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AIMS Early identification of patients with febrile neutropenia (FN) is desirable for initiation of preventive treatment, such as with antibiotics. In this study, the time courses of two inflammation biomarkers, interleukin (IL)-6 and C-reactive protein (CRP), following adjuvant chemotherapy of breast cancer, were characterized. The potential to predict development of FN by IL-6 and CRP, and other model-derived and clinical variables, was explored. METHODS The IL-6 and CRP time courses in cycles 1 and 4 of breast cancer treatment were described by turnover models where the probability for an elevated production following initiation of chemotherapy was estimated. Parametric time-to-event models were developed to describe FN occurrence to assess: (i) predictors available before chemotherapy is initiated; (ii) predictors available before FN occurs; and (iii) predictors available when FN occurs. RESULTS The IL-6 and CRP time courses were successfully characterized with peak IL-6 typically occurring 2 days prior to CRP peak. Of all evaluated variables the CRP time course was most closely associated with the occurrence of FN. Since the CRP peak typically occurred at the time of FN diagnosis it will, however, have limited value for identifying the need for preventive treatment. The time course of IL-6 was the predictor that could best forecast FN events. Of the variables available at baseline, age was the best, although in comparison a relatively weak, predictor. CONCLUSIONS The developed models add quantitative knowledge about IL-6 and CRP and their relationship to the development of FN. The study suggests that IL-6 may have potential as a clinical predictor of FN if monitored during myelosuppressive chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]