Pharmacokinetic/pharmacodynamic modeling of etoposide tumor growth inhibitory effect in Walker-256 tumor-bearing rat model using free intratumoral drug concentrations.
The purpose of this study was to establish a population pharmacokinetic/pharmacodynamic (PK/PD) model linking etoposide free tumor and total plasma concentrations to the inhibition of solid tumor growth in rats. Walker-256 tumor cells were inoculated subcutaneously in the right flank of Wistar rats, which were randomly divided in control and two treated groups that received etoposide 5 or 10mg/kg i.v. bolus every day for 8 and 4days, respectively, and tumor volume was monitored daily for 30days. The plasma and intratumoral concentrations-time profiles were obtained from a previous study and were modeled by a four-compartment population pharmacokinetic (popPK) model. PK/PD analysis was conducted using MONOLIX v.4.3.3 on average data and by mean of a nonlinear mixed-effect model. PK/PD data were analyzed using a modification of Simeoni Tumor Growth Inhibition (TGI) model by introduction of an Emaxfunction to take into account the concentration dependency of k2variableparameter (variable potency). The Simeoni TGI-Emaxmodel was capable to fit schedule-dependent antitumor effects using the tumor growth curves from the control and two different administered schedules. The PK/PD model was capable of describing the tumor growth inhibition using total plasma or free tumor concentrations, resulting in higher k2max(maximal potency) for free concentrations (25.8mL·μg-1·day-1- intratumoral vs. 12.6mL·μg-1·day-1total plasma). These findings indicate that the plasma concentration may not be a good surrogate for pharmacologically active free tumor concentrations, emphasizing the importance of knowing drug tumor penetration to choose the best antitumor therapy.
Pharmaceutical Sciences Graduate Program, College of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Brazil; CAPES Foundation, Ministry of Education of Brazil, Brasília, DF, Brazil; College of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
Maiara Cássia
MC
Pigatto
College of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
Renatha Menti
RM
Roman
Dipartimento di Ingegneria Industriale e dell'Informazione, University of Pavia, Italy.
Letizia
L
Carrara
Pharmaceutical Sciences Graduate Program, College of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Brazil; College of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
Andréia
A
Buffon
Dipartimento di Ingegneria Industriale e dell'Informazione, University of Pavia, Italy.
Paolo
P
Magni
Pharmaceutical Sciences Graduate Program, College of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Brazil; College of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. Electronic address: dalla.costa@ufrgs.br.
Teresa
T
Dalla Costa
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002279:Carcinoma 256, Walker / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005047:Etoposide / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006131:Growth Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D047368:Tumor Burden / Q000187:drug effects* / Q000502:physiology
D000972:Antineoplastic Agents, Phytogenic; D006131:Growth Inhibitors; D005047:Etoposide
Cancer chemotherapy; Etoposide; Mathematical model; Pharmacokinetics/pharmacodynamics; Tissue penetration; Walker-256 tumor