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 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)=(6.588 x C(2.5 h))+(146.4 x C(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.
Mathijssen
R H J
RH
Department of Medical Oncology, Erasmus MC-Daniel den Hoed, PO Box 5201, 3008 AE Rotterdam, The Netherlands.
Verweij
J
J
Loos
W J
WJ
de Bruijn
P
P
Nooter
K
K
Sparreboom
A
A
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000473:pathology; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D010051:Ovarian Neoplasms / Q000473:pathology; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011897:Random Allocation; D014407:Tumor Cells, Cultured / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000097:blood / Q000188:drug therapy
D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; D000077146:Irinotecan; D002166:Camptothecin