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© 1999 American Society for Clinical Oncology Phase I and Pharmacokinetic Study of Irinotecan Administered as a Low-Dose, Continuous Intravenous Infusion Over 14 Days in Patients With Malignant Solid TumorsFrom the Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, and Department of Pharmacy and Pharmacology, Slotervaart Hospital/Netherlands Cancer Institute, Amsterdam, the Netherlands; and Rhône-Poulenc Rorer Recherche-Développement, Anthony Cedex, France. Address reprint requests to Virginia M.M. Herben, MD, Department of Pharmacy and Pharmacology, Slotervaart Hospital, 1066 EC Amsterdam, the Netherlands; email apvhe{at}slz.nl
PURPOSE: To evaluate the feasibility of administering irinotecan as a continuous intravenous infusion for 14 to 21 days. PATIENTS AND METHODS: Patients with solid tumors refractory to standard therapy received continuous infusions of irinotecan by means of an ambulatory infusion pump. The starting dosage was 12.5 mg/m2/d for 14 days every 3 weeks. After identification of the maximum-tolerated dose for the 14-day infusion schedule, the protocol was amended to prolong the infusion duration to 17 and 21 days. Pharmacokinetics of irinotecan and SN-38 and its glucuronide were determined using high-performance liquid chromatography and noncompartmental modeling. RESULTS: Thirty-three patients received 85+ courses. At the first dose level (12.5 mg/m2/d), cumulative grade 3 or 4 diarrhea and grade 3 or 4 neutropenia occurred in three of five patients. At a dosage of 10 mg/m2/d, 14-day administration resulted in grade 4 diarrhea in two of six patients and one episode of grade 4 vomiting occurred, whereas with 17-day administration, one episode of grade 3 nausea and two episodes of grade 3 or 4 diarrhea were observed in six patients. Increasing the number of days of infusion to 21 days was not feasible because of cumulative diarrhea. Hematologic toxicity was rare. The mean metabolic SN-38 area under the curve/irinotecan area under the curve ratio was 16% ± 6% compared with 3% to 5% after short infusion schedules involving therapeutic dosages. Partial responses were observed in two patients with extraovarian and colorectal cancer. CONCLUSION: The recommended dosage is 10 mg/m2/d for 14 days, repeated every 3 weeks. Enhanced metabolism of irinotecan to SN-38 may explain in part the low recommended dose for this schedule.
IRINOTECAN (CPT-11) IS a new, semisynthetic, water-soluble anticancer agent that is derived from the plant alkaloid camptothecin. It has been approved in a majority of countries worldwide for second-line treatment of advanced colorectal cancer after fluorouracil-based therapy and has demonstrated activity against a variety of other tumors.1,2 Irinotecan and other camptothecin analogs are selective inhibitors of topoisomerase I, a nuclear enzyme responsible for variations in the topologic form of DNA during replication and transcription.3 Topoisomerase I inhibitors bind covalently to and stabilize the DNA–topoisomerase I complex. This causes single-strand breaks in DNA, which prevent its replication and inhibit RNA synthesis and, consequently, cell division. The cytotoxic effects of irinotecan and its more potent metabolite SN-38 are specific for the S phase of the cell cycle. Because the activity of cell cycle–specific drugs is assumed to be exposure time–dependent rather than concentration-dependent, prolonged administration could increase antitumor activity.4 However, in vivo preclinical studies have yielded conflicting results. Several investigators5-7 have shown that in tumor-bearing mice, for similar total doses administered, camptothecin analogs are more effective when administered in prolonged low-dose schedules than when given at higher doses for shorter durations. Others8 have reported that the cytotoxicity of irinotecan was not markedly schedule-dependent. Schedule-dependent cytotoxicity of irinotecan is not known in the clinic. Phase I studies, performed in Europe, the United States, and Japan, have used different schedules of administration with different recommended dosages or schedules.1,2 Three schedules are used: a 30- to 90-minute infusion once every 3 weeks, a weekly 90-minute infusion, and a fortnightly 90-minute infusion. The different schedules have demonstrated comparable activity in the treatment of advanced colorectal cancer.9-12 In an attempt to determine whether a clinically relevant schedule dependency exists for this active new drug, we initiated a phase I study involving a continuous infusion schedule, which is very different from short infusion schedules. A 14-day infusion schedule was chosen because free topoisomerase I in WBCs was shown to be progressively depleted until day 14 of a 21-day continuous low-dose infusion of the analog topotecan.13 The objectives of the study were to define the maximum-tolerated dose (MTD) of irinotecan administered as a continuous intravenous infusion over 14 days and to recommend a safe dose for phase II testing, to determine the quantitative and qualitative toxic effects and dose-limiting toxicity (DLT) of the schedule, to determine the pharmacokinetics of irinotecan and its metabolites SN-38 and SN-38 glucuronide (SN-38G), and to document any antitumor activity.
