Increased Plasma Concentrations of Unbound SN-38, the Active Metabolite of Irinotecan, in Cancer Patients with Severe Renal Failure

Purpose Delayed plasma concentration profiles of the active irinotecan metabolite SN-38 were observed in cancer patients with severe renal failure (SRF), even though SN-38 is eliminated mainly via the liver. Here, we examined the plasma concentrations of unbound SN-38 in such patients. Methods Plasma unbound concentrations were examined by ultrafiltration . Physiologically-based pharmacokinetic (PBPK) models of irinotecan and SN-38 were established to quantitatively assess the principal mechanism for delayed SN-38 elimination. Results The area under the plasma unbound concentration-time curve (AUC u ) of SN-38 in SRF patients was 4.38-fold higher than that in normal kidney patients. The unbound fraction of SN-38 was also 2.6-fold higher in such patients, partly because SN-38 protein binding was displaced by the uremic toxin 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF). This result was supported by correlation of the unbound fraction of SN-38 with the plasma CMPF concentration, which negatively correlated with renal function. PBPK modeling indicated substantially reduced influx of SN-38 into hepatocytes and approximately one-third irinotecan dose for SRF patients to produce an unbound concentration profile of SN-38 similar to normal kidney patients. Conclusion The AUC u of SN-38 in SRF cancer patients is much greater than that of normal kidney patients primarily because of the reduced hepatic uptake of SN-38.