Modulation of irinotecan metabolism by ketoconazole.
OBJECTIVE
Irinotecan (CPT-11) is a prodrug of SN-38 and has been registered for the treatment of advanced colorectal cancer. It is converted by the cytochrome P450 3A4 isozyme (CYP3A4) into several inactive metabolites, including 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC). To investigate the role of CYP3A4 in irinotecan pharmacology, we evaluated the consequences of simultaneous treatment of irinotecan with a potent enzyme inhibitor, ketoconazole, in a group of cancer patients.


METHODS
A total of seven assessable patients was treated in a randomized, cross-over design with irinotecan (350 mg/m(2) intravenously for 90 minutes) given alone and followed 3 weeks later by irinotecan (100 mg/m(2)) in combination with ketoconazole (200 mg orally for 2 days) or vice versa. Serial plasma, urine, and feces samples were obtained up to 500 hours after dosing and analyzed for irinotecan, metabolites (7-ethyl-10-hydroxycamptothecin [SN-38], SN-38 glucuronide [SN-38G], and APC), and ketoconazole by high-performance liquid chromatography.


RESULTS
With ketoconazole coadministration, the relative formation of APC was reduced by 87% (P =.002), whereas the relative exposure to the carboxylesterase-mediated SN-38 as expected on the basis of dose (area under the plasma concentration-time curve normalized to dose) was increased by 109% (P =.004). These metabolic alterations occurred without substantial changes in irinotecan clearance (P =.90) and formation of SN-38G (P =.93).


CONCLUSIONS
Inhibition of CYP3A4 in cancer patients treated with irinotecan leads to significantly increased formation of SN-38. Simultaneous administration of various commonly prescribed inhibitors of CYP3A4 can potentially result in fatal outcomes, and up to four-fold reductions in irinotecan dose are indicated.
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek), University Hospital Rotterdam, The Netherlands.
Diederik F S
DF
Kehrer
Ron H J
RH
Mathijssen
Jaap
J
Verweij
Peter
P
de Bruijn
Alex
A
Sparreboom
D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D000077146:Irinotecan; D007654:Ketoconazole / Q000008:administration & dosage / Q000494:pharmacology*; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000935:Antifungal Agents; D000972:Antineoplastic Agents, Phytogenic; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011355:Prodrugs; D000077146:Irinotecan; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole; D002166:Camptothecin