Eligibility Criteria Patients were eligible for the study if they had a histologically demonstrated solid tumor for which no therapy with greater potential than that of irinotecan existed. Other eligibility criteria included age 18 to 70 years, World Health Organization performance status  2, and estimated life expectancy  12 weeks. Previous chemotherapy had to be discontinued for at least 4 weeks before entry into the study, or 6 weeks in the case of mitomycin, nitrosourea, or extended-field radiation therapy. Patients had to be eligible and willing to undergo insertion of a portable device and indwelling catheter (Port-a-Cath; SIMS/Deltec, Inc, St Paul, MN). Patients had to have acceptable bone marrow function, defined as a neutrophil count 2,000/µL, a hemoglobin level 10.0 g/dL, and a platelet count 100,000/µL; adequate hepatic function, defined as serum bilirubin level 1.25 times the upper limit of normal laboratory range or 1.5 times when related to liver metastases, transaminase levels 2.5 times the normal upper limit or five times when related to liver metastases; and adequate renal function, defined as serum creatinine level 1.36 mg/dL (120 µmol/L). Ineligibility criteria included a history of treatment with irinotecan or any inhibitor of topoisomerase I, chronic enteropathy (eg, Crohn's disease, ulcerative colitis, or extensive intestinal resection), symptomatic brain metastasis or carcinomatous leptomeningitis, bowel obstruction or subobstruction, uncontrolled infection, major visceral failure, or a history of other cancer except in situ cervical carcinoma or basal- or spindle-cell carcinoma of the skin. The study protocol was approved by the Medical Ethics Committee of the hospital, and all patients gave written informed consent.
Toxicity and Response Evaluation
Dose Escalation
Drug Administration
Treatment of Diarrhea
Pharmacokinetics Plasma levels of the lactone and carboxylate forms of irinotecan and SN-38 and the total form (lactone plus carboxylate) of SN-38G were determined separately with a validated reversed-phase high-performance liquid chromatography (HPLC) system with fluorescence detection, as developed in our laboratory.16 Total (lactone plus carboxylate) SN-38 level was determined by alkalinization of the plasma methanol extracts to convert all drug into the carboxylate form. SN-38G levels were determined as the difference in total SN-38 concentrations before and after incubation of plasma samples (100 µL) with beta-glucuronidase (500 units; type X-A from Escherichia coli; Sigma Chemical Co, St Louis, MO). Within-run and between-run precision was always less than 12% in the concentration ranges of interest (1.0 to 100 ng/mL and 0.5 to 25 ng/mL for irinotecan and SN-38, respectively). The average accuracies were within 94% and 120%. The extraction efficiencies of irinotecan as the lactone and carboxylate forms were 110% ± 6% and 107% ± 0.2%, respectively. For SN-38, the extraction efficiencies were 96% ± 6%, 95% ± 7%, and 98% ± 9% for the lactone, carboxylate, and total forms, respectively. Urine was diluted (1:25 or 1:50) with methanol and alkalinized with 0.01 mol/L borax solution, and a 20-µL aliquot was injected onto the HPLC column. The chromatographic conditions for the quantification of irinotecan, SN-38, and SN-38G as their total forms (lactone plus carboxylate) in urine were identical to those in plasma. The pharmacokinetic parameters were calculated using a model-independent approach. The area under the plasma concentration–time curve (AUC) was estimated by the linear trapezoidal method up to the last measured data point. Total body clearance from plasma (CL) was calculated by dividing the total administered irinotecan dose by the AUC. The terminal rate constant k was determined by log-linear regression analysis of the terminal phase of the plasma concentration–time curve. The terminal half-life was calculated as 0.693/k. The extent of metabolism of irinotecan to SN-38 in plasma was expressed by a metabolic ratio value, defined as the ratio of the SN-38 AUC over the irinotecan AUC. The extent of glucuronidation of SN-38 to SN-38G in plasma was expressed by a glucuronidation ratio value, defined as the ratio of the SN-38G AUC over the SN-38 AUC. The biliary index, a surrogate measure of SN-38 concentrations in the bile draining into the intestine, was defined as the product of the irinotecan AUC and the ratio of the SN-38 AUC over the SN-38G AUC.17 The percentage of the administered irinotecan dose recovered in the urine as unchanged drug, SN-38, or SN-38G over 24 hours after the start of the infusion was calculated as the amount excreted in the urine divided by the total administered dose times 100%. Data are given as mean ± SD.
