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

Abstract

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 Cl/F of 57.09 L (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 the literature. An increase in creatinine clearance and a decrease in alkaline phosphatase led to an increase in palbociclib Cl/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/µg; 28.8% IIV), Mean Transit Time (MTT; 5.29 days; 17.9% IIV) and γ (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 CressSS (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 CressSS lower than 100 µg/L.

Population Pharmacokinetics of Palbociclib and Its Correlation with Clinical Efficacy and Safety in Patients with Advanced Breast Cancer

“…Data from the manufacturer suggest a more severe neutropenia with increasing palbociclib exposure [4]. These results have been recently confirmed in a recent real-world data analysis [13]. However, to our knowledge, no real-world study reported on both PK-toxicity and PK-efficacy results in the same population.…”

“…Regarding our exposure-toxicity model, the estimated PD parameters are aligned with the literature values [13,19]. Due to data sparseness, EC 50 was fixed to the value estimated in a previously published model, in which palbociclib doses from 25 to 225 mg allowed a reliable estimate of the drug effect parameters [19].…”

“…Based on previously published models [ 13 , 19 ], palbociclib’s effect was implemented on the proliferation compartment. A linear (Equation (1)) and an E max (Equation (2)) functions were tested and compared to describe the palbociclib-induced neutropenic effect: with C palbo being the model-predicted palbociclib concentration in the central compartment, Slope being the sensitivity to drug myelotoxicity, E max being the maximum effect of palbociclib on k prol , and EC 50 being the palbociclib concentration that produced a 50% effect.…”

“…The covariates investigated for their impact on palbociclib PK were as follows: age, body weight, body mass index, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (BILT), albumin, alkaline phosphatase (ALK), administration under fasting conditions, co-administration of CYP3A4 inhibitors or inducers, co-administration of proton-pump inhibitor (PPI), and cycle number on apparent clearance (CL/F); fasting conditions and PPI co-administration on absorption rate constant (k a ); fasting conditions on lag time (ALAG); and body weight on apparent central volume of distribution (V c /F). Although renal elimination is not the major route of palbociclib elimination, creatinine (CRT) and estimated glomerular filtration rate (eGFR, estimated with the Cockroft and Gault formula) were tested on palbociclib CL/F since a recent study reported an association with palbociclib exposure [ 13 ]. The characteristics available for testing their effect on PD parameters were as follows: age, body weight, ALK, BILT, gamma-glutamyltransferase (GGT), albumin, AST, ALT, eGFR, association with fulvestrant, chemotherapy in the previous treatment line, and POCT measurement.…”

“…Based on previously published models [13,19], palbociclib's effect was implemented on the proliferation compartment. A linear (Equation (1)) and an E max (Equation ( 2)) functions were tested and compared to describe the palbociclib-induced neutropenic effect:…”