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© 2002 American Society for Clinical Oncology Dosage Adjustment and Pharmacokinetic Profile of Irinotecan in Cancer Patients With Hepatic DysfunctionByFrom the Department of Medicine, Gustave Roussy Institute, Villejuif, and Aventis Pharma, Vitry-sur-Seine, France. Address reprints requests to Eric Raymond, MD, PhD, Department of Medicine, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France; email: raymond{at}igr.fr
PURPOSE: To determine the recommended dose (RD) and the pharmacokinetic profile of irinotecan and its metabolites in cancer patients with hyperbilirubinemia. PATIENTS AND METHODS: Patients were assigned to four treatment groups according to their baseline total bilirubin level. Patients in group I (bilirubin within normal range) and group II (bilirubin 1.0 to 1.5 times upper limit of normal [ULN]) received a dose of 350 mg/m2 every 3 weeks. Patients in groups III (bilirubin 1.51 to 3.0 times ULN) and IV (bilirubin > 3.1 times ULN) received starting doses of 175 and 100 mg/m2, respectively. RDs were defined according to the dose-limiting toxicity (DLT) experienced at cycle 1. RESULTS: Thirty-three patients including 21 gastrointestinal cancers were included. Grade 4 febrile neutropenia and diarrhea were common DLTs in patients with hyperbilirubinemia. At a dose of irinotecan 350 mg/m2, DLTs were observed in two of seven and one of five patients in groups I and II, respectively. In group III, escalated doses of irinotecan 175, 200, and 240 mg/m2 were associated with DLTs in one of seven, one of five, and three of six patients, respectively. No DLT was observed in group IV. High bilirubin and alkaline phosphatase levels were associated with an exponential decrease in the clearance of irinotecan. Pharmacokinetic analysis showed that the relative increase in exposure was likely caused by reduced biliary excretion.
CONCLUSION: We showed that baseline total bilirubin level could be used to determine the appropriate dose of irinotecan in cancer patients with hepatic dysfunction. Doses of 350 mg/m2 and 200 mg/m2 were considered RDs in patients with bilirubin values
IRINOTECAN IS A broad-spectrum anticancer drug1-3 with dose-limiting toxicities (DLTs) that consist of early onset of cholinergic syndrome, late diarrhea, and febrile neutropenia.4 On the basis of large randomized clinical trials that demonstrated significant survival benefits of irinotecan (350 mg/m2 administered as a 30- to 90-minute intravenous infusion every 3 weeks) either alone or in combination with fluorouracil, irinotecan was accepted in several countries as first-line5,6 or second-line chemotherapy7,8 for the treatment of patients with colorectal cancer using both weekly and every-3-week regimens. The DLTs appear to be schedule-dependent, with less frequent cholinergic and hematologic toxicity but more frequent late diarrhea with the weekly regimen as compared with the every-3-week schedule.5-8 In humans, irinotecan is mainly eliminated unchanged by the liver and to a minor extent by the kidneys.9-12 Irinotecan has two main metabolic pathways that predominantly take place in the liver (Fig 1); it can be converted into inactive metabolites (APC and NPC) by the CYP3A4 isoenzyme13,14 and into an active metabolite, SN-38, by carboxylesterase enzymes.15 The relationship between the pharmacokinetics of irinotecan, SN-38, and the incidence of toxicity is complex, with reports suggesting a correlation between the plasma concentration of SN-38 and diarrhea in mice and in humans.16-18 SN-38 is further metabolized through conjugation into SN-38 glucuronide (SN-38-G) by uridine diphosphate glucuronosyltransferase (UGT-1A1), the same isoenzyme responsible for glucuronidation of bilirubin.19 An inverse relationship between SN-38 glucuronidation rates and severity of diarrhea has been reported, indicating that glucuronidation of SN-38 might protect against irinotecan-induced gastrointestinal toxicity. In addition, the occurrence of severe neutropenia and diarrhea has been reported in patients with various degrees of deficiency in the UGT-1A1 activity (Gilbert’s syndrome).20,21 Furthermore, baseline total bilirubin level has been shown to predict the likelihood of severe neutropenia and diarrhea in irinotecan-based chemotherapy.16,19 These results suggest either competition between SN-38 and bilirubin for the UGT-1A1 enzyme or a delay in the biliary excretion of the drug. In both cases, these demonstrate the importance of liver function in the detoxification and excretion of irinotecan and its metabolites.