Statistical Analysis
Pharmacokinetic-Pharmacodynamic Analysis
The data were fit using linear, log-linear, and sigmoidal maximum effect models, using the software package Siphar (Siphar SIMED, Créteil, France). Only data obtained during the first course were used.
Thirty-three patients received 85+ courses. Patient characteristics are outlined in Table 2. The median number of courses administered per patient was two (range, one to eight). Twenty-eight patients were assessable for toxicity during the first treatment course. Five patients were not assessable because of early infusion termination for non–drug-related reasons: one patient who had a history of arrhythmia experienced cardiac arrhythmia and grade 2 nausea and/or vomiting several hours after the start of the infusion; a second patient with a history of cardiovascular abnormalities developed a suspected myocardial infarction on the fourth day of infusion; another patient was hospitalized on the sixth day of infusion with fever and erysipelas; a fourth patient was hospitalized on the seventh day of infusion with tumor-related severe nausea and vomiting, bowel obstruction was diagnosed, and the patient died from sepsis 2 weeks later; and a fifth patient died on the 12th day of infusion from respiratory insufficiency caused by rapidly progressive disease. Besides these five patients, five other patients did not receive a second course according to this protocol, because of rapidly progressive disease (three patients), persistent diarrhea (one patient), and refusal (one patient).
Four patients were treated at two dose levels because of severe gastrointestinal toxicity during the first treatment course (Table 1): in two patients at dose level I, the daily dose was reduced to 10 mg/m2 in the second course; and in two patients, the infusion duration was reduced from 17 and 21 days to 14 days. No intrapatient dose escalations occurred. Drug-related early infusion discontinuation was required in eight courses (10%). Sixteen courses (20%) had to be postponed for 1 week because of unresolved toxicity. Fifteen patients were hospitalized because of the following drug-related events: diarrhea, with or without nausea and/or vomiting (11 patients); neutropenia, with or without diarrhea and/or fever (two patients); and nausea and/or vomiting (two patients). Hospitalization because of catheter obstruction was required in five courses (6%).
Hematologic Toxicity
Nonhematologic Toxicity
Delayed diarrhea generally developed 5 to 13 days after the start of the irinotecan infusion and lasted for a median period of 3 days (range, 1 to 28 days). Patients had a median of two diarrheal episodes (range, 1 to 5 episodes) per course. Diarrhea generally responded to high-dose loperamide. Six patients additionally received ciprofloxacin (seven courses), whereas octreotide was administered to three patients (three courses). Grade 3 or 4 nausea and vomiting occurred in five courses (6%) (Table 3). Grade 1 or 2 nausea and vomiting occurred in 63% and 29%, respectively, of all courses and responded well to standard antiemetics. Other adverse events possibly associated with irinotecan administration included mild to moderate anorexia (5%, grade 3 in one course), abdominal cramps (18%), fatigue (30%, grade 3 in 10 courses), malaise (4%, grade 3 in two courses), and transient increases in serum creatinine (3%), bilirubin (8%), and transaminase (4%) levels. Grade 3 or 4 liver enzyme abnormalities were noted in two patients (4% of courses). Alopecia was rare and was never greater than grade 1.
