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© 2002 American Society for Clinical Oncology Modulation of Irinotecan Metabolism by KetoconazoleByFrom the Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek), University Hospital Rotterdam, the Netherlands. Address reprint requests to Alex Sparreboom, PhD, Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek), University Hospital Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands; email: sparreboom{at}onch.azr.nl
PURPOSE: 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. PATIENTS AND METHODS: A total of seven assessable patients was treated in a randomized, cross-over design with irinotecan (350 mg/m2 intravenously for 90 minutes) given alone and followed 3 weeks later by irinotecan (100 mg/m2) 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). CONCLUSION: 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.
THERE IS CONSIDERABLE motivation for understanding adverse drug interactions with anticancer agents because of their narrow therapeutic index and the numerous concomitant medications that are administered routinely or intermittently.1 Indeed, drug interactions, including those with anticancer agents, are a major cause of morbidity and mortality in modern medical practice,2 causing more than 100,000 deaths per year in the United States and making it between the fourth and sixth leading cause of death in 1994.1 Usually such interactions arise as a result of altered pharmacodynamics or pharmacokinetics of the drugs involved.3 In the latter case, this is usually due to changes in metabolic routes, and several mechanisms contributing to clinically important interactions have been identified, including expression of cytochrome P450 (CYP) isozymes. This class of enzymes, particularly the CYP3A4 isozyme, is responsible for the oxidation of more than 50% of all drugs currently administered to humans,4 resulting in more polar and usually pharmacologically inactive metabolites, which can be excreted efficiently by the kidneys and the liver. It is evident that anticancer substrate drugs given in combination with drugs that are efficiently metabolized by CYP3A4 are likely to result in serious toxicity. However, most of the data currently available to evaluate possible drug interactions with anticancer agents have been addressed by animal experiments or the use of test systems in vitro.4 In this study, we investigated the effect of CYP3A4 inhibition, using the model inhibitor ketoconazole,5 on the pharmacokinetics and toxicity profile of irinotecan (CPT-11), which is an important drug used in the treatment of colorectal cancer6 and a partial substrate of the CYP3A4 isozyme.7
Patients and Treatment Patients were eligible if they had a histologically confirmed diagnosis of metastatic colorectal cancer and proven progressive disease after first-line chemotherapy (with fluorouracil) or a malignancy for which there was no effective standard regimen. Additional eligibility criteria were identical as documented elsewhere.8,9 The original primary end point of the study was a measurable effect of ketoconazole on 7-ethyl-10-hydroxycamptothecin (SN-38) and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC) pharmacokinetics. Based on the SD of the changes expected in irinotecan disposition (sd), a power (1-ß) of 0.8 (80%), a clinically relevant difference (  ; standardized difference, 2/sd) of 30%, and a two-sided significance level ( ) of 0.01 (1%), a patient sample size of seven was required in a paired, two-sided analysis. The sd was estimated from an unpublished data set of 26 patients treated with irinotecan at 350 mg/m2 and the assumption of no variance increase as a result of ketoconazole coadministration. The Ethics Board of the Rotterdam Cancer Institute approved the protocol, and all patients signed informed consent before study entry. Patients screened and meeting study entry criteria were randomly assigned to receive either irinotecan alone (as a 90-minute intravenous infusion) at a dose of 350 mg/m2 and followed 3 weeks later by irinotecan at a dose of 100 mg/m2 given in combination with ketoconazole (200 mg) orally 1 hour before and 23 hours after the infusion of irinotecan, or both treatment cycles were given vice versa. A restricted randomization was performed to avoid bias in cycle sequence and to keep the number of patients close for both arms. This was achieved by choosing a randomized block at random using a table of random numbers to create the allocation sequence. Before drug administration, the clinical irinotecan formulation (Aventis Pharmaceuticals, Hoevelaken, the Netherlands) was diluted in 250 mL of isotonic sodium chloride. Patients received a standard regimen of ondansetron and dexamethasone therapy, both given 30 minutes before chemotherapy. Atropine (0.25 mg) was administered subcutaneously as a prophylaxis for irinotecan-induced acute cholinergic syndrome in case the patient experienced this side effect in the previous cycle. Physical examination and toxicity assessment were performed on a weekly basis, as were clinical chemistry tests, for both treatment cycles.