About 60% of patients with colorectal carcinoma develop liver metastasis with various degrees of hepatic dysfunction caused by liver involvement and/or biliary obstruction. Hepatic dysfunction mainly consists of abnormal biologic liver tests reflecting chronic cholestasis with elevation in the levels of bilirubin, alkaline phosphatase (ALP), and gamma glutamyl transferase (GGT) with or without abnormal levels of AST and/or ALT.22 The impact of hepatic dysfunction on the toxicity and pharmacokinetic profile of irinotecan and its metabolites has been poorly studied and, although case reports have been published,23,24 no dose recommendations are currently available. Therefore, this study was designed to identify the recommended dose and the pharmacokinetic profile of irinotecan in cancer patients presenting with varying degrees of hepatic dysfunction.
Inclusion Criteria Eligibility criteria were as follows: histologically proven solid tumor resistant to conventional treatments; age  18 years; World Health Organization performance status  2; adequate bone marrow function (leukocyte count 4.0 x 109/L, hemoglobin 10 g/dL, absolute neutrophil count 2.0 x 109/L, and platelet count 100 x 109/L); serum creatinine values the upper limit of normal [ULN]); no chemotherapy, hormone, or radiation therapy within 4 weeks before irinotecan (6 weeks for previous treatment with nitrosourea, mitomycin, or radiotherapy); no intercurrent or history of heart failure, respiratory failures, uncontrolled diabetes, severe infection, chronic enteropathy, occlusive and subocclusive bowel syndrome, cerebral metastasis, and psychiatric disorders; no chemotherapy with irinotecan within 6 months of the start of the study; no concomitant experimental new drugs; and signed informed consent according to institutional and national guidelines. Additional criteria excluded patients with severe hepatic dysfunction: prothrombin time (PT) less than 50% and activated partial thromboplastin time within normal limits; AST and/or ALT levels more than 20 times ULN; active hepatitis C or human immunodeficiency virus serology; and clinical signs indicating hepatic encephalopathy (drowsiness, confusion, and asterixis).
Pretreatment and Follow-Up Examinations
Treatment Procedures Irinotecan (5-mL ready-to-use vials containing 100 mg of CPT-11) was diluted in 250 mL (0.9% NaCl) and given as a 30-minute intravenous infusion every 21 days. Patients in groups I and II received 350 mg/m2 irinotecan (recommended by previous trials25). In group III, the starting dose of irinotecan was 175 mg/m2, with subsequent dose escalation to 240 or 350 mg/m2. The starting dose of 100 mg/m2 selected for patients in group IV was determined on the basis of the toxicity and pharmacokinetic results obtained from patients in group III.
In the event of cholinergic syndrome, subcutaneous injection of atropine sulphate 0.25 mg was administered and then given preventively for subsequent cycles. Ondansetron or granisetron could be given preventively for nausea and vomiting. Delayed diarrhea was treated with loperamide (administered at the first occurrence of liquid stool) at a dose of one capsule every 2 hours for at least 12 hours, and for a further 12 hours after the last occurrence of diarrhea. Prophylactic use of loperamide was not permitted. If vomiting or fever (
Follow-Up and Dose Escalation Procedures
Patients in groups I and II were enrolled simultaneously. For groups III and IV, a minimum of three patients per group were initially included at each dose level. An interval of 3 weeks was required between the enrollment of the first and the second patients, followed by a 2-week interval for subsequent patients at each dose level. If a DLT was observed in zero of three patients or Tumors were evaluated and/or measured at baseline and reassessment at every other course using World Health Organization standard criteria. To be considered assessable for activity, a patient had to have received a minimum of two cycles (unless early progression occurred).
