Perrine Courlet1, Evelina Cardoso2, Athina Stravodimou3, Jean-Philippe Zurcher3,
Khalil Zaman3, Haithem Chtioui4, Isabella Locatelli5, Lea Darnaud6, Benoit Blanchet6, Carole Bandiera7, Dorothea Wagner3, Marie-Paule Schneider7, Monia Guidi1, Chantal Csajka1
1. Centre for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital, Switzerland 2. Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Switzerland
3. Service of Oncology, Lausanne University Hospital, Switzerland
4. Service of Clinical Pharmacology, Lausanne University Hospital, Switzerland
5. Center for Primary Care and Public Health (Unisanté), University of Lausanne, Switzerland 6. Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, Paris, France 7. School of Pharmaceutical Sciences, University of Geneva, Switzerland
Neutropenia is the most frequent dose-limiting toxicity reported in patients receiving palbociclib, a CDK4/6 inhibitor prescribed for the treatment of metastatic breast cancer. Palbociclib is gene- rally administered at a dose of 125 mg once daily (qd) for 21 consecutive days (ON treatment period) followed by 7 days OFF treatment (standard administration schedule). The objective of this study was to investigate the pharmacokinetic-pharmacodynamic (PK/PD) relationships for toxicity (absolute neutrophil counts, ANC) and efficacy (progression-free survival, PFS).
Data were collected as part of the Optimizing oral Targeted Anticancer Therapies study initiated at Lausanne1.A semi-mechanistic PK/PD model was used to predict palbociblib concentration-time pro- files and ANC time-course using a population approach (NONMEM). The well-known neutropenia model including drug-specific (Emax, EC50) and system-related parameters (baseline ANC, mean transit time and a feedback parameter) was employed to describe palbociclib neutropenic effect2. Influence of demographic and clinical characteristics was evaluated on PK and PD parameters.
Model-based simulations were performed to evaluate the effect of palbociclib dosage regimen on neutropenia incidence and severity (ANC nadir and duration of neutropenia). Both changes in palbociclib daily dose (i.e. 125, 100 or 75 mg qd) and extension of OFF-phases were eva- luated. Palbociclib haematotoxicity was classified according to the Common Terminology Criteria for Adverse Events3. Cox proportional hazards models were developed to evaluate the influence of palbociclib exposure (cumulative area under the curve over 90 days, AUCcum90) on PFS (https://www.r-project.org).
A total of 255 palbociclib plasma concentrations and 1174 ANC values from 44 patients were available. A two-compartment model with first-order absorption and elimination, and a lag-time adequately described palbociclib PK. The coadministration of proton-pump inhibitors in fasting conditions increased palbociclib clearance by 56%.
The neutropenia model successfully described the ANC time-course. None of the tested covariates was retained on the PD parameters. Model-based simulations indicated that after the initiation of a standard administration schedule, ANC decreased and reached nadir after 24-25 days, regardless of the dose. A rebound then occurred during the following 11 days. The same pattern was predicted during each subsequent cycle, with no trend of worsening ANC values over repeated cycles. A better ANC recovery was observed with longer OFF periods. Under a standard administration schedule, incidence but not severity of each neutropenia grade increased with dose. Neutropenia grade 4 was predicted in 0.4% and 16% of the simulated individuals with the highest and lowest baseline ANC values, respectively.
Among the 44 patients included, 19 progressed, with a median PFS of 17 months (interquartile range 8-27). Cox analyses revealed a trend for better PFS with increasing AUCcum90 in older patients.
To our knowledge, this is the first study evaluating PK-PD relationships of palbociclib using real- world data. Palbociclib-induced neutropenia appears reversible and non-cumulative. This model may support dosing regimen adjustments and guide clinicians for treatment strategies optimi- zation. Further studies are required to draw definitive conclusions about the exposure-response relationship.
This work has been supported since April 2017 by the Swiss Cancer Research Foundation (grant HSR-4077-11-2016).
Keywords: palbociclib, pharmacokinetics, neutropenia.
1. Bandiera C, Cardoso E, Locatelli I, Digklia A, Zaman K, Diciolla A, et al. Optimizing oral targeted anticancer therapies study for patients with solid cancer. JMIR Res Protoc. 2021;10(6):e30090.
2. Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol. 2002;20(24):4713-21.
3. U.S. Department of health and human Services. Common Terminology Criteria for Adverse Events (CTCAE) 2017 Available from: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf