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Pharmacokinetic Variability Drives Palbociclib-Induced Neutropenia in Metastatic Breast Cancer Patients: Drug-Drug Interactions Are the Usual Suspects.
Leenhardt, Fanny; Fiteni, Frédéric; Gauthier, Ludovic; Alexandre, Marie; Guiu, Séverine; Firmin, Nelly; Pouderoux, Stéphane; Viala, Marie; Lossaint, Gerald; Gautier, Chloé; Mollevi, Caroline; Gracia, Matthieu; Gongora, Celine; Mbatchi, Litaty; Evrard, Alexandre; Jacot, William.
Afiliação
  • Leenhardt F; Institut du Cancer de Montpellier, Université de Montpellier, 208 rue des Apothicaires, 34298 Montpellier, France.
  • Fiteni F; Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, 34090 Montpellier, France.
  • Gauthier L; Laboratoire de Pharmacocinétique, Faculté de Pharmacie, Université de Montpellier, 34090 Montpellier, France.
  • Alexandre M; Service d'Oncologie Médicale, CHU de Nîmes, CEDEX 9, 930029 Nîmes, France.
  • Guiu S; Institut Desbrest d'Epidemiologyie et de Santé Publique, INSERM UMR 1302, Université de Montpellier, 34090 Montpellier, France.
  • Firmin N; Institut du Cancer de Montpellier, Université de Montpellier, 208 rue des Apothicaires, 34298 Montpellier, France.
  • Pouderoux S; Institut du Cancer de Montpellier, Université de Montpellier, 208 rue des Apothicaires, 34298 Montpellier, France.
  • Viala M; Institut du Cancer de Montpellier, Université de Montpellier, 208 rue des Apothicaires, 34298 Montpellier, France.
  • Lossaint G; Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, 34090 Montpellier, France.
  • Gautier C; Institut du Cancer de Montpellier, Université de Montpellier, 208 rue des Apothicaires, 34298 Montpellier, France.
  • Mollevi C; Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, 34090 Montpellier, France.
  • Gracia M; Institut du Cancer de Montpellier, Université de Montpellier, 208 rue des Apothicaires, 34298 Montpellier, France.
  • Gongora C; Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, 34090 Montpellier, France.
  • Mbatchi L; Institut du Cancer de Montpellier, Université de Montpellier, 208 rue des Apothicaires, 34298 Montpellier, France.
  • Evrard A; Institut du Cancer de Montpellier, Université de Montpellier, 208 rue des Apothicaires, 34298 Montpellier, France.
  • Jacot W; Institut du Cancer de Montpellier, Université de Montpellier, 208 rue des Apothicaires, 34298 Montpellier, France.
Pharmaceutics ; 14(4)2022 Apr 11.
Article em En | MEDLINE | ID: mdl-35456675
Palbociclib is a good candidate for therapeutic drug monitoring (TDM) due to its narrow therapeutic range and frequency of toxicities, particularly high-grade neutropenia. In this prospective, bicentric clinical trial, we evaluated the palbociclib exposure−toxicity relationship and determined the relevant sources of palbociclib pharmacokinetic variability, including drug−drug interactions (DDI). We followed 58 patients (mean age: 62.9 years) for 1 year. The geometric median of palbociclib plasma trough concentration (Ctrough) was 74.1 ng/mL. Neutropenia occurred in 70.7% of patients (high grade in 67.2% of patients). High-grade neutropenia occurrence during the first two palbociclib cycles was higher in patients with lower neutrophil count at initiation (p = 0.002). Palbociclib plasma Ctrough was correlated with high-grade neutropenia occurrence during the first two cycles (p = 0.024, OR 5.51). Co-treatment with agents that may interfere with palbociclib PK significantly influenced palbociclib Ctrough (p < 0.05). CYP3A4/P-glycoprotein inhibitors increased by 25% palbociclib Ctrough (p = 0.035), while antacids reduced it by 20% (p = 0.036). However, DDI did not have any significant effect on high-grade neutropenia occurrence (p > 0.05). This study confirms the major role of TDM to manage palbociclib safe use from the first week of treatment, particularly the significant incidence of hematological toxicity. Moreover, this first dedicated prospective study confirmed the importance of characterizing co-treatments to limit the DDI risk with oral-targeted therapies.
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Texto completo: 1 Base de dados: MEDLINE Tipo de estudo: Observational_studies / Risk_factors_studies Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Tipo de estudo: Observational_studies / Risk_factors_studies Idioma: En Ano de publicação: 2022 Tipo de documento: Article