Pharmacokinetic Analysis Quantitative analysis of total, lactone, and carboxylate forms of irinotecan and its metabolites (SN-38, SN-38-G, and APC) was performed using reverse-phase high-performance liquid chromatography with fluorescence detection.25,26 The limit of quantitation was 10 ng/mL for irinotecan and 2.5 ng/mL for SN-38. The binding of metabolite SN-38 to plasma proteins was assessed for each patient using the plasma sample collected at the end of the intravenous infusion and was assessed by an equilibrium dialysis technique. Maximum plasma concentration, area under the plasma concentration-time curve (AUC), terminal half-life, and metabolic AUC ratio (SN-38/irinotecan, SN-38-G/SN-38, and APC/irinotecan) were determined by noncompartmental analysis using WinNonlin software (Scientific Consulting, Inc, Cary, NC). Total body clearance and volume of distribution at steady-state were also calculated for irinotecan.
Statistical Analysis
Patient Characteristics Thirty-three patients were enrolled onto this study. Baseline patient characteristics are listed in Table 1. Treatment groups were comparable with respect to demographic and pretreatment characteristics. Thirty patients had received previous chemotherapy (median number of prior chemotherapy regimens, two; range, zero to seven) including fluorouracil in 23 patients and cisplatin in 21 patients. Thirty patients (91%) had hepatic involvement with liver metastasis at study entry. No patient had a biliary tract obstruction with dilatation that required endoscopic or transhepatic biliary drainage. The profile of hepatic abnormalities was typical of chronic cholestasis caused by liver metastasis (characterized by abnormal baseline bilirubin, ALP, GGT, and/or AST/ALT levels). None of the patients had an isolated hyperbilirubinemia that would have suggested Gilbert’s syndrome. Baseline albumin values were normal in all patients. The distribution of laboratory values in each group is listed in Table 1.
All the patients completed at least one cycle of treatment and were assessable for toxicity and determination of the MTD. Seven instead of six patients were entered onto groups I and III (175-mg/m2 dose level). One patient initially assigned to group II had a further increase in baseline bilirubin at the time of treatment and was reassigned to group III. Another patient assigned to group II had a decreased baseline bilirubin value and was reassigned to group I. A total of 97 cycles of treatment were administered. The median number of cycles received per patient was two (range, one to six). Nine deaths occurred during the study; none of these were related to study medication. Reasons for treatment discontinuation are listed in Table 2.
MTD and Recommended Doses at Cycle 1 Two patients in group I and one patient in group II experienced a DLT after receiving irinotecan 350 mg/m2 (Table 2). This confirmed that the dose of 350 mg/m2 could be recommended in patients with bilirubin values 1.5 times ULN. In group III, at the dose of 175 mg/m2, one of seven patients experienced a DLT consisting of febrile grade 4 neutropenia. Therefore, dose escalation was permitted to continue to irinotecan 240 mg/m2. At this dose, three of six patients experienced DLTs at cycle 1 consisting of grade 4 diarrhea (one patient) and grade 4 neutropenia (two patients). At this dose level, a total of five patients required dose reduction and three patients had treatment delay at subsequent cycles (relative dose-intensity, 0.80; range, 0.76 to 0.98), suggesting that this dose level could not be safely recommended. On the basis of these data, we decided to subsequently explore an intermediate dose of irinotecan 200 mg/m2 (dose between 175 and 240 mg/m2). At this dose, one of five patients experienced a grade 4 febrile neutropenia that required dose reduction. Considering the slow accrual in this population, it was decided to stop the dose exploration without including a sixth patient at this dose. A total of 10 cycles were given at the dose of 200 mg/m2 without any dose reduction or treatment delay for DLT during the first two cycles (relative dose-intensity, 1.0; range, 0.68 to 1.0). This suggested that this dose was suitable for patients with bilirubin values ranging from 1.5 to 3.0 times ULN. Patients in group IV received only one cycle of treatment at the dose of 100 mg/m2 during which no DLT was observed. Most patients in this group experienced rapid hepatic tumor progression associated with aggravation of liver dysfunction and worsening of performance status. In group IV, dose escalation was not carried out for ethical reasons and no dose recommendation was possible.
