Topoisomerase I and II inhibitors: Irinotecan and Etoposide

Mechanism

Pharmacological Class and Group

Antineoplastic enzymatic inhibitors of Topoisomerase I (semi-synthetic derivatives of camptothecin: Irinotecan) and inhibitors of Topoisomerase II (derivatives of podophyllotoxin: Etoposide), phase-specific of the cell cycle (S and G2/M phases).

Mechanism of Action

Both drugs interfere with the topological cycle of the double helix, preventing cell replication:

• Irinotecan: It is a prodrug that undergoes selective hepatic hydrolysis to generate the active metabolite SN-38 (up to 1000 times more potent than the parent molecule). SN-38 selectively binds to the DNA-coupled enzyme Topoisomerase I, preventing the reassociation of single-strand cuts (single-strand breaks) generated during the unspinning of the double helix. When the replication fork in S phase collides with this complex, irreversible double-strand breaks and cell death are induced.
• Etoposide: It physically and reversibly couples to the enzyme Topoisomerase II bound to DNA, blocking the ligation of double-strand breaks necessary to resolve the topological knots of DNA supercoiling during transcription and mitosis, leading to cellular genomic fragmentation.

Pharmacokinetics

Metabolism of SN-38 by UGT1A1 and the UGT1A1*28 Polymorphism

Metabolic clearance of SN-38 (the active metabolite of irinotecan) occurs selectively in the liver through the glucuronidation pathway mediated by the enzyme uridine diphosphate glucuronosyltransferase UGT1A1, transforming it into inactive SN-38G that is excreted bile:

SN-38 Active UGT1A1 SN-38G Inactive Sustained Biliary Excretion

Patients who inherit loss-of-function polymorphisms in the promoter of the UGT1A1 gene (with the homozygous mutated allele UGT1A1*28, typical of Gilbert's syndrome, being the most clinically relevant) have expression of the enzyme decreased by 70%. This leads to a massive increase in the area under the curve of free plasma SN-38, triggering life-threatening gastrointestinal toxicity and severe neutropenia if the initial dose is not adjusted.

High Resolution Pharmacokinetics

• Absorption of Etoposide: It has a variable oral bioavailability of approximately 50%, which allows oral treatment with double the dose calculated intravenously, requiring careful monitoring.
• Metabolism: Irinotecan is activated to SN-38 in the liver by microsomal carboxylesterases, undergoing deactivation by UGT1A1. Etoposide is inactivated by CYP3A4-mediated hepatic o-demethylation and conjugation with sulfates or glucuronides.
• Elimination: Inactive SN-38 is predominantly excreted via bile into the intestinal lumen, where it can be reactivated to SN-38 by beta-glucuronidase enzymes of the colonic bacterial microbiota, inducing late enterotoxicity. Etoposide is eliminated by renal clearance (40-60% unchanged).

Indicators and dose

Clinical Indications and Frequent Regimens

• Irinotecan: Metastatic colorectal cancer as first or second line therapy (FOLFIRI Scheme: Irinotecan + 5-Fluorouracil + Leucovorin), advanced pancreatic cancer (in liposomal lipid formulation).
• Etoposide: Small cell lung cancer (EP Scheme: Etoposide + Cisplatin), testicular germ cell tumors (BEP Regimen: Bleomycin + Etoposide + Cisplatin), rescue conditioning schemes for hematopoietic transplant.

Dosage and Clinical Adjustment

• Irinotecan IV (FOLFIRI): 180 mg/m² as a short infusion of 90 minutes every 14 days.
• IV etoposide (EP): 100 - 120 mg/m²/day for 3 consecutive days every 21 days.
• Clinical Adjustments: If homozygous UGT1A1*28 polymorphism is identified, it is suggested to empirically reduce the initial dose of irinotecan by 25-30% of the scheduled dose. In moderate renal failure (Cl_Cr 15-50 mL/min), the dose of etoposide should be reduced by 25%.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Underlying chronic inflammatory bowel disease (for irinotecan).
• Severe liver failure (total bilirubin > 3 mg/dL).
• Confirmed hypersensitivity to the active ingredient or excipients.
• Deep basal uncorrected myelosuppression.

Relative Contraindications

• Known homozygous polymorphism UGT1A1*28 (Gilbert) (requires strict reduction of irinotecan dose).
• Moderate renal dysfunction (for etoposide, requires close monitoring of urinary clearance).

Adverse Effects (ADR) and Specific Toxicity

• Myelosuppression: Dose-dependent dose-limiting neutropenia with nadir at 10-14 days.
• Diarrhea due to Irinotecan: It is clinically classified into two different pathophysiological entities:
  • Acute Diarrhea (Cholinergic): Appears during the first 24 hours post-infusion, mediated by reversible inhibition of systemic acetylcholinesterase. It presents with abdominal colic, miosis, tearing and profuse sweating. It is treated immediately with Atropine (0.25 - 1.0 mg subcutaneously or IV).
  • Late Diarrhea (Secretary): Appears from the second day after infusion, secondary to direct damage from reactivated SN-38 on the colonic mucosa. It can cause severe dehydration and electrolyte imbalance. It is managed in a mandatory and early manner with high doses of Loperamide (4 mg PO initially, followed by 2 mg every 2 hours) continuously until completing 12 hours without stools.
• Secondary oncogenesis (Etoposide): Increased risk of developing secondary acute myeloid leukemia associated with rearrangements of the MLL gene at the 11q23 locus, with a short latency period of 2 to 3 years post-treatment.