the pharmacokinetic/ pharmacodynamic (PK/PD) model to depict the relation between palbociclib con-centrations and absolute neutrophil counts (ANC). Palbociclib samples were routinely collected during therapeutic drug monitoring, whereas ANC were retrospectively retrieved from the patient files.
The optimal popPK model was a mono-compartmental model with a first-order absorption constant of 0.187 h-1 and an apparent clearance Cl/F of 57.09L (32.8% of inter individuality variability (IIV)). The apparent volume of distribution (1580 L) and the lag-time (Tlag: 0.658 h) were fixed to values from literature. A increase in creatinine clearance and an decrease in alkaline phosphatase led to an increase in palbociclib Cl/F. To describe ANC kinetics during treatment, Friberg’s model with linear drug effect was used. Parameters estimated were Base (2.92 G/L; 29.6% IIV), Slope (0.0011 L/μg; 28.8% IIV), Mean Transit Time (MTT; 5.29 days; 17.9% IIV) and (0.102).
This study shows that the higher the estimated CressSS (trough concentration at steady state), the higher the risk of developing neutropenia. In order to have a risk lower than 20% to develop a grade 4 neutropenia, patient should have an estimated CressSS lower than 100 μg/L.
Keywords: palbociclib, neutropenia, pharmacokinetic/pharmacodynamic.