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Irinotecan

A Review of its Pharmacological Properties and Clinical Efficacy in the Management of Advanced Colorectal Cancer

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Abstract

Synopsis

Irinotecan (CPT-11) is a semisynthetic derivative of camptothecin. It and other camptothecin analogues/derivatives appear to exert their antitumour activity by binding to topoisomerase I. The active metabolite of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), has demonstrated potent growth inhibition of human colorectal cancer cells in vitro, with superior activity to fluorouracil.

In phase II clinical studies in patients with advanced colorectal cancer, objective response rates after irinotecan therapy ranged between 20.5 and 32%. These studies used a range of irinotecan regimens including 350 mg/m2 once every 3 weeks (Europe), 125 to 150 mg/m2 once a week for 4 weeks followed by a 2-week drug-free interval (US) and 100 mg/m2 /week or 150 mg/m2 every 2 weeks (Japan). The median duration of response ranged between 5.6 and 10.6 months. Disease stabilisation occurred in 30 to 71.2% of patients. Objective response rates to irinotecan therapy in patients who had received no prior chemotherapy were similar to those in patients pretreated with fluorouracil. Importantly, irinotecan also induced responses in some patients with tumours refractory to fluorouracil.

Severe (grade 3 or 4) neutropenia and diarrhoea, which occurred in up to 40% of patients receiving irinotecan therapy in phase II studies, require careful monitoring and appropriate management.

Thus, irinotecan is a valuable agent for the second-line treatment of patients with advanced colorectal cancer who fail to respond to or relapse after fluorouracil therapy.

Pharmacodynamic Properties

The antitumour agent irinotecan is a semisynthetic derivative of camptothecin. Irinotecan has shown growth inhibitory activity in vitro against human colon tumour cells and freshly explanted colorectal tumours; however, its metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) had considerably greater activity. SN-38 had similar potency to camptothecin and was a more potent inhibitor of human colon cell line growth than fluorouracil, mitomycin or cisplatin in vitro. Irinotecan produced 70 to 85% inhibition of growth of human colon tumour xenografts implanted in nude mice.

No synergistic effect on antitumour activity was observed when irinotecan was administered either before or after fluorouracil or etoposide in immunedeprived mice bearing human tumour xenografts.

Tumours overexpressing the multidrug-resistance gene mdr1 generally remain sensitive to the camptothecin class of drugs.

Mechanisms proposed to account for resistance to irinotecan include reduced topoisomerase I levels in resistant compared with parent tumour cells, reduced topoisomerase I activity and reduced hydrolysis of irinotecan to its metabolite SN-38.

Pharmacokinetic Properties

Irinotecan is metabolised by the carboxylesterase enzyme system to its active metabolite SN-38. Peak plasma concentrations (Cmax) of irinotecan are reached by the end of intravenous infusion, whereas those of SN-38 occur about 0.5 to 2 hours after the infusion period. Cmax values for irinotecan increased in a dose-dependent manner, ranging between 1.3 and 2.3 mg/L following administration of a 100 mg/m2 dose of irinotecan. There was significant interpatient variation in the area under the plasma concentration-time curve (AUC). AUC values for SN-38 generally correlated with those of irinotecan.

Irinotecan had a large mean volume of distribution, ranging between 104 and 211 L/m2, after intravenous infusion of 100 to 350 mg/m2.

Both irinotecan and SN-38 are subject to pH-dependent hydrolysis of the active closed lactone ring structure to an inactive open ring carboxylate. The AUC ratio of active closed ring form versus total varied from 33.9 to 44% and from 44.7 to 64%, respectively, for irinotecan and SN-38.

Plasma clearance of irinotecan was between 11 and 26 L/m2 /h and the mean residence time was generally between 9 and 12 hours, independent of dose.

Elimination of irinotecan was triphasic, the first elimination phase lasting 1.2 to 12 minutes and the second phase 1.2 to 2.5 hours. The terminal elimination half-life (t1/4) was between 5.5 and 12.5 hours. SN-38 generally had a longer t1/4: 7.7 to 17 hours. 10 to 26% of an administered dose of irinotecan and 0.18 to 0.26% of SN-38 were eliminated in the urine over a 24-hour period.

Coadministration of irinotecan and fluorouracil slightly decreased the metabolism of irinotecan to its active metabolite SN-38 early in 1 study; However, this reduction was not evident later in the trial and is unlikely to be clinically important.

Clinical Efficacy

Phase I studies investigated the maximum tolerable dose (MTD) of irinotecan and the optimal dosage regimen in patients with a range of malignancies. Irinotecan 350 mg/m2 once every 3 weeks was associated with a lower incidence of limiting toxicity (diarrhoea and neutropenia — see tolerability summary) than other dosage regimens investigated in Europe. In the US, dosages of 240 mg/m2 once every 3 weeks or 150 mg/m2 every week for 4 weeks followed by a 2-week drug-free interval were considered optimal; in Japan, MTDs were 30 mg/m2 /day by continuous intravenous infusion for 5 days or 200 mg/m administered once every 3 to 4 weeks.