Pharmacokinetics
The influence of prior exposure to irinotecan on the pharmacokinetic parameters could be examined during 21 second courses, nine third courses, eight fourth courses, four fifth courses, and two sixth courses (data not shown). Overall, the irinotecan CL, metabolic ratio, and glucuronidation ratio were not markedly altered during subsequent courses compared with the first course. Baseline patient and biochemical characteristics were examined as possible determinants of the pharmacokinetic parameters. No significant relationships could be identified between irinotecan CL, the metabolic ratio, or the glucuronidation ratio and the following characteristics: age, sex, performance status, serum creatinine level, transaminase levels, alkaline phosphatase level, prior abdominopelvic irradiation, and liver metastases. Irinotecan CL was negatively correlated with serum bilirubin levels (rs = -.41, P = .025).
Pharmacodynamics
Responses
In this phase I trial, we found that administration of irinotecan as a continuous low-dose infusion is feasible. Diarrhea, combined with nausea and/or vomiting, was dose limiting. Diarrhea seemed to be a cumulative toxicity and precluded repeated administration of irinotecan at doses above 10 mg/m2/d (dose levels I and II) or for more than 17 days (dose levels V and VI), despite aggressive treatment with high doses of loperamide. The recommended dosage for further phase II testing is 10 mg/m2/d for 14 days (total dose, 140 mg/m2) every 3 weeks. At this dose, a total of 25 courses were administered to 11 patients. Treatment delays and early infusion discontinuation because of toxicity resulted in an actual dose-intensity of 125.7 mg/m2/3 weeks (90%). This dose-intensity is approximately 40% of the dose-intensity obtained with short infusion schedules of irinotecan. Drug-related hospitalization was required in 19% of cycles. Except for three episodes of severe neutropenia at the first dosage of 12.5 mg/m2/d, hematologic toxicity was rare. Other toxicities attributed to irinotecan treatment included fatigue, anorexia, malaise, and abdominal cramps. The acute cholinergic syndrome, observed with short infusion schedules, was absent in the current study. Objective antitumor responses were observed in an extensively pretreated patient with extraovarian cancer and in a fluorouracil-pretreated patient with colorectal cancer. The mean metabolic SN-38/irinotecan AUC ratio was 16%. This value was higher than values observed after short infusion schedules involving infusion once every 3 weeks or once weekly (mean metabolic ratio, 3% to 5%).19-21 SN-38 rather than irinotecan is considered to be the active species in vivo, because SN-38 is a 100- to 1,000-fold more potent topoisomerase I inhibitor than the parent drug in in vitro models.22 This extensive metabolism of irinotecan to the active metabolite SN-38 may thus explain in part the low recommended dose for the continuous infusion schedule. To demonstrate that the higher metabolic ratio with the continuous infusion schedule compared with reported short infusion schedules is not a result of differences in analytic methodology between investigators, we simultaneously determined plasma concentrations of irinotecan and metabolites in samples obtained during the first treatment course in five patients receiving irinotecan 350 mg/m2 as a short 90-minute infusion once every 3 weeks in our institute.18 The obtained pharmacokinetic parameters are presented in Tables 4 and 5 and are in agreement with previously published data.19-21 Irinotecan clearance and the glucuronidation ratio were comparable after both infusion schedules (unpaired t test, P = .30 and .49, respectively). In contrast, the metabolic ratio was significantly higher after continuous infusion compared with short infusion of irinotecan (P < .0001). The data clearly show that the extent of metabolism of irinotecan to SN-38 is dependent on the rate of intravenous infusion of irinotecan and indicate that prolonged exposure to low doses of irinotecan results in a more efficient conversion of the parent drug into its active metabolite. Nonlinear pharmacokinetics of irinotecan have been previously reported in rodents. Irinotecan metabolic clearance to SN-38 was decreased at higher doses, whereas renal and biliary clearance remained constant, which may reflect carboxylesterase saturation.23,24 In humans, some investigators have demonstrated stable irinotecan clearance and a proportional increase in SN-38 AUC as a function of dose,20 whereas others have found saturation of carboxylesterase and glucuronidation pathways.17,25,26 The reason for these different results