Population Pharmacokinetics of Palbociclib in aReal-World Situation
Palbociclib is an oral cyclin-dependent kinase inhibitor that is used in combination with aromatase inhibitors in the treatment of postmenopausal women with metastatic breast cancer. Its metabolism profile is associated with an important interpatient variability. We performed a population pharmacokinetics study of palbociclib in women routinely followed in a cancer center. One hundred and fifty-one samples were analyzed. The sampling times after administration ranged from 0.9 to 75 h and the samples were taken between 1 and 21 days after the beginning of the palbociclib cycle. Palbociclib was determined using a validated mass spectrometry method. The best model that described the concentrat…
Lipoproteins LDL versus HDL as nanocarriers to target either cancer cells or macrophages
free open access article 31 p.; International audience; In this work, we have explored natural unmodified low- and high-density lipoproteins (LDL and HDL) as selective delivery vectors in colorectal cancer therapy. We show in vitro in cultured cells and in vivo (NanoSPECT/CT) in the CT-26 mice colorectal cancer model that LDLs are mainly taken up by cancer cells, while HDLs are preferentially taken up by macrophages. We loaded LDLs with cisplatin and HDLs with the heat shock protein-70 inhibitor AC1LINNC, turning them into a pair of “Trojan horses” delivering drugs selectively to their target cells as demonstrated in vitro in human colorectal cancer cells and macrophages, and in vivo. Coupl…
Model-based approach to describe G-CSF effects in carboplatin-treated cancer patients.
Granulocyte colony-stimulating factor (G-CSF) is often used in cancer patients receiving cytotoxic drugs to prevent or reduce high grade neutropenia. We propose a pharmacokinetic/pharmacodynamic model to describe myelotoxicity in both G-CSF treated and non-treated patients that shall increase our understanding of G-CSF effects. The model was built from absolute neutrophil counts (ANC) obtained in 375 carboplatin-treated patients, 47 of whom received G-CSF. It includes some prior information on G-CSF taken from the literature. Simulations were performed to understand differences in G-CSF effects and explore the impact of G-CSF formulation. Our model well described the data in all patients. M…
Pharmacokinetic/Pharmacodynamic Model of Neutropenia in Real-Life Palbociclib-Treated Patients
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 collec…
Therapeutic drug monitoring as a tool to optimize 5-FU-based chemotherapy in gastrointestinal cancer patients older than 75 years.
Abstract Aims Most clinical trials exclude elderly people, leading to a limited understanding of the benefit-to-risk ratio in this population. Despite existing data regarding the oncological management of elderly receiving fluorouracil (5-FU)-based regimen, our objective was to investigate 5-FU exposure/toxicity relationship in patients ≥75 years and compare the effectiveness of 5-FU therapeutic drug monitoring between elderly and younger patients. Methods Hundred fifty-four patients (31 of whom are older than 75 years) with gastrointestinal cancers, who were to receive 5-FU–based regimens, were included in our study. At cycle 1 (C1), the 5-FU dose was calculated using patient's body surfac…
Artificial increase of uracilemia during fluoropyrimidine treatment can lead to DPD deficiency misinterpretation
Each year in France, >75 000 patients receive fluoropyrimidines, including 5-fluorouracil (5-FU) and its oral prodrug capecitabine (Xeloda), to treat digestive, breast and head and neck cancers.1 Among them, ∼20% will experience severe hematological and digestive toxicities and <2% will have a fatal outcome in the first two cycles. A part of these toxicities may result from a deficiency in dihydropyrimidine dehydrogenase (DPD) which catabolizes the endogenous uracil (U) into dihydrouracil (UH2) as well as 5-FU. In 2018, French Health Authorities [Haute Autorité de Santé (HAS) and Institut National du Cancer, (INCa)] recommended the evaluation of the enzymatic activity of DPD by measuring th…
Impact of granulocyte colony‐stimulating factor on FOLFIRINOX‐induced neutropenia prevention: A population pharmacokinetic/pharmacodynamic approach
Aims Granulocyte colony-stimulating factor (G-CSF) is frequently prescribed to prevent chemotherapy-induced neutropenia, but the administration schedule remains empirical in case of bimonthly chemotherapy such as FOLFIRINOX regimen. This pharmacokinetic/pharmacodynamic (PK/PD) study was performed to determine the effect of different G-CSF regimens on the incidence and duration of neutropenia following FOLFIRINOX administration in order to propose an optimal G-CSF dosing schedule. Methods A population PK/PD model was developed to describe individual neutrophil time course from absolute neutrophil counts (ANC) obtained in 40 advanced cancer patients receiving FOLFIRINOX regimen. The structura…
Association of 5-FU Therapeutic Drug Monitoring to DPD Phenotype Assessment May Reduce 5-FU Under-Exposure
In order to limit 5-fluorouracil (5-FU) toxicity, some health agencies recommend evaluating dihydropyrimidine dehydrogenase (DPD) deficiency before any 5-FU treatment introduction. In our study, we investigated relationships between 5-FU clearance and markers of DPD activity such as uracilemia (U), dihydrouracilemia (UH2)/U ratio, or genotype of the gene encoding DPD (DPYD). All patients with gastrointestinal cancers who received 5-FU-based regimens form March 2018 to June 2020 were included in our study. They routinely benefited of a pre-therapeutic DPYD genotyping and phenotyping. During 5-FU infusion, blood samples were collected to measure 5-FU steady-state concentration in order to ada…
Trastuzumab-emtansine induced pleural and pericardial effusions
Introduction Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate which combine trastuzumab (T), a monoclonal antibody targeting the human epidermal growth factor receptor-2 (HER2), and a cytotoxic molecule derived from maytansine (DM1). Case report We report the first case of T-DM1-associated pleural and pericardial effusions three weeks after the second course of T-DM1 in a patient with breast cancer. Drug-induced pleural and pericardial effusions was implicated in the absence of other etiologies. The Naranjo Scale indicated a probable drug-induced adverse reaction. Management & outcome: The patient fully recovered after thoracentesis and discontinuation of T-DM1. The patient h…
Lack of everolimus diffusion in pleural fluid during pleural progression of breast cancer: A case report
Background We report here a case where no everolimus pleural diffusion was evidenced at the same time of pleural progression of a metastatic breast cancer treated with everolimus and exemestane. Case description A 69-year-old woman was diagnosed in October 2006 with stage III invasive ductal breast adenocarcinoma. After nine months of everolimus and exemestane treatment, she presented with a pleural progression. Everolimus concentration was measured in blood and in pleural fluid. Residual blood concentration was at 9.1 ng/mL, while no everolimus was observed in the pleural fluid. Management and outcome Due to inefficacy of everolimus in this patient, she was switched to palbociclib and fulv…
G-CSF dosing schedule to prevent eribulin-induced neutropenia: Can modelling and simulation help?
e20673 Background: Eribulin is a microtubule inhibitor indicated for the treatment of patients with metastatic breast cancer and should be administered on day 1 and 8 of each 21-day cycle. Neutrope...