Hematologic Toxicity
Nonhematologic Toxicity As expected, the most frequent nonhematologic toxicities were acute cholinergic syndrome and delayed diarrhea. No unexpected toxicity related to treatment with irinotecan was reported. Grade 1/2 cholinergic syndrome occurred in 18 patients and 30% of cycles. Grade 3/4 cholinergic syndrome was observed in only four patients (two, zero, one, and one patient in groups I, II, III, and IV, respectively) and in 4% of cycles. Atropine was efficient to treat irinotecan-related cholinergic syndromes. Eighteen patients (50.5% of cycles) experienced delayed grade 1/2 diarrhea. Grade 3/4 diarrhea was observed in two patients in group I, one patient in group II, and two patients in group III (only at the higher irinotecan dose of 240 mg/m2). Treatment with loperamide was sufficient to treat delayed diarrhea in both groups. Grade 1 and 2 nausea-vomiting were reported in 17 and 16 patients, respectively. Grade 3/4 vomiting was reported in two patients and 3% of cycles. Grades 1/2 and 3/4 anorexia was reported in five patients and one patient, respectively. Grade 1/2 asthenia was observed in 10 patients, with grade 3/4 asthenia occurring in only three patients and in 2% of cycles. Ten patients experienced a worsening of hepatic dysfunction that was associated with documented tumor progression of the underlying cancer and was not considered to be related to irinotecan toxicity.
Pharmacokinetics Pharmacokinetic profiles of irinotecan and its metabolites are shown in Fig 2. Mean AUC ratios of lactone versus total irinotecan were 0.26 ± 0.10 (coefficient of variation [CV], 39%) and 0.22 ± 0.11 (CV, 50%) in groups II and III, respectively. Mean AUC ratios of lactone versus total SN-38 were 0.66 and 0.74 ± 0.3 (CV, 40%) in groups II and III, respectively.
Table 4 and Fig 3 show the pharmacokinetic profile for irinotecan and its main metabolites. Mean SN-38 protein binding was 94.7% ± 2.1%, 92.3% ± 1.0%, 94.4% ± 2.2%, and 96.1% ± 0.2% in groups I, II, III, and IV, respectively (P = .25). Renal excretions of irinotecan and SN-38 were about 15% and 0.3% of the total dose and similar across the groups, respectively. Renal excretions of SN-38-G and APC were not measured.
As shown in Fig 4, clearance of irinotecan was reduced across all groups of patients with hyperbilirubinemia. Hyperbilirubinemia was associated with an exponential decrease in irinotecan clearance (Fig 5). Above 40 µmol/L bilirubin, the clearance leveled off to a minimum value around 5 L/h/m2 (range, 4 to 6 L/h/m2). Other hepatic parameters that appeared well correlated with the clearance of irinotecan were ALP and GGT (Fig 5), whereas AST, ALT, albumin, and PT showed no significant correlation (P > .1). SN-38, SN-38-G, and APC showed also an increase in dose-normalized AUCs with increasing bilirubin levels (Fig 6).
Response In this heavily pretreated population, one partial response occurred in a patient treated in group I. Fourteen patients (42.4%) had stable disease and 14 patients (42.4%) had tumor progression.
Irinotecan demonstrated activity in patients with advanced colorectal cancer4-8 at the dose of 350 mg/m2 in patients with 1.5 times ULN baseline bilirubin.4,9 Because of liver metastasis, many patients with gastrointestinal cancers present with various degrees of hyperbilirubinemia,22 but no dose recommendation has been established for irinotecan in patients with bilirubin values more than 1.5 times ULN. Because chronic cholestasis is frequently observed in patients with liver metastasis, total bilirubin at baseline was considered the most representative biologic parameter of a clinical situation in which a dose adjustment of irinotecan would be required. In this study, we observed that baseline bilirubin levels vary with time and need to be analyzed immediately before drug infusion to assign patients to the appropriate dose of irinotecan. In our study, all patients with hyperbilirubinemia had concomitant liver metastases and/or liver tumor involvement. In six cases of hepatocellular carcinoma, hepatic dysfunction was related to either direct tumor invasion and/or the underlying liver cirrhosis (no active viral B or C hepatitis). However, no patient had evidence of liver insufficiency and/or Child-Pugh scores B or C uncompensated cirrhosis. At study entry, all the patients with elevated bilirubin levels had concomitant elevations of GGT, APL, and/or transaminases, excluding the possibility of patients with sole concomitant Gilbert’s disease.
