Pharmacokinetics of liposomal cytarabine in AML patients treated with CPX-351 (Vyxeos®): role of cytidine deaminase status

XVIIIes Journées du GPCO

Mélanie Donnette1, Mourad Hamimed1, Joseph Ciccolini1, 5,
Yael Berda-Haddad
2, Elise Kaspi3, Geoffroy Venton4, Bruno Lacarelle5, Regis Costello4, L’Houcine Ouafik6, Laure Farnault4, Raphaelle Fanciullino1

  1. SMARTc: Simulation & Modeling : adaptative Response for Therapeutics in Cancer, CRCM Inserm UMR 1068, France

  2. Laboratoire de Biologie Medicale, La Conception University hospital of Marseille, France

  3. Cellular biology unit, la Timone University Hospital of Marseille, INSERM, MMG, Aix Marseille Univ, France

  4. Hematology and Cellular Therapy Department, La Conception University hospital of Marseille, France

  5. Laboratoire de Pharmacocinétique et Toxicologie, La Timone University Hospital

    of Marseille 6 Laboratoire de Transfert en Oncologie Biologie, Nord Unuversity Hispoital of Marseille, France

CPX-351 (Vyxeos®) is a liposomal formulation encapsulating cytarabine and daunorubicin for treating Acute Myeloid Leukemia patients. Here we have monitored the plasma levels of released, liposomal and total cytarabine, and derived the pharmacokinetics parameters using a population- modeling approach in 9 patients treated with this liposomal nanoparticle. Results showed sus- tained exposure with reduced clearance and prolonged half-life, plus a high concentration of both liposomal nanoparticles and cytarabine levels in bone marrow 15 days after the administration.

A large inter-individual variability was observed on pharmacokinetics parameters. Interestingly, phenotype of cytidine deaminase, the liver enzyme that metabolizes cytarabine, had an strong impact on the PK parameters of the liposomal form, i.e. poormetabolizer patients showing higher drug levels, sustained exposure and reduced clearance.This proof-of-concept study strongly suggests that CDA status could have a major impact on cytarabine PK when administered as a liposomal form.