title: Population Pharmacokinetic Modeling of Etoposide Free Concentrations in Solid Tumor.
abstract: This study aimed to determine free etoposide (ETO) concentrations in two regions of Walker-256 (W256) solid tumor using microdialysis and to establish a population pharmacokinetic (popPK) model to describe simultaneously free tumor and total plasma concentrations.
  
  
  
  W256 tumor-bearing Wistar rats received ETO 10 or 20 mg/kg i.v. bolus. Free ETO concentrations were sampled from central and peripheral regions of the tumor via CMA/20 probes for up to 7 h, whereas blood samples were collected via carotid artery cannulation. Total plasma and free tumor concentration-time profiles were analyzed by non-compartmental approach using WinNonlin® v. 5.3. PopPK modeling was conducted using MONOLIX v.4.3.3.
  
  
  
  ETO penetration was higher in the periphery (61 ± 15% and 61 ± 29%) than in tumor center (34 ± 6% and 28 ± 11%) following 10 and 20 mg/kg doses, respectively (ANOVA, α = 0.05). A 4-compartment model fitted ETO concentration-time profiles in all sampling compartments.
  
  
  
  The popPK model allowed the simultaneous fitting of plasma and tumor concentrations and a better understanding of ETO distribution in solid tumors. ETO plasma concentrations are not a good surrogate for tumoral exposure, emphasizing the importance of knowing intratumoral concentrations to predict drug response.
authors.affiliation: Pharmaceutical Sciences Graduate Program, College of Pharmacy, Federal University of Rio Grande do Sul, Av. Ipiranga, 2752, Porto Alegre, RS, 90.610-000, Brazil.|CAPES Foundation, Ministry of Education of Brazil, Brasília, DF, Brazil.
authors.forename: Maiara Cássia
authors.initials: MC
authors.lastname: Pigatto
authors.affiliation: Pharmaceutical Sciences Graduate Program, College of Pharmacy, Federal University of Rio Grande do Sul, Av. Ipiranga, 2752, Porto Alegre, RS, 90.610-000, Brazil.
authors.forename: Bibiana Verlindo
authors.initials: BV
authors.lastname: de Araujo
authors.affiliation: Pharmaceutical Sciences Graduate Program, College of Pharmacy, Federal University of Rio Grande do Sul, Av. Ipiranga, 2752, Porto Alegre, RS, 90.610-000, Brazil.
authors.forename: Bruna Gaelzer Silva
authors.initials: BG
authors.lastname: Torres
authors.affiliation: Department of Pharmaceutics, Center for Pharmacometrics & Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Dipartimento di Ingegneria Industriale e dell'Informazione, University of Pavia, Pavia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Magni
authors.affiliation: Pharmaceutical Sciences Graduate Program, College of Pharmacy, Federal University of Rio Grande do Sul, Av. Ipiranga, 2752, Porto Alegre, RS, 90.610-000, Brazil. dalla.costa@ufrgs.br.
authors.forename: Teresa
authors.initials: T
authors.lastname: Dalla Costa
mesh_terms: D000818:Animals; D005047:Etoposide / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D017551:Microdialysis / Q000379:methods; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution / Q000502:physiology
chemical_list: D005047:Etoposide
keywords: anticancer; drug tumor penetration; etoposide; microdialysis; population pharmacokinetics