This study together with previous trials4-7 shows that irinotecan 350 mg/m2 was an appropriate dose in patients with bilirubin In group III, the pattern of DLT and severity of other toxicities were similar to those in group I. In this group of patients, the recommended dose of irinotecan 200 mg/m2 was proposed. Similar mean AUCs for the lactone and carboxylate forms of irinotecan and SN-38 suggest that group III patients (receiving irinotecan 200 mg/m2) were exposed to equivalently active concentrations of irinotecan and SN-38 than group I patients with only one DLT at cycle 1 (median dose-intensity of about 100%). Although a limited number of patients were treated in group III at the 200-mg/m2 dose level, the recommended 44% decrease in dose is in agreement with the overall 40% decrease in clearance in all 16 patients in group III (Fig 3 and Table 4). On the basis of data provided in this study, no recommendation can be made for patients receiving schedules other than the every-3-week regimen. In this study, only three patients with bilirubin values greater than three times ULN were treated at the initial dose of 100 mg/m2. Because those three patients experienced rapid tumor progression, it was considered unethical to continue the dose escalation, and no treatment recommendation was established in this group. Pharmacokinetic data showed moderate interpatient variability in terms of maximum plasma concentration and AUC for irinotecan and a high variability for SN-38 and other metabolites across the groups. Our pharmacokinetic data are consistent with previous studies.11 Plasma albumin levels could have changed free SN-38 concentrations through two mechanisms, that is, change in total number of binding sites and shift in the lactone/carboxylate ratio because of their different affinity constants. However, lactone/carboxylate interconversion and binding of the two entities to albumin are all reversible reactions, and in our view this does not prevent an overall equilibrium to be attained in the assay. Achievement of a steady-state equilibrium of lactone/carboxylate forms of several camptothecin derivatives (including CPT-11 and SN-38) in the presence of human serum albumin was previously reported by Burke and Mi.27
Interestingly, hyperbilirubinemia was associated with an increase in the dose-normalized AUCs of irinotecan, SN-38, and other metabolites associated with an exponential decrease in the clearance of irinotecan. For bilirubin values In groups II to IV, increase in relative SN-38 exposure could occur from either increased formation or decreased elimination. Because SN-38-G and APC showed also an increase in dose-normalized AUCs with increasing bilirubin levels, the hepatic metabolism of irinotecan by UGT-1A1 and CYP3A4 isoenzymes appeared to remain functional in patients with hyperbilirubinemia. Therefore, the decrease in irinotecan clearance in this study was most likely caused by reduced biliary clearance brought about by cholestasis. Although this study could not directly address the efficacy of irinotecan, evidence of minor responses and tumor stabilization was observed in groups I to IV, confirming that antitumor activity could be maintained despite dose adjustments of irinotecan.23 In summary, the dose of irinotecan 350 mg/m2 every 3 weeks can be recommended for group I and group II patients. For group III and group IV patients, a significant increase in the dose-normalized exposure to both irinotecan and its active metabolite SN-38 was observed, with an exponential decrease in the clearance of irinotecan. Therefore, a dose reduction of irinotecan was required in these groups. The dose recommended for group III patients was irinotecan 200 mg/m2 every 3 weeks.
E.R. and V.B. contributed equally to this work and should be considered as joint first authors. We thank P. Dielenseger, M. Granier, and D. Leleu for their contribution to the pharmacokinetic sampling of this study; Jean-Claude Vergniol for bioanalytical sample analysis; Françoise Bree for unbound drug analysis; and Patrica Lefebvre and Colette Guimart for their contribution to pharmacokinetic analysis. We also thank Aliette Hua and Souad Mekhaldi for their participation in collecting the data.
