Pharmacokinetic determinants of palbociclib hematological toxicity

Abstract Introduction CDK4/6 inhibitors, such as palbociclib, are prescribed in association with hormonal therapy in metastatic breast cancer patients. In Phase II/III studies, high neutropenia occurred in more than one in two patients leading to significant dose reductions, palbociclib interruptions and additional hematological samplings. Like most oral targeted drug, therapeutic drug monitoring (TDM) may be of interest for monitoring plasma exposition and optimize their dosage. We evaluated the correlation of this toxicity with palbociclib pharmacokinetics (PK), and classical sources of PK variabilities. Materials and method This is an open-label biomarker study conducted in subjects with first-line ER+/HER2- metastatic breast cancer treated with a palbociclib-aromatase inhibitor association (NCT04025541). Primary endpoint was the correlation between palbociclib trough concentration (Ctrough) at day 15 of first cycle of treatment (D15C1) and incidence of grade 3/4 neutropenia, within the first two months of treatment. Secondary endpoints included the analysis of variables associated with grade 3/4 neutropenia, with D15C1 palbociclib Ctrough values, and correlations with genetic polymorphisms in selected genes involved in palbociclib PK. Co-medications were collected to assess drug-drug interactions (DDI) risk and the potential impact on palbociclib PK. Results 58 patients, with mean age of 62.9 years, were included and followed up for 1 year. Clinicopathological variables were classical for the setting. One third of the population was taking concurrently a CYP3A4 and/or Pgp inhibitor, and one fourth an anti-acid medication, drugs that may interact with palbociclib. High-grade neutropenia occurred in 67.2% of patients (70.7% all grade neutropenia). One third of patients required a dose reduction, mainly for hematological toxicity. The geometric median of palbociclib plasma Ctrough was 74.1 ng/ml (interquartile range 61.3 - 101.5). Other covariates influencing the PK of palbociclib were significant in the univariate analysis. Indeed, while age > 65.5 years old (median) and reduced renal function (< 88.5 ml/min, median) were correlated with increased palbociclib concentration (p=0.003 and p=0.017, respectively) in univariate analysis. In multivariate analysis, higher neutrophil counts at inclusion (HR=0.54 for each 109/L increase in neutrophils count, range 0.33 - 0.87, p=0.002) while higher (>74.1 ng/mL, HR 5.51, range 1.10 - 27.6, p=0.024) plasma concentration of palbociclib were the only 2 variables correlated with the incidence of neutropenia. PK of palbociclib is closely related to co-medications, with majored exposition in CYP3A4 inhibitor cohort (106 vs 71.3 ng/ml, p=0.031, HR 0.22) or reduced exposition in anti-acid cohort (72.2 vs 80 ng/ml, p= 0.016, HR -0.27). Lastly, the homozygote G/G allele of the NRI2 (PXR) variant (Rs10934498) was associated with reduced palbociclib concentration (p=0.031) in univariate analysis. Conclusion We have characterized PK/toxicity correlation of palbociclib, regarding high-grade neutropenia. D15C1 higher palbociclib Ctrough is associated with the occurrence of high-grade neutropenia. As drug-drug interaction appears to be the most relevant source of palbociclib Ctrough variability in our cohort, a special attention must be paid to comedications in this population of patients. This is the first prospective study which characterizes biomarkers of toxicity associated with palbociclib treatment. Therapeutic drug monitoring can be a tool to limit high grade toxicities under palbociclib. Citation Format: Fanny Leenhardt, Frédéric Fiteni, Ludovic Gauthier, Marie Alexandre, Séverine Guiu, Nelly Firmin, Stéphane Pouderoux, Chloé Gautier, Gerald Lossaint, Alexandre Payen, Celine Gongora, Litaty Mbatchi, Alexandre Evrard, William Jacot. Pharmacokinetic determinants of palbociclib hematological toxicity [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-23.