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

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.

Adherence to the CDK 4/6 Inhibitor Palbociclib and Omission of Dose Management Supported by Pharmacometric Modelling as Part of the OpTAT Study

“…In scenario A, the concentrations are lower than the median observed in the simulated patients. This observation is consistent over this patient's cycles and could be attributed to several extrinsic factors potentially increasing palbociclib elimination for this patient (e.g., co-administration of proton-pump inhibitors in fasting conditions [35], increase in creatinine clearance or decrease in alkaline phosphatase [36]). (a,c)-and absolute neutrophil count-solid lines in (b,d)-and their 95% prediction intervals-dotted lines.…”

“…NB: the dots in (a) represent the observed plasma palbociclib concentrations in a real patient included in the OpTAT study in both A and B1 scenarios.In scenario A, the concentrations are lower than the median observed in the simulated patients. This observation is consistent over this patient's cycles and could be attributed to several extrinsic factors potentially increasing palbociclib elimination for this patient (e.g., co-administration of proton-pump inhibitors in fasting conditions[35], increase in creatinine clearance or decrease in alkaline phosphatase[36]).…”

“…The population PK-PD model previously developed with data from the OpTAT study [35] was used to evaluate the influence of medication implementation on palbociclib PK and neutropenia. We used different medication implementation scenarios based on real-life patients' implementation schemes retrieved from our database: (A) optimal implementation (i.e., one dose taken during 21 days followed by 7 days of treatment break); (B1) during the 21 days in phase ON, one dose is omitted at day 18, and is not caught up at cycle end (i.e., the OFF phase is initiated for 7 days from day 22); (B2) during the 21 days in phase ON, one dose is omitted at day 18, which is caught up at cycle end at day 22 (i.e., the OFF phase is initiated from day 23 for 6 days, leading to a shorter OFF period before the next cycle start); (C) during the 21 days in phase ON, the 2 first doses are omitted at day 1 and 2, which are caught up at cycle end at day 22 and 23 (i.e., the OFF phase is initiated from day 24 for 5 days, leading to a shorter OFF period before the next cycle start).…”

Abemaciclib pharmacology and interactions in the treatment of HR+/HER2− breast cancer: a critical review

“… 35 This interaction was supposed to determine decreased PAL efficacy and increased toxicity. 35 – 37 Due to these observations, PAL capsule have been recently reformulated into tablets, whose absorption is not affected by gastric pH or PPI use. The existence of interference between PPI and RIB remains controversial, whereas it has not been reported for ABE.…”