title: Etoposide pharmacokinetics and survival in patients with small cell lung cancer: a multicentre study.
abstract: OBJECTIVE
  To investigate the prognostic value of systemic exposure to etoposide (Area Under the concentration Curve (AUC(VP16))) on overall survival (OS) in patients with small cell lung cancer (SCLC).
  
  
  METHODS
  Data from 52 patients with limited stage (n=17) or metastatic (n=35) SCLC were analysed. They received at least two courses of etoposide (120mg/(m(2)day) on 3 days) combined with either doxorubicin-ifosfamide (AVI, n=29) or platinum compounds (carboplatin: n=16; cisplatin: n=7). Population pharmacokinetic-pharmacodynamic (PK-PD) study was performed using NON-linear Mixed Effect Model (NONMEM) and Splus software with univariate and multivariate analyses.
  
  
  RESULTS
  Etoposide plasma concentration vs. time was described by a two compartment model. Etoposide clearance (CL) was significantly dependant on serum creatinine (Scr). Ifosfamide (IFO) coadministration increased etoposide clearance by 28% (median CL(VP16): 2.42L/h vs. 1.89L/h, p<0.0005) leading to a reduced systemic exposure (median AUC(VP16): 260mgh/L vs. 339mgh/L). No influence of body surface area (BSA) on CL(VP16) was observed. Median percent decrease of absolute neutrophil count (ANC) after the first chemotherapy course was greater when etoposide 24h concentration was above 0.33mg/L (88% vs. 0%, p=0.028). Median OS was significantly longer in patients treated without ifosfamide (11.0 months vs. 7.0 months, p=0.049) and in patients with CL(VP16)<2.22L/h (14 months vs. 7 months, p=0.013) and AUC(VP16)>254.8mgh/L (11 months vs. 7 months, p=0.048). The independent prognostic factors regarding OS were LDH, CL(VP16) and AUC(VP16).
  
  
  CONCLUSIONS
  In this study it was found that CL(VP16) is reduced in patients with elevated serum creatinine, whilst ifosfamide coadministration increases CL(VP16) and reduces AUC(VP16), demonstrating the interaction between VP16 and ifosfamide. CL(VP16) and AUC(VP16) correlate significantly with overall survival of patients with SCLC patients receiving etoposide regimens.
authors.affiliation: Université de Lyon, Lyon F-69003, France. benoit.you@chu-lyon.fr
authors.forename: Benoit
authors.initials: B
authors.lastname: You
authors.forename: Brigitte
authors.initials: B
authors.lastname: Tranchand
authors.forename: Pascal
authors.initials: P
authors.lastname: Girard
authors.forename: Claire
authors.initials: C
authors.lastname: Falandry
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ribba
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chabaud
authors.forename: Pierre-Jean
authors.initials: PJ
authors.lastname: Souquet
authors.forename: Isabelle
authors.initials: I
authors.lastname: Court-Fortune
authors.forename: Véronique
authors.initials: V
authors.lastname: Trillet-Lenoir
authors.forename: Cécile
authors.initials: C
authors.lastname: Fournel
authors.forename: Michel
authors.initials: M
authors.lastname: Tod
authors.forename: Gilles
authors.initials: G
authors.lastname: Freyer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D015080:Mesna / Q000008:administration & dosage; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000401:mortality
chemical_list: D005047:Etoposide; D004317:Doxorubicin; D016190:Carboplatin; D015080:Mesna; D007069:Ifosfamide