1. Jaxel C, Kohn KW, Wani MC, et al: Structure-activity study of the actions of camptothecin derivatives on mammalian topoisomerase I: Evidence for a specific receptor site and relation to antitumor activity. Cancer Res 49: 1465-1469, 1989 2. Bissery MC, Vrignaud P, Lavelle F, et al: Preclinical antitumor activity and pharmacokinetics of irinotecan (CPT-11) in tumor-bearing mice. Ann N Y Acad Sci 803: 173-180, 1996[CrossRef][Medline] 3. Zamboni WC, Stewart CF, Cheshire PJ, et al: Studies of the efficacy and pharmacology of irinotecan against human colon tumor xenograft models. Clin Cancer Res 4: 743-753, 1998[Abstract]
4. Vanhoefer U, Harstrick A, Achterrath W, et al: Irinotecan in the treatment of colorectal cancer: Clinical overview. J Clin Oncol 19: 1501-1518, 2001 5. Rougier P, Van Cutsem E, Bajetta E, et al: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure inpatients with metastatic colorectal cancer. Lancet 352: 1407-1412, 1998[CrossRef][Medline] 6. Cunningham D, Pyrhonen S, James RD, et al: Randomised trial of irin-otecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352: 1413-1418, 1998[CrossRef][Medline] 7. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 355: 1041-1047, 2000[CrossRef][Medline]
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16. Gupta E, Lestingi TM, Mick R, et al: Metabolic fate of irinotecan in humans: Correlation of glucuronidation with diarrhea. Cancer Res 54: 3723-3725, 1994 17. Araki E, Ishikawa M, Iigo M, et al: Relationship between development of diarrhea and the concentration of SN-38, an active metabolite of CPT-11, in the intestine and the blood plasma of athymic mice following intraperitoneal administration of CPT-11. Jpn J Cancer Res 84: 697-702, 1993[CrossRef][Medline] 18. Kudoh S, Fukuoka M, Masuda N, et al: Relationship between the pharmacokinetics of irinotecan and diarrhea during combination chemotherapy with cisplatin. Jpn J Cancer Res 86: 406-413, 1995[CrossRef][Medline] 19. Iyer L, Hall D, Das S, et al: Phenotype-genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism. Clin Pharmacol Ther 65: 576-582, 1999[CrossRef][Medline]
20. Wasserman E, Mijara A, Lokiec F, et al: Severe CPT-11 toxicity in patients with Gilbert’s syndrome: Two case reports. Ann Oncol 8: 1049-1051, 1997 21. Wasserman E, Myara A, Lokiec F, et al: Bilirubin (BIL) and SN-38: Pharmacokinetic/pharmacodynamic correlation. Ann Oncol 8: 1049-1051, 1998 22. Cohen AM, Shank B, Friedman MA: Colorectal cancer, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 3). Philadelphia PA, Lippincott, 1989, pp 895-964
23. Van Groeningen CJ, van der Vijgh WJF, Baars JJ, et al: Altered pharmacokinetics and metabolism of CPT-11 in liver dysfunction: A need for guidelines. Clin Cancer Res 6: 1342-1346, 2000 24. Ong SY, Clarke SJ, Bishop J, et al: Toxicity of irinotecan (CPT-11) and hepato-renal dysfunction. Anticancer Drugs 12: 619-625, 2001[CrossRef][Medline]
25. Abigerges D, Chabot GG, Armand JP, et al: Phase I and pharmacologic studies of the camptothecin analogue irinotecan administered every 3 weeks in cancer patients. J Clin Oncol 13: 210-221, 1995 26. Barilero I, Gandia D, Armand JP, et al: Simultaneous determination of the camptothecin analogue CPT-11 and its active metabolite SN-38 by high-performance liquid chromatography: Application to plasma pharmacokinetic studies in cancer patients. J Chromatogr 575: 275-280, 1992[Medline] 27. Burke TG, Mi Z: The structural basis of camptothecin interactions with human serum albumin: Impact on drug stability. J Med Chem 7: 40-46, 1994[Medline] Submitted March 22, 2002; accepted July 15, 2002.
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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
