A kinetic-pharmacodynamic model of palbociclib reveals an influence of body weight on neutropenia onset.
Christophe Passot (1), David Ternant (2), Pauline Du Rusquec (1), Paule Augereau (1), Mario Campone (1), Anne Patsouris (1), Jean-Sébastien Frenel (1)
(1) Integrative Center for Oncology, Nantes/Angers, France ; (2) University of Tours, EA 7501 Innovation and Cell Targeting Group, CHRU de Tours, Laboratory of Pharmacology-Toxicology, Tours, France.
Objectives: Palbociclib is a cyclin-dependent kinase 4/6 inhibitor labeled for the treatment of estrogenreceptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer (mBC), in combination with endocrine therapy. The starting posology is 125 mg once daily for 21 days followed by 7 days off treatment, without adaptation according to patient’s weight. The onset of neutropenia during the three first cycles may lead to dose reduction or treatment discontinuation for more than 7 days. Identification of covariates influencing dose-limiting neutropenia may lead to dose individualization at treatment initiation. In this study using real-world data, we aimed at describing the relationship between palbociclib dosage and absolute neutrophil count (ANC) and at assessing the interindividual variability.
Methods: Data from patients treated with palbociclib during the year 2017 in the Integrative Center for Oncology in Nantes-Angers (France) were collected retrospectively in medical records. Palbociclib dose and administration days as well as ANC were collected throughout the three first treatment cycles. Demographic (age, body weight) and biologic (creatinine, urea, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase and total bilirubin) data were collected at baseline. The relationship between palbociclib treatment and ANC was described with a population kinetic-pharmacodynamic (K-PD) [1] model using Monolix 2018R2 software (Lixoft, Orsay, France). Demographic and biologic data mentioned above were tested as covariates on K-PD parameters.
Results: Data were collected for 56 mBCpatients. The median age was 63 y.o. (range 29-88) and the medium body weight was 62 kg (range 35-103). Three cycles of palbociclib were administered in 43 patients, 2 cycles in 8 patients and 1 cycle in 5 patients. A total of 540 ANC were available with a median of 8 ANC for each patient. Absolute neutrophil counts were described using a semi-mechanistic Friberg model [2]. Briefly, the model consists of a proliferating progenitors compartment, three transit compartments where neutrophils mature and a compartment of circulating neutrophils. The effect of palbociclib on progenitors proliferation rate was described with an inhibitory Emax model. The values (interindividual variability) of estimated population parameters were: the elimination rate constant from the virtual compartment KDE=0.11 days-1 (-), the maximum effect Emax=0.65 (-), the infusion rate from virtual compartment that leads to 50% inhibition of neutrophils proliferation constant EDK50=256 mg.day-1 (0.34), the baseline ANC value Circ0=3.97 G/L (0.33), the feedback parameter γ=0.15 (-) and the mean transit time MTT= 3.12 days (0.342). Body weight significantly increased EDK50 (βWT=0.736, Δ-2log likelihood=-6.77, p=0.009).
Conclusions: This work is to our knowledge the first reporting a semi-mechanistic K-PD model developed to describe myelosuppression in human. The influence of body weight on palbociclib EDK50 may be related to CL and/or EC50 [2]. An influence of weight on clearance of palbociclib has been previously reported [3]. Measurement of palbociclib concentrations in future studies could allow determining if weight also influence EC50. The present study suggests that dose adaptation at treatment initiation according to body weight may allow a decrease of the incidence of onset of neutropenia.
References:
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