¹Department of Medical Oncology, Erasmus MC–Daniel den Hoed, PO Box 5201, 3008 AE Rotterdam, The Netherlands

Correspondence: A Sparreboom, E-mail: sparreboom@onch.azr.nl

Received 20 December 2001; Revised 29 April 2002; Accepted 12 May 2002.

Abstract

We have shown previously that the terminal disposition half-life of SN-38, the active metabolite of irinotecan, is much longer than earlier thought. Currently, it is not known whether this prolonged exposure has any relevance toward SN-38-induced toxicity. Here, we found that SN-38 concentrations present in human plasma for up to 3 weeks after a single irinotecan infusion induce significant cytotoxicity in vitro. Using pharmacokinetic data from 26 patients, with sampling up to 500 h, relationships were evaluated between systemic exposure (AUC) to SN-38 and the per cent decrease in absolute neutrophil count (ANC) at nadir, or by taking the entire time course of ANC into account (AOC). The time course of SN-38 concentrations (AUC_500 h) was significantly related to this AOC (P<0.001). Based on these findings, a new limited-sampling model was developed for SN-38 AUC_500 h using only two timed samples: AUC_500 h=(6.588C_2.5 h)+(146.4C_49.5 h)+15.53, where C_2.5 h and C_49.5 h are plasma concentrations at 2.5 and 49.5 h after start of infusion, respectively. The use of this limited-sampling model may open up historic databases to retrospectively obtain information about SN-38-induced toxicity in patients treated with irinotecan.