Irinocan 40/Irinocan 100 Mechanism of Action

Pharmacotherapeutic group: Other Antineoplastic agents.
Pharmacology: Pharmacodynamics: Mechanism of action: Irinotecan is a semi synthetic derivative of camptothecin. It is an Antineoplastic agent, which acts as a specific inhibitor of DNA topoisomerase I. It is metabolised by carboxylesterase in most tissues to SN-38, which was found to be more active than Irinotecan in purified topoisomerase I and more cytotoxic than Irinotecan against several murine and human tumor cell lines. The inhibition of DNA topoisomerase I by Irinotecan or SN38 induces single strand DNA lesions which blocks the DNA replication fork and are responsible for the cytotoxicity. This cytotoxic activity was found time dependent and was specific to the S phase.
In vitro, Irinotecan and SN-38 were not found to be significantly recognized by the P-glycoprotein MDR, and displays cytotoxic activities against doxorubicin and vinblastine resistant cell lines.
Furthermore, Irinotecan has a broad antitumor activity in vivo against murine tumor models (P03 pancreatic ductal adenocarcinoma, MA16/C mammary adenocarcinoma, C38 and C51 colon adenocarcinomas) and against human xenografts (Co-4 colon adenocarcinoma, Mx-1 mammary adenocarcinoma, ST-15 and SC-16 gastric adenocarcinomas). Irinotecan is also active against tumours expressing the P-glycoprotein MDR (vincristine and doxorubicin resistant P388 leukaemia's).
Beside the antitumour activity of Irinotecan, the most relevant pharmacological effect is the inhibition of acetylcholinesterase.
Pharmacokinetics: In a phase I study in 60 patients with a dosage regimen of a 30 minute intravenous infusion of 100 to 750 mg/m² every three weeks, Irinotecan showed a biphasic or tri phasic elimination profile. The mean plasma clearance was 15 L/h/m² and the volume of distribution at steady state (Vss): 157 L/m². The mean plasma half-life of the first phase of the tri phasic model was 12 minutes, of the second phase 2.5 hours, and the terminal phase half life was 14.2 hours. SN-38 showed a biphasic elimination profile with a mean terminal elimination half life of 13.8 hours. At the end of the infusion, at the recommended dose of 350 mg/m², the mean peak plasma concentrations of Irinotecan and SN-38 were 7.7 μg/mL and 56 ng/mL, respectively, and the mean area under the curve (AUC) values were 34 μg·h/mL and 451 ng·h/mL, respectively. A large inter individual variability in pharmacokinetic parameters is generally observed for SN-38.
A population pharmacokinetic analysis of Irinotecan has been performed in 148 patients with metastatic colorectal cancer, treated with various schedules and at different doses in phase II trials. Pharmacokinetic parameters estimated with a three compartment model were similar to those observed in phase I studies. All studies have shown that Irinotecan (CPT11) and SN-38 exposure increase proportionally with CPT11 administered dose; their pharmacokinetics are independent of the number of previous cycles and of the administration schedule.
In vitro, plasma protein binding for Irinotecan and SN-38 was approximately 65 % and 95 % respectively.
Mass balance and metabolism studies with 14 C-labeled drug have shown that more than 50% of an intravenously administered dose of Irinotecan is excreted as unchanged drug, with 33% in the faeces mainly via the bile and 22% in urine.
Two metabolic pathways account each for at least 12% of the dose: Hydrolysis by carboxylesterase into active metabolite SN-38, SN-38 is mainly eliminated by glucuronidation, and further by biliary and renal excretion (less than 0.5% of the Irinotecan dose). The SN-38 glucuronite is subsequently probably hydrolysed in the intestine.
Cytochrome P450 3A enzymes dependent oxidations resulting in opening of the outer piperidine ring with formation of APC (aminopentanoic acid derivate) and NPC (primary amine derivate).
Unchanged Irinotecan is the major entity in plasma, followed by APC, SN-38 glucuronide and SN38. Only SN-38 has significant cytotoxic activity.
Irinotecan clearance is decreased by about 40% in patients with bilirubinemia between 1.5 and 3 times the ULN. In these patients a 200 mg/m² Irinotecan dose leads to plasma drug exposure comparable to that observed at 350 mg/m² in cancer patients with normal liver parameters.