Pharmacologic Analysis Pertinent pharmacokinetic parameters, including peak concentration, area under the plasma concentration-time curve (AUC), total plasma clearance (defined as the ratio of dose administered in mg/m2 and AUC), the rate constant of the terminal disposition phase, and the half-life of the terminal disposition phase were calculated using a linear three-compartment model running on Siphar version 4.0 (InnaPhase, Philadelphia, PA).13 Metabolic ratios were calculated from plasma AUCs as well as urinary and fecal excretion data, as described previously.14 Previously, it has been shown that the AUC of irinotecan is dose-proportional over a large dose range (100 to 750 mg/m2) in the tested 3-week regimen with the drug administered as a 90-minute intravenous infusion, indicating a linear pharmacokinetic behavior.7 Similarly, irinotecan metabolite concentrations increase linearly with the dose, and metabolic ratios are dose-independent in this dose range.7 Therefore, values for total plasma clearance of irinotecan and the various metabolic ratios between the treatment courses with and without ketoconazole co-administration were compared directly without any correction. Plasma concentrations of ketoconazole were measured by reversed-phase HPLC with UV detection.15 Pharmacodynamic evaluation involved analysis of pretherapy and nadir values of WBC counts and absolute neutrophil counts as a function of treatment course expressed in absolute values (in 109/L) and in percent decrease relative to pretherapy values (eg, [pretherapy value - nadir value/pretherapy value] x 100%).
Enzyme Activity in Plasma
Hepatic Metabolism In Vitro
Drug Transport Assays
Statistical Considerations
Patients and Toxicity Profiles To determine the influence of CYP3A4 inhibition by ketoconazole on irinotecan pharmacokinetics and toxicity, a total of nine patients were accrued to the study. In two of nine patients, ketoconazole was only administered on day 1 in the combined schedule, and these patients were considered not assessable. Of the seven remaining patients, three were male and four were female, with a median age of 54 years old (range, 42 to 71 years) and a median performance score of 1 (range, 0 to 2). All patients completed the study within the scheduled time without delay. The predominant disease type was colorectal cancer (n = 5), and the principal toxicity consisted of neutropenia. Paired analysis of hematologic pharmacodynamic parameters indicated that the degree of myelosuppression, including the percent decrease in absolute neutrophil count, was similar between the courses, despite a 3.5-fold reduced irinotecan dose when given in combination with ketoconazole (Table 1). Nonhematologic toxicities (nausea, vomiting, and diarrhea) were observed on both arms but were also not substantially different in severity or incidence.
Irinotecan Disposition and Effects of Ketoconazole Because ketoconazole is a known potent inhibitor of CYP3A4, and given the prominent role of this enzyme in irinotecan metabolism, we assessed the influence of ketoconazole on disposition profiles (Table 2). The peak concentration of ketoconazole was 4.72 ± 2.53 µg/mL, and the AUC amounted to 15.4 ± 9.80 µg·h/mL, which is similar to previous findings.5 In the presence of ketoconazole, the relative exposure to the CYP3A4-mediated metabolite APC was reduced by 87% (P = .002), whereas the relative exposure to the pharmacologically active metabolite SN-38 increased by 109% (P = .004). The opposing effects of these metabolic routes on drug elimination left the systemic clearance of irinotecan almost unaffected (P = .90). Similarly, ketoconazole had no effect on circulating levels of SN-38G (P = .93), suggesting no effect on beta-glucuronidation pathways. The cumulative exposure to the total of all metabolites, on a molar basis and normalized to a 350-mg/m2 dose, was also not dependent on the presence of ketoconazole (13.7 ± 5.00 µM·h v 11.5 ± 4.50 µM·h; P = .65). In addition, the cumulative fecal excretion of irinotecan, expressed as the percentage of the absolute dose excreted in feces within the first 56 hours after drug administration, was not different in the presence or absence of ketoconazole (13.8% ± 15.9% v 19.5% ± 13.9%; P = .48). However, the fecal recovery of SN-38 was increased by 207%, and that of APC was reduced by 78.0%. The similarity of the terminal disposition phases in the plasma of these metabolites (Fig 1) between treatment courses indicates that the altered fecal excretion in the presence of ketoconazole is related to altered formation rather than diminished biliary secretion.
Ex Vivo Analysis of Esterase Activity in Patient Plasma To gain insight into the observed altered pharmacokinetic behavior of irinotecan in the presence of ketoconazole, various in vitro experiments were performed. The esterase activity in patient plasma, measured for 50 hours after irinotecan administration using the artificial substrate o-nitrophenyl acetate, was relatively consistent and independent of sampling time points, with mean values of 20.7 ± 1.58 µmol/min/mg and 20.9 ± 2.40 µmol/min/mg in the absence and presence of ketoconazole, respectively (P = .89).
