Pharmacokinetic–pharmacodynamic modelling of the schedule-dependent effect of the anti-cancer agent CHS 828 in a rat hollow fibre model

• Published in: European journal of pharmaceutical sciences Vol. 25; no. 1; pp. 163 - 173
• Main Authors: Friberg, Lena E., Hassan, Saadia B., Lindhagen, Elin, Larsson, Rolf, Karlsson, Mats O.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier B.V 01.05.2005; Elsevier
• Subjects: Animals; Antineoplastic Agents - pharmacokinetics; Area Under Curve; Biological and medical sciences; Cancer; Cell Line, Tumor; CHS 828; Cyanides - pharmacokinetics; Cyanides - pharmacology; Cyanides - toxicity; Cyanides/pharmacokinetics/pharmacology/toxicity; Dose-Response Relationship, Drug; General pharmacology; Guanidines - pharmacokinetics; Guanidines - pharmacology; Guanidines - toxicity; Guanidines/pharmacokinetics/pharmacology/toxicity; Humans; Male; Medical sciences; Models, Biological; NONMEM; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; PK/PD modelling; Rats; Rats, Sprague-Dawley; Schedule dependence; PK/PD modelling; CHS 828; Schedule dependence; NONMEM; Cancer; Antineoplastic agent; Pharmacokinetic pharmacodynamic relationship; Pharmaceutical technology; Rat; Rodentia; Vertebrata; Mammalia; Animal; Drug; Cell Line; Sprague-Dawley; Rats; Tumor; Dose-Response Relationship; Models; Biological
• ISSN: 0928-0987; 1879-0720; 1879-0720
• DOI: 10.1016/j.ejps.2005.02.006

N-(6-Chlorophenoxyhexyl)- N′-cyano- N″-4-pyridylguanidine (CHS 828) is a novel anticancer agent that shows schedule-dependent effects in vitro and in vivo, as well as in Phase I clinical trials. A rat hollow fibre model was used to investigate whether this dependency is due to pharmacokinetic and/or pharmacodynamic factors. The effect on two cell lines, MDA-MB-231 (breast cancer) and CCRF-CEM (leukaemia) were studied after CHS 828 was administered orally as a single dose or in a 5-day schedule, at different total dose levels. The 5-day schedules were associated with greater effects on both cell lines compared with single doses. A one-compartment pharmacokinetic model, with a half-life of 2.3 h and a consecutive zero- and first-order process to describe dissolution and absorption, fit the concentration data. Pharmacokinetics were dose-dependent, as the fraction absorbed decreased with increasing dose. Clearance increased with accumulative exposure. Twenty hours after administration, concentrations started to increase again, probably due to coprophagy. Pharmacokinetic–pharmacodynamic models characterized the cell growth and cell kill over time and showed that schedule-dependent antitumour effects were present also when the dose-dependent pharmacokinetics were accounted for. The prolonged schedules of CHS 828 were therefore associated with greater antitumour effects than single doses of the same total exposure.