Pharmacology: Pharmacodynamics: Mechanism of action: Irinotecan exerts antitumor activity by inhibiting the intranuclear enzyme topoisomerase I. This enzyme plays a key role in maintaining the structure of DNA during translation, transcription, and replication by inducing single strand breaks and relieving the torsional strain. Irinotecan and its active metabolite SN-38 bind to the topoisomerase/DNA complex. The formation of topoisomerase I/camptothecin/DNA-cleavable complex effects damage through interference with DNA metabolism and damage to the DNA replication fork. They stabilize topoisomerase I DNA breaks, causing irreversible double-strand breaks through interference with the process of replication. Mammalian cells cannot efficiently repair these double-strand breaks and thus lead to apoptosis or cell death. Since topoisomerase I complexes with DNA only during DNA synthesis, the cytotoxic action of the irinotecan metabolite likely takes place during S-phase. Reduced expression of topoisomerase I is a mechanism of resistance to irinotecan.
Pharmacokinetics: Irinotecan is a relatively inactive prodrug, which is converted by carboxylesterases to SN-38. SN-38 is responsible for the majority of in vivo antitumor activity of the drug. Irinotecan and its active metabolite SN-38 exist both as an active closed ring lactone form and an open ring inactive hydroxy acid anion form. A pH-dependent equilibrium exists between the two forms. An acidic pH promotes formation of the lactone form, whereas a more basic pH yields the hydroxy acid anion form. SN-38 has 100- to 1000- fold greater antitumor activity than irinotecan. SN-38 is responsible for the majority of in vivo antitumor activity of the drug. The drug offers an advantage over camptothecin by virtue of its water - solubility and lesser degree of toxicity and an improved toxicity profile.
After intravenous (IV) infusion of irinotecan hydrochloride injection in humans, plasma concentrations of irinotecan decline in a multiexponential manner with a mean terminal elimination half-life of approximately 6 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 10 hours. The half-life of the lactone (active) form of irinotecan and SN-38 are similar to those of total irinotecan and SN-38, as the lactone and hydroxy acid anion forms are in equilibrium. Although the pharmacokinetics of irinotecan are highly variable over the dose range of 50 mg/m
2 to 350 mg/m
2, area under the curve (AUC) of irinotecan increases linearly with dose. Maximum concentrations of the active metabolite SN-38 are generally seen within 1 hour following the end of a 90-minute infusion of irinotecan. Upon intravenous administration, irinotecan shows a bioavailability of 14% and V
d of 141 to 255 L/m
2. SN-38 and SN-38G (Glucoronide) were found to have availability equal to 3% and 10% of irinotecan, respectively.
Irinotecan exhibits moderate plasma protein binding (30% to 68%). The metabolic conversion of irinotecan to the active metabolite SN-38 is mediated by carboxylesterase enzymes and occurs primarily in the liver. SN-38 subsequently undergoes conjugation to form a glucuronide. The disposition of irinotecan has not been fully elucidated in humans. The urinary excretion of irinotecan is 11% to 20%; SN-38, <1%; and SN-38 glucuronide, 3% No change in pharmacokinetic parameters is found in pediatric patients.
Pharmacokinetic parameters for irinotecan and SN-38 following 90-minute infusions of irinotecan at 125 mg/m
2 were determined in a phase II study in patients with metastatic carcinoma of the colon or rectum and are summarized as follows: See table.
Click on icon to see table/diagram/image
Toxicology: Preclinical and Clinical Studies: As a single agent antitumor activity has been seen in several in vitro and in vivo experimental tumor model, as well as pleiotropically drug - resistant tumor cell lines and human tumor xenografts: including mammary carcinoma MX-1, gastric adenocarcinoma ST-15, colon carcinoma Co-4, and squamous cell lung carcinoma QG-56. In combination tumor activity has been shown to be additive or synergistic with cisplatin, carboplatin, mitomycin C, cytarabine, amsacrine, mitoxantrone, doxorubicin, bleomycin, and etoposide.
Lethality is observed after single IV irinotecan doses of approximately 111 mg/kg in mice and 73 mg/kg in rats (approximately 2.6 and 3.4 times the recommended human dose of 125 mg/m
2, respectively). Death is preceded by cyanosis, tremors, respiratory distress, and convulsions.
Patients with advanced disease who receive 5-FU-based chemotherapy inevitably experience progressive disease, usually within 6 to 8 months of beginning treatment. Three multicentered, phase II, open-label clinical trials were conducted to evaluate the efficacy of single-agent therapy with irinotecan injection. They involved a total of 304 patients with metastatic colorectal cancer that recurred or progressed following prior 5-FU-based therapy. All three studies used the same dosage schedule. Irinotecan was administered as a 90 minute intravenous infusion once weekly for 4 weeks, followed by a 2-week rest (one course). These studies were designed to evaluate tumor response rate. Based on the intent-to-treat population, the response to therapy was 20.8% (10/48) in the San Antonio study and 13.3% (12/90) in the Mayo/NCCTG study. In the US Multicenter study, the response rate was 14.1% (9/64) for the patients who received the 125 mg/m
2; starting dose and 7.8% (8/102) for the patients who received an initial dose of 100 mg/m
2. In the intent-to-treat analysis of the pooled data across all three studies, 193 of the 304 patients began therapy at the recommended starting dose of 125 mg/m
2. Among these 193 patients, there were two CRs and 27 PRs for an overall response rate of 15% (29/304).
Response rates to irinotecan Injection were similar in males and females and among patients older and younger than 65 years. Rates were also similar in patients with cancer of the colon or cancer of the rectum and in patients with single and multiple metastatic sites. For all 304 patients, median survival time was 9.0 months. The effect of irinotecan hydrochloride on time to disease progression has not been evaluated in randomized clinical trials.