Effect of Ketoconazole on SN-38 Metabolism by Human Liver Microsomes
Polarized Transport of SN-38 in Human Intestinal Cells The flux of irinotecan and SN-38 across Caco-2 cell monolayers when the drug was loaded on the apical side of the cells was essentially linear for up to 3 hours (Fig 2). In the presence of the P-glycoprotein/BCRP inhibitor GF120918, the Papp for the apical to basolateral transport increased from 3.6 x 10-6 to 7.0 x 10-6 cm/sec and from 3.6 x 10-6 to 9.7 x 10-6 cm/sec for irinotecan and SN-38, respectively, consistent with the known prominent role of P-glycoprotein and BCRP activity in SN-38 transport.26 With ketoconazole, the flux of irinotecan and SN-38 was increased by 47.2% (Papp, 5.3 x 10-6 cm/sec) and 55.6% (Papp, 5.6 x 10-6 cm/sec), respectively, whereas the addition of ketoconazole to GF120918 had essentially no additional effect as compared with GF120918 alone (irinotecan; Papp, 6.2 x 10-6 cm/sec; SN-38; Papp, 8.0 x 10-6 cm/sec). Because Caco-2 cells fail to express significant CYP3A4 activity under the culture conditions used,24 the most likely explanation for the observed effect on drug transport is inhibition of P-glycoprotein activity, a known property of ketoconazole.27
This study shows that inhibition of CYP3A4 by the potent enzyme inhibitor ketoconazole results in a substantial pharmacokinetic interaction with irinotecan. The overall results indicate a significantly reduced exposure to the principal oxidative metabolite APC by 87%, as well as highly increased (approximately 109%) circulating concentrations of the pharmacologically active metabolite SN-38. These data not only emphasize the need to consider the plausibility of kinetic interactions in the development of anticancer drugs, but also have a direct significant clinical relevance for chemotherapeutic treatment with irinotecan. Clinically, one of the most important pathways of irinotecan elimination consists of an esterase-mediated hydrolysis of the bipiperidine moiety, leading to SN-38 (considered essential for antitumor activity).7 Subsequently, UDP glucuronosyltransferase 1A1 (UGT1A1) mediates a beta-glucuronic-acid conjugation, forming SN-38G,7 a metabolite that may play a role as a precursor for hydrolysis by intraluminal glucuronidases to form SN-38 in the occurrence of irinotecan-induced diarrhea.28 The previous recognition that irinotecan is a substrate of CYP3A4 is a salient finding because it makes the agent potentially subject to a host of enzyme-mediated drug interactions, even with commonly prescribed medication.18 For example, the prototypical CYP3A4 inhibitor troleandromycine inhibits the conversion of irinotecan into APC in vitro almost completely,18 which is consistent with our current in vivo findings (see http://www.drug-interactions.com for an updated CYP drug interaction table). In addition, both loperamide and racecadotril inhibit APC formation by more than 50%, whereas ondansetron causes inhibition by more than 25%,18 suggesting that some degree of interaction is to be expected with simultaneous administration of these agents with irinotecan. The potential clinical implications of CYP3A4-mediated metabolism of irinotecan have until now received little more than cursory interest from both pharmacologists and oncologists, most likely because the contribution of this pathway to the overall elimination of irinotecan is rather low10 and in view of the fact that oxidative metabolism of irinotecan is generally considered an efficient detoxification route.18 Previously, it was demonstrated that co-administration of irinotecan with another substrate of CYP3A4, cyclosporine, results in significantly reduced irinotecan clearance in both rodents and humans.29,30 There was no change in the volume of distribution at steady-state (indicative for unchanged protein and tissue binding) and in the metabolic conversion of irinotecan to SN-38 because of the cyclosporine pretreatment, implicating reduced biliary secretion of the parent drug as the potential cause for this interaction.29 The current observation that inhibition of CYP3A4-mediated metabolism of irinotecan by ketoconazole leads to an induced esterase-mediated hydrolysis to form SN-38 was thus rather unexpected, and to discriminate between increased formation and reduced elimination of SN-38 as the principal mechanism underlying this phenomenon, several additional in vitro experiments were performed. By measuring the total esterase activity in the plasma of patients, ketoconazole was found to have no inducing effect on circulating enzyme levels that might explain the increase in relative exposure to SN-38. However, these data need to be interpreted with caution because it has not yet been conclusively demonstrated that the plasma hydrolysis of the artificial substrate used (o-nitrophenyl acetate) is an accurate marker of irinotecan activation. Moreover, it is not known whether o-nitrophenyl acetate is a substrate for either of the two currently identified human carboxylesterase isoforms31 or whether plasma enzyme activity correlates with hepatic activity, which may be more relevant to the plasma pharmacokinetics. We found that ketoconazole had no effect on SN-38 biotransformation in human liver microsomes, in contrast to a previous observation suggesting prominent CYP3A4-mediated oxidation of SN-38 to a polar, currently unidentified compound.23 Our in vitro data obtained in the Caco-2 cell monolayers suggest that ketoconazole