title: Population Pharmacokinetics of Gemcitabine and dFdU in Pancreatic Cancer Patients Using an Optimal Design, Sparse Sampling Approach.
abstract: Gemcitabine remains a pillar in pancreatic cancer treatment. However, toxicities are frequently observed. Dose adjustment based on therapeutic drug monitoring might help decrease the occurrence of toxicities. In this context, this work aims at describing the pharmacokinetics (PK) of gemcitabine and its metabolite dFdU in pancreatic cancer patients and at identifying the main sources of their PK variability using a population PK approach, despite a sparse sampled-population and heterogeneous administration and sampling protocols.
  
  
  
  Data from 38 patients were included in the analysis. The 3 optimal sampling times were determined using KineticPro and the population PK analysis was performed on Monolix. Available patient characteristics, including cytidine deaminase (CDA) status, were tested as covariates. Correlation between PK parameters and occurrence of severe hematological toxicities was also investigated.
  
  
  
  A two-compartment model best fitted the gemcitabine and dFdU PK data (volume of distribution and clearance for gemcitabine: V1 = 45 L and CL1 = 4.03 L/min; for dFdU: V2 = 36 L and CL2 = 0.226 L/min). Renal function was found to influence gemcitabine clearance, and body surface area to impact the volume of distribution of dFdU. However, neither CDA status nor the occurrence of toxicities was correlated to PK parameters.
  
  
  
  Despite sparse sampling and heterogeneous administration and sampling protocols, population and individual PK parameters of gemcitabine and dFdU were successfully estimated using Monolix population PK software. The estimated parameters were consistent with previously published results. Surprisingly, CDA activity did not influence gemcitabine PK, which was explained by the absence of CDA-deficient patients enrolled in the study. This work suggests that even sparse data are valuable to estimate population and individual PK parameters in patients, which will be usable to individualize the dose for an optimized benefit to risk ratio.
authors.affiliation: *SMARTc, CRO2, UMR S_911, Aix-Marseille Université, Marseille, France; †IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, ICM, Université de Montpellier, Montpellier, France; ‡Digestive Oncology Unit, La Timone Hospital, AP-HM, Aix-Marseille Université, Marseille, France; §Gastroenterology Department, CHRU Besançon, Besançon, France; ¶Digestive Pathologies Department, CHU Clermont-Ferrand, Clermont-Ferrand, France; ‖Pôle de Médecine, Centre Antoine Lacassagne, Nice, France; **Institut Arnault Tzanck, Saint Laurent du Var, France; and ††Service Interdisciplinaire de Cancérologie, Riviera-Chablais Hospital, Vevey, Switzerland.
authors.forename: Cindy
authors.initials: C
authors.lastname: Serdjebi
authors.forename: Florence
authors.initials: F
authors.lastname: Gattacceca
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Seitz
authors.forename: Francine
authors.initials: F
authors.lastname: Fein
authors.forename: Johan
authors.initials: J
authors.lastname: Gagnière
authors.forename: Eric
authors.initials: E
authors.lastname: François
authors.forename: Abakar
authors.initials: A
authors.lastname: Abakar-Mahamat
authors.forename: Gael
authors.initials: G
authors.lastname: Deplanque
authors.forename: Madani
authors.initials: M
authors.lastname: Rachid
authors.forename: Bruno
authors.initials: B
authors.lastname: Lacarelle
authors.forename: Joseph
authors.initials: J
authors.lastname: Ciccolini
authors.forename: Laetitia
authors.initials: L
authors.lastname: Dahan
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003564:Cytidine Deaminase / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016903:Drug Monitoring / Q000379:methods; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D003564:Cytidine Deaminase; D000093542:Gemcitabine