Pharmacokinetic/Pharmacodynamic Model of Neutropenia in Real-Life Palbociclib-Treated Patients

Palbociclib is an oral CDK4/6 inhibitor 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 palbociclib-treated patients. A population pharmacokinetic (popPK) model was first constructed to describe palbociclib pharmacokinetic (PK). Individual PK parameters obtained were then used in the pharmacokinetic/pharmacodynamic (PK/PD) model to depict the relation between palbociclib concentrations and absolute neutrophil counts (ANC). The models were built with a population of 143 patients. 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 CI/F of 57.09 L (32.8% of inter individuality variability (IIV)). The apparent volume of distribution (1580 L) and the lag-time (T-lag: 0.658 h) were fixed to values from the literature. An increase in creatinine clearance and a decrease in alkaline phosphatase led to an increase in palbociclib CI/F. To describe ANC kinetics during treatment, Friberg's PK/PD model, with linear drug effect, was used. Parameters estimated were Base (2.92 G/L; 29.6% IIV), Slope (0.0011 L/mu g; 28.8% IIV), Mean Transit Time (MTT; 5.29 days; 17.9% IIV) and gamma (0.102). The only significant covariate was age on the initial ANC (Base), with lower ANC in younger patients. PK/PD model-based simulations show that the higher the estimated C-ressSS (trough concentration at steady state), the higher the risk of developing neutropenia. In order to present a risk lower than 20% to developing a grade 4 neutropenia, the patient should show an estimated C-ressSS lower than 100 mu g/L.

Automated summary

A study investigated the kinetics of circulating neutrophils in patients treated with palbociclib. A popPK model and a PK/PD model were constructed, showing a correlation between higher estimated C-ressSS and increased risk of developing neutropenia.