might interfere with active drug transport mediated by P-glycoprotein, which is consistent with previous observations that ketoconazole is a (poor) inhibitor of P-glycoprotein.27 In our patients, we observed that co-administration with ketoconazole had a marked effect on the fecal elimination of both APC and SN-38. However, the similarity of the terminal disposition phases in plasma of both metabolites between treatment courses indicates that the increased fecal excretion of SN-38 in the combination courses is unlikely related to diminished (P-glycoprotein-mediated) biliary secretion. Collectively, these findings suggest that the pharmacokinetic interference described here seems to be the result of inhibition of one of two competing enzymes involved in (hepatic) irinotecan metabolism, which results in shunting of parent drug to SN-38. As mentioned previously, various classes of enzymes are involved in irinotecan metabolism, and variability in the expression of each of these will contribute to variability in drug handling between patients. In addition, this variability is further influenced by the recognition that polymorphic drug-metabolizing enzymes (eg, UGT1A1) exist that can alter drug disposition.32 Recent studies have shown that determination of UGT1A1-gene promotor polymorphism (UGT1A1*28) may identify patients with altered SN-38 glucuronidation rates and greater susceptibility to irinotecan-induced toxic effects.33,34 In view of our current observation that CYP3A4-mediated metabolism of irinotecan might be more important than held previously, we have recently initiated a prospective trial to corroborate the usefulness of gene diagnosis of UGT1A1 in combination with CYP3A4 polymorphism before irinotecan chemotherapy. In addition, because CYP3A5 represents at least 50% of the total hepatic CYP3A content in people polymorphically expressing CYP3A5, this isozyme may be the most important genetic contributor to interindividual and interracial differences in CYP3A-dependent drug clearance and in responses to many agents.35 In this context, however, it is of particular importance that recent data indicate that the in vitro metabolism of irinotecan by Ad 293 cells or human liver microsomes expressing CYP3A5 was markedly different because, in contrast to kinetic studies performed in cells expressing CYP3A4, instead of APC, a new metabolite was formed by de-ethylation of the camptothecin moiety.36 The production of this metabolite was totally absent from incubations with microsomes devoid of CYP3A5 and was almost completely prevented in vitro by the addition of ketoconazole, confirming the involvement of CYP3A isozymes. Importantly, the catalytic activity and the relative affinity of irinotecan for CYP3A5 were substantially weaker than those of CYP3A4.36 This finding, as well as the polymorphic expression of CYP3A5 suggest that the de-ethylated metabolite plays a minor role in irinotecan disposition, and that effects of ketoconazole on CYP3A5 have no important clinical ramifications in this particular case. Clinically we found that hematologic toxicity and nonhematologic toxicity between the treatment courses were similar despite the reduced irinotecan dose in the presence of ketoconazole, which might be explained by the increased exposure to SN-38. Previously, the idea of intentionally adding ketoconazole to systemic treatment with CYP3A4 substrate drugs (eg, cyclosporine) for the purpose of decreasing toxicity and costs through a reduction in dosage regimens has been advanced.37 However, before taking advantage of the metabolic interaction between ketoconazole and irinotecan described here to supply the two drugs as a unique preparation for clinical use, a number of important questions needs to be solved. Most importantly, it is not yet known whether systemic circulating concentrations of SN-38 have any predictive ability toward antitumor activity. In fact, recent data from a study of irinotecan administered in combination with cyclosporine (a competitive inhibitor of CYP3A4) and phenobarbital (an inducer of UGT1A1) suggest responses to treatment in patients with metastatic colorectal and esophageal cancer without any significant diarrhea, despite a low exposure to SN-38.38 This finding supports the hypothesis that intratumoral hydrolysis of irinotecan by a carboxylesterase may be more important than plasma concentrations of SN-38.39,40 This suggests that the concept of using intentional CYP3A4-mediated interactions with irinotecan therapy may increase toxicity but not the overall antitumor activity. In conclusion, ketoconazole considerably increased the plasma concentrations of the pharmacologically active irinotecan metabolite SN-38 relative to those expected on the basis of dose as a result of inhibition of CYP3A4-mediated biotransformation. With concomitant use of irinotecan and ketoconazole (or other potent substrates or inhibitors of CYP3A4), potentially fatal interactions are likely, and extreme caution and substantial dose reductions should be used if both drugs have to be administered together.
We thank Sharyn Baker, PharmD, and Phil Potter, PhD, for help with the plasma carboxylesterase assay; Glaxo Wellcome for providing GF120918; and Walter Loos, PhD, and Kees Nooter, PhD, for their suggestions.
Presented, in part, at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications, Miami Beach, FL, October 29 to November 2, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
Q/
