Maiara Cássia Pigatto1,2, Bibiana Verlindo de Araujo1, Bruna Gaelzer Silva Torres1, Stephan Schmidt3, Paolo Magni4, Teresa Dalla Costa5. 1. Pharmaceutical Sciences Graduate Program, College of Pharmacy, Federal University of Rio Grande do Sul, Av. Ipiranga, 2752, Porto Alegre, RS, 90.610-000, Brazil. 2. CAPES Foundation, Ministry of Education of Brazil, Brasília, DF, Brazil. 3. Department of Pharmaceutics, Center for Pharmacometrics & Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA. 4. Dipartimento di Ingegneria Industriale e dell'Informazione, University of Pavia, Pavia, Italy. 5. 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.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
PURPOSE: 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. METHODS: 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. RESULTS: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. CONCLUSIONS: 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.
Entities:
Keywords:
anticancer; drug tumor penetration; etoposide; microdialysis; population pharmacokinetics
Authors: Pieter Colin; Lieselotte De Smet; Chris Vervaet; Jean-Paul Remon; Wim Ceelen; Jan Van Bocxlaer; Koen Boussery; An Vermeulen Journal: Pharm Res Date: 2014-05-22 Impact factor: 4.200
Authors: Ian F Tannock; Carol M Lee; Jonathon K Tunggal; David S M Cowan; Merrill J Egorin Journal: Clin Cancer Res Date: 2002-03 Impact factor: 12.531
Authors: S Kaul; L N Igwemezie; D J Stewart; S Z Fields; M Kosty; N Levithan; R Bukowski; D Gandara; G Goss; P O'Dwyer Journal: J Clin Oncol Date: 1995-11 Impact factor: 44.544
Authors: Triantafyllos Stylianopoulos; John D Martin; Matija Snuderl; Fotios Mpekris; Saloni R Jain; Rakesh K Jain Journal: Cancer Res Date: 2013-04-30 Impact factor: 12.701