is unclear but may be related to differences in dose range and schedule. In the present study, the plasma concentrations of SN-38 and SN-38G relative to irinotecan were comparable on days 7, 14, and 17 or 21 during one treatment course (Fig 1) and also between courses. This indicates that there was no induction or saturation of the carboxylesterase or glucuronyl-transferase enzyme systems during 14 to 21 days of irinotecan infusion and that the enzyme systems were not influenced by prior treatment with irinotecan. In vitro, loperamide (50 µmol/L) was found to inhibit the carboxylesterase-catalyzed biotransformation of irinotecan to SN-38.27 In clinical trials involving short infusion schedules, this potential interaction was unlikely to be of considerable significance, because loperamide is usually administered at a time when most of the irinotecan has been cleared from the body. Indeed, no alterations in pharmacokinetic parameters have been observed. Instead, in the present study loperamide was frequently given at high doses during and after the infusion. However, a clear influence on the metabolism to SN-38 could not be detected, because of the limited number of blood samples taken during the infusion. Furthermore, because the CADD-PLUS infusion pump is in fact an intermittent-flow device, any observed fluctuation in steady-state levels most likely resulted from the bolus of irinotecan, which was delivered every 15 minutes by the device. In vitro and in vivo in tumor-bearing mice, topoisomerase I inhibitors displayed exposure time–dependent rather than concentration-dependent cytotoxicity.4-7 Prolonged exposure increases the probability that tumor cells will be exposed to topoisomerase I inhibitors during DNA replication. The underlying reason for schedule dependency of camptothecins—ie, cell cycle specificity—is therefore pharmacodynamic rather than pharmacokinetic; thus, maintaining a high concentration for a short period does not necessarily produce the same effect as does maintaining a low concentration for a prolonged period, even if the total AUCs per treatment period are equal. This was exemplified clinically by oral administration of the camptothecin analog topotecan. Oral topotecan demonstrated schedule dependency in DLT when four different administration schedules, ranging from once-daily dosing for 5 days to twice-daily dosing for 21 days, were examined.28 Short-term oral administration resulted in granulocytopenia, whereas prolonged administration resulted in intestinal side effects as DLT. However, the AUC per course at the MTD was similar for each of the administration schedules. The current study showed that at the recommended dose, the irinotecan AUC per course was lower than after short infusion schedules,19,29 but the AUC of the active metabolite SN-38 (mean, 1.4 h·µmol/L) was comparable to values obtained after short infusions of 350 mg/m2 once every 3 weeks (mean AUC, 1.2 h·µmol/L29) or 145 mg/m2 weekly for 4 weeks every 6 weeks (mean AUC, 1.9 h·µmol/L/3 weeks19). Given these pharmacokinetic results, therefore, no schedule preference with regard to irinotecan administration can be expressed. On the basis of the theoretic benefit of prolonged topoisomerase I enzyme inhibition, the lower total dose of irinotecan, and the preliminary evidence of activity, prolonged administration seems to be a promising method of delivering irinotecan. The optimal administration schedule of irinotecan in the clinic is still uncertain. Phase II trials of irinotecan conducted in the United States, Europe, and Japan using different administration schedules have shown consistent response rates in the treatment of advanced colorectal cancer. A European randomized phase II multicenter trial of irinotecan in patients with metastatic colorectal cancer is currently ongoing using four different administration schedules: 350 mg/m2 in a 90-minute infusion every 3 weeks, 250 mg/m2 in a 90-minute infusion every 2 weeks, 125 mg/m2 in a 90-minute infusion for 4 weeks every 6 weeks, and 10 mg/m2/d in a 14-day continuous infusion every 3 weeks. It is hoped that this study will determine whether a clinically relevant schedule dependency with regard to response rate exists for irinotecan and what the optimal administration schedule is.
Supported by a grant from Rhône-Poulenc Rorer Recherche-Développement, Anthony Cedex, France. We thank Ludy Valkenet for assistance with data collection and Dafne Mazee and Saskia Zeedijk for technical assistance with the analytic assays. We also thank the medical and nursing staffs of the Antoni van Leeuwenhoek Hospital for the care and support of the patients in this study.
