Irinotecan pharmacokinetics-pharmacodynamics: the clinical relevance of prolonged exposure to SN-38

We have shown previously that the terminal disposition half-life of SN-38, the active metabolite of innotecan, is much longer than earlier thought, Currently, it is not known whether this prolonged exposure has any relevance SN-38-induced toxicity, Here, we found that SN-38 concentrations present in human plasma for up to 3 after a jingle innotecan 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 ACC (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 N)=(6.588 x C-2.5 h)+(146.4 x C-49.5 h)+15.53, where C-25 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 innotecan.