Modulation of Irinotecan Metabolism by Ketoconazole

Kehrer, Diederik F.S.; Mathijssen, Ron H.J.; Verweij, Jaap; Bruijn, Peter de; Sparreboom, Alex

doi:10.1200/jco.2002.08.177

Cited by 117 publications

(65 citation statements)

References 20 publications

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“…However, a possible explanation would be the fact that R115777 is known to inhibit CYP3A4 activity in human hepatic microsomal preparations, albeit at in vitro concentrations that are five-fold higher than the peak concentrations observed in the present study (Bohets, 1998). Previous investigations have shown that inhibition of CYP3A4 in patients on irinotecan treatment leads to shunting of parent drug to esterase-mediated hydrolysis to form SN-38 (Kehrer et al, 2002). The notion that the primary CYP3A4-mediated irinotecan metabolite APC is formed out of the carboxylate form of irinotecan (Xie et al, 2002), the pharmacokinetics of which are affected most, lends further support to a prominent role of CYP3A4 in the metabolism of irinotecan.…”

Section: Discussionmentioning

confidence: 75%

Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor

et al. 2004

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The aims of this study were to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of irinotecan given with oral R115777 (tipifarnib), a farnesyl protein transferase inhibitor. Patients were treated with escalating doses of irinotecan with interval-modulated dosing of R115777 (continuously or on days 1 -14, and repeated every 21 days). In total, 35 patients were entered onto the trial for a median duration of treatment of 43 days (range, 5 -224 days). Neutropenia and thrombocytopenia were the dose-limiting toxicities; other side effects were mostly mild. The MTD was established at R115777 300 mg b.i.d. for 14 consecutive days with irinotecan 350 mg m À2 given every 3 weeks starting on day 1. Three patients had a partial response and 14 had stable disease. In the continuous schedule, the area under the curves of irinotecan and its active metabolite SN-38 were 20.0% (P ¼ 0.004) and 38.0% (Po0.001) increased by R115777, respectively. Intermittent dosing of R115777 at a dose of 300 mg b.i.d. for 14 days every 3 weeks is the recommended dose of R115777 in combination with the recommended single-agent irinotecan dose of 350 mg m À2 .

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Section: Discussionmentioning

confidence: 75%

Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor

et al. 2004

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“…We retrospectively studied records from patients participating to various prospective clinical trials on CPT-11 in which pharmaco-kinetic monitoring was involved; the full clinical profiles are documented elsewhere (Kehrer et al, 2000(Kehrer et al, , 2001a(Kehrer et al, , 2002. All patients had a histologically or cytologically confirmed malignant solid tumour for which CPT-11 was considered to be a treatment option.…”

Section: Patients and Treatmentmentioning

confidence: 99%

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

et al. 2002

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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 (P50.001). 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 =(6.5886C 2.5 h )+(146.46C 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. Irinotecan (CPT-11) belongs to the family of camptothecins, and is a member of the class of topoisomerase I inhibitors. A broad spectrum of anti-tumour activity was seen in preclinical models as well as in patients, with responses observed in various disease types, including colorectal, lung, cervical, and ovarian cancers (Mathijssen et al, 2001;Vanhoefer et al, 2001). CPT-11 is a prodrug that requires activation to the active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), which is approximately 100-to 1000-fold more active than the parent drug (Hertzberg et al, 1989). A host of enzymes, including carboxylesterases to form SN-38 (Humerickhouse et al, 2000), UDP glucuronosyltransferases mediating SN-38 glucuronidation to form the b-glucuronic acid conjugate, SN-38G, (Iyer et al, 1998), intestinal and endogenous b-glucuronidases causing deconjugation of SN-38G (Sparreboom et al, 1998; Slatter et al, 2000), as well as cytochrome P-450 isoforms (Haaz et al, 1999;Santos et al, 2000) to form APC and NPC are involved in CPT-11 metabolism. In addition, several drug-transporting proteins, notably a canalicular multispecific organic anion transporter (cMOAT) located on the bile canalicular membrane (Chu et al, 1998), and P-glycoprotein (Chu et al, 1999), can influence CPT-11 elimination through hepatobiliary secretion and intestinal (re-)absorption.As a result of these (and probably also other presently unknown) mechanisms, CPT-11 and its metabolites are subject to large interindividual kinetic variability (Mathijssen et al, 2002a), and show relatively long disposition half-lives. We have recently shown that by applying an extended sampling-time period of 500 h, the circulation time of SN-38 in cancer patients was found to be substantially longer than held previously (Kehrer et al, 2000). We hypothesised that, because of the poorly defined relationships between pharmacokinetic parameters and pharmacodynamic outcome of CPT-11 treatment (Mathijssen et al, 2001), ...

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“…It is a prodrug of the active metabolite, SN-38, and is converted by the CYP3A4 enzyme into several inactive metabolites. Recently, Kehrer et al demonstrated that concomitant administration of irinotecan with ketoconazole, an inhibitor of CYP3A4, causes alteration in the metabolism of irinotecan [156]. They showed that ketoconazole considerably increased the plasma concentrations of SN-38 as a result of inhibition of CYP3A4-mediated biotransformation.…”

Section: Modulation Of the Pharmacokinetics Of Irinotecanmentioning

confidence: 99%

Improvement of Oral Drug Treatment by Temporary Inhibition of Drug Transporters and/or Cytochrome P450 in the Gastrointestinal Tract and Liver: An Overview

2002

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The oral bioavailability of many cytotoxic drugs is low and/or highly variable. This can be caused by high affinity for drug transporters and activity of metabolic enzymes in the gastrointestinal tract and liver. In this review, we will describe the main involved drug transporters and metabolic enzymes and discuss novel methods to improve oral treatment of affected substrate drugs. Results of preclinical and clinical phase I and II studies will be discussed in which affected substrate drugs, such as paclitaxel, docetaxel, and topotecan, are given orally in combination with an inhibitor of drug transport or drug metabolism. Future randomized studies will, hopefully, confirm that this strategy for oral treatment is at least as equally effective and safe as standard intravenous administration of these drugs. The Oncologist 2002;7:516-530

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Modulation of Irinotecan Metabolism by Ketoconazole

Cited by 117 publications

References 20 publications

Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor

Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor

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

Improvement of Oral Drug Treatment by Temporary Inhibition of Drug Transporters and/or Cytochrome P450 in the Gastrointestinal Tract and Liver: An Overview

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