TY - JOUR
T1 - A phase I trial of pharmacologic modulation of irinotecan with cyclosporine and phenobarbital
AU - Innocenti, Federico
AU - Undevia, Samir D.
AU - Ramírez, Jacqueline
AU - Mani, Sridhar
AU - Schilsky, Richard L.
AU - Vogelzang, Nicholas J.
AU - Prado, Marisol
AU - Ratain, Mark J.
PY - 2004/11
Y1 - 2004/11
N2 - The anticancer agent irinotecan has been demonstrated to improve the survival rate in patients with metastatic colorectal cancer. Its usage has been limited by severe toxicity. To modulate irinotecan pharmacokinetics and reduce the prevalence of severe toxicity, patients were treated with cyclosporine (INN, ciclosporin) and the irinotecan dose was increased from 25 to 72 mg/m 2 weekly. Phenobarbital was then added, allowing dose escalation to 144 mg/m2. Dose-limiting toxicities were neutropenia and diarrhea. Irinotecan was well tolerated at the recommended phase II dose of 120 mg/m 2, with a 6% prevalence of grade 4 neutropenia and an 18% prevalence of grade 3 diarrhea. Cyclosporine increased 7-ethyl-10-hydroxycamptothecin (SN-38) area under the concentration-time curve (AUC) by 23% to 630% and reduced irinotecan clearance by 39% to 64% when compared with historical controls. Phenobarbital increased irinotecan clearance by 27% (P ≤. 001) and reduced SN-38 AUC by 75% (P ≤. 001) when compared with patients treated with cyclosporine alone. Five partial responses were observed. Pharmacokinetic modulation of irinotecan with cyclosporine and phenobarbital has been demonstrated; further studies are necessary to evaluate whether this strategy improves the therapeutic index.
AB - The anticancer agent irinotecan has been demonstrated to improve the survival rate in patients with metastatic colorectal cancer. Its usage has been limited by severe toxicity. To modulate irinotecan pharmacokinetics and reduce the prevalence of severe toxicity, patients were treated with cyclosporine (INN, ciclosporin) and the irinotecan dose was increased from 25 to 72 mg/m 2 weekly. Phenobarbital was then added, allowing dose escalation to 144 mg/m2. Dose-limiting toxicities were neutropenia and diarrhea. Irinotecan was well tolerated at the recommended phase II dose of 120 mg/m 2, with a 6% prevalence of grade 4 neutropenia and an 18% prevalence of grade 3 diarrhea. Cyclosporine increased 7-ethyl-10-hydroxycamptothecin (SN-38) area under the concentration-time curve (AUC) by 23% to 630% and reduced irinotecan clearance by 39% to 64% when compared with historical controls. Phenobarbital increased irinotecan clearance by 27% (P ≤. 001) and reduced SN-38 AUC by 75% (P ≤. 001) when compared with patients treated with cyclosporine alone. Five partial responses were observed. Pharmacokinetic modulation of irinotecan with cyclosporine and phenobarbital has been demonstrated; further studies are necessary to evaluate whether this strategy improves the therapeutic index.
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U2 - 10.1016/j.clpt.2004.07.016
DO - 10.1016/j.clpt.2004.07.016
M3 - Article
C2 - 15536463
AN - SCOPUS:7944223784
SN - 0009-9236
VL - 76
SP - 490
EP - 502
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
IS - 5
ER -