Phase II clinical trials were conducted in patients with advanced colorectal cancer who were either chemotherapy-naive or had received previous therapy with fluorouracil. Irinotecan 350 mg/m once every 3 weeks induced an objective response in 20.5% of 156 evaluable patients in an initial European study; the median duration of response was 9.1 months and the 1-year survival rate was 43.1%. Objective response rates in 3 subsequent trials ranged between 6.5 and 14%.

In US studies, in which irinotecan 100 to 150 mg/m2 was administered once weekly for 4 weeks followed by a 2-week drug-free interval, objective response rates ranged between 8.6 and 32% and the median duration of response was 5.6 to 8.1 months. Disease stabilisation occurred in 30 to 71.2% of patients.

In a Japanese study, irinotecan 100 mg/m2 /week or 150 mg/m2 once every 2 weeks induced responses in 27% of patients with a median duration of 10.6 months. Disease stabilisation was observed in 30% of patients.

Tolerability

Digestive system events such as diarrhoea, nausea and vomiting were common drug-related adverse events in the 304 patients treated with irinotecan in US phase II trials. Other common adverse events included asthenia, abdominal pain, leuco-penia and neutropenia. At least 1 of these adverse events occurred in >50% of patients; <31% of patients had adverse events of grade 3 or 4 severity. The most common grade 3 or 4 adverse event was delayed diarrhoea, which was reported in 93 of 304 (30.6%) patients. Grade 3 or 4 nausea occurred in 51 (16.8%) patients.

Irinotecan caused grade 3 or 4 neutropenia in 80 (26.3%) patients but clinical complications arising from myelosuppression were relatively infrequent. Nine patients developed neutropenic fever (concurrent grade 4 neutropenia and ≥ grade 2 fever). Nine patients who received irinotecan during US phase II trials discontinued therapy because of adverse events (diarrhoea and/or neutropenia/leucopenia) considered by the investigator(s) to be drug-related. There was 1 death possibly attributable to a drug-related adverse event (neutropenia).

The most common adverse events in European phase II studies were delayed diarrhoea (grade 3 or 4 in 38.5% of patients), cholinergic syndrome (including early diarrhoea) [grade 3 or 4 in 10.3% of patients], nausea and/or vomiting (grade 3 or 4 in 18.9% of patients), neutropenia (grade 3 or 4 in 39.6% of patients), asthenia and alopecia.

There were 66 episodes of fever and/or infection associated with grade 3 or 4 neutropenia; 2 patients died with sepsis associated with grade 3 or 4 neutropenia.

Most patients experienced alopecia and ≈50% experienced complete hair loss.

Dosage and Administration

The recommended dosage of irinotecan for the treatment of patients with advanced colorectal cancer in Europe is 350 mg/m2 once every 3 weeks administered as a ≥30-minute intravenous infusion. The dosage should be reduced in patients who experience severe neutropenia or develop infections associated with neutropenia. Treatment should be delayed until full recovery in cases of severe neutropenia or severe gastrointestinal adverse events.

The recommended initial dose of irinotecan in the US is 125 mg/m2 administered as a 90-minute intravenous infusion. The recommended treatment regimen is 1 weekly dose for 4 weeks followed by a 2-week drug-free interval. This 6-week regimen may be repeated; subsequent doses should be adjusted upwards (to as high as 150 mg/m2) or downwards (to as low as 50 mg/m2) in 25 to 50 mg/m2 steps depending on tolerance of treatment. Treatment can be continued indefinitely provided patients do not develop intolerable adverse events.

Contraindications include chronic inflammatory bowel disease, hypersensitivity to irinotecan or one of its excipients, pregnancy and lactation.

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Various sections of the manuscript reviewed by: J.P. Armand, Département de Médecine, Institut Gustave-Roussy, Villejuif, France; G. Catimel, Center Regional Léon Bérard, Lyon, France; P.J. Houghton, Department of Molecular Pharmacology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA; R. Knox, CRC Centre for Cancer Therapeutics at the Institute of Cancer Research, London, England; Y. Pommier, National Institutes of Health, Bethesda, Maryland, USA; L.P. Rivory, Department of Medicine, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia; N. Saijo, National Cancer Center Research Institute, Tokyo, Japan; L.B. Saltz, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; H.J. Schmoll, Klinik und Poliklinik für Innere Medizin, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany; Y. Shimada, National Cancer Center Hospital, Tokyo, Japan; B.K. Sinha, Biochemical and Molecular Pharmacology Section, Clinical Pharmacology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

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Wiseman, L.R., Markham, A. Irinotecan. Drugs 52, 606–623 (1996). https://doi.org/10.2165/00003495-199652040-00013

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