1. O'Reilly S, Rowinsky EK: The clinical status of irinotecan (CPT-11), a novel water soluble camptothecin analogue: 1996. Crit Rev Oncol Hematol 24:47-70, 1996[Medline] 2. Masuda N, Kudoh S, Fukuoka M: Irinotecan (CPT-11): Pharmacology and clinical applications. Crit Rev Oncol Hematol 24:3-26, 1996[Medline]
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Burris HA III, Hanauske AR, Johnson RK, et al: Activity of topotecan, a new topoisomerase I inhibitor, against human tumor colony-forming units. J Natl Cancer Inst 84:1816-1820, 1992 5. Supko JG, Plowman J, Dyker DJ, et al: Relationship between the schedule dependence of 9-amino-20(S)-camptothecin (AC; NSC 603071) antitumor activity in mice and its plasma pharmacokinetics. Proc Am Assoc Cancer Res 33:432, 1992 (abstr) 6. Houghton PJ, Cheshire PJ, Hallman JD II, et al: Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol 36:393-403, 1995[Medline] 7. Furuta T, Yokokura T: Effect of administration schedules on the antitumor activity of CPT-11, a camptothecin derivative. Jpn J Cancer Chemother 17:121-130, 1990 8. Bissery MC, Vrignaud P, Lavelle F, et al: Experimental antitumor activity and pharmacokinetics of the camptothecin analog irinotecan (CPT-11) in mice. Anticancer Drugs 7:437-460, 1996[Medline]
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Rothenberg ML, Eckardt JR, Kuhn JG, et al: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 14:1128-1135, 1996 11. Pitot HC, Wender DB, O'Connell MJ, et al: Phase II trial of irinotecan in patients with metastatic colorectal cancer. J Clin Oncol 15:2910-2919, 1997[Abstract]
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Rougier P, Bugat R, Douillard JY, et al: Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 15:251-260, 1997 13. Hochster H, Liebes L, Sorich J, et al: Effect of prolonged topotecan infusion on topoisomerase I levels: A phase I and pharmacodynamic study. Clin Cancer Res 3:1245-1252, 1997[Abstract] 14. World Health Organization: Handbook for Reporting Results of Cancer Treatment (WHO publication no. 48). Geneva, Switzerland, World Health Organization, 1979 15. National Cancer Institute: Guidelines for Reporting of Adverse Drug Reactions. Bethesda, MD, National Cancer Institute, 1998 16. Herben VMM, Mazee D, Van Gortel-Van Zomeren DM, et al: Sensitive determination of the carboxylate and lactone forms of the novel antitumor drug irinotecan and its active metabolite in plasma by HPLC. J Liquid Chromatography Related Technol 21:1541-1558, 1998
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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 18. Cunningham D, Van Cutsem E, Ten Bokkel Huinink W, et al: Open-label multicentre phase II study to confirm efficacy and safety of irinotecan-HCl (CPT-11) in metastatic 5-FU resistant colorectal cancer. Br J Cancer 74:18, 1996 (abstr) 19. Gupta E, Mick R, Ramirez J, et al: Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients. J Clin Oncol 15:1502-1510, 1997[Abstract]
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Negoro S, Fukuoka M, Masuda N, et al: Phase I study of weekly intravenous infusion of CPT-11, a new derivative of camptothecin, in the treatment of non-small cell lung cancer. J Natl Cancer Inst 83:1164-1168, 1991 27. Rivory LP, Bowles MR, Robert J, et al: Conversion of irinotecan (CPT-11) to its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), by human liver carboxylesterase. Biochem Pharmacol 52:1103-1111, 1996[Medline]
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Abigerges D, Chabot GG, Armand J-P, et al: Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients. J Clin Oncol 13:210-221, 1995 Submitted September 1, 1998; accepted February 11, 1999.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
) and carboxylate (
) forms of irinotecan, the lactone (
) and carboxylate (•) forms of SN-38, and total SN-38G (|a9) in a patient treated with irinotecan 10 mg/m2/d administered as a 14-day continuous infusion. (B) Postinfusion levels.
