Pharmacokinetic-pharmacodynamic modelling of the schedule-dependent effect of the anti-cancer agent CHS 828 in a rat hollow fibre model.
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 2.3h 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.
Friberg
Lena E
LE
Division of Pharmacokinetics and Drug Therapy, Uppsala University, Uppsala, Sweden. lfriberg@pharmacy.uq.edu.au
Hassan
Saadia B
SB
Lindhagen
Elin
E
Larsson
Rolf
R
Karlsson
Mats O
MO
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D045744:Cell Line, Tumor; D003486:Cyanides / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D003486:Cyanides; D006146:Guanidines; C401312:N-(6-chlorophenoxyhexyl)-N''-cyano-N''-4-pyridylguanidine