Topotecan

Topotecan has the same mechanism of action as irinotecan and is believed to exert its cytotoxic effects during the S-phase of DNA synthesis. Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single strand breaks. This ternary complex interferes with the moving replication fork, which leads to the induction of replication arrest and lethal double-stranded breaks in DNA. As mammalian cells cannot efficiently repair these double strand breaks, the formation of this ternary complex eventually leads to apoptosis (programmed cell death).

Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (-1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme–substrate complex, Topotecan acts as an uncompetitive inhibitor.

Increased clearance with phenytoin. G-CGF to be given 24 hr after completion of treatment with topotecan as concurrent admin may prolong duration of neutropenia. Increased bone marrow supression with other cytotoxic drugs (e.g. cisplatin) so dose reduction may be needed.

Neutropenia (nadir of white cell count occurs about 9-12 days after admin), thrombocytopenia and anaemia. GI upset, total alopecia, headache, dyspnoea. Fatigue, weakness, malaise, pruritus and hyperbilirubinaemia.

Pregnancy category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Preexisting bone marrow depression. Frequent monitoring of peripheral blood cell counts during treatment. Do not continue subsequent courses until neutrophils recover to >1000 cells/mm³, platelets recover to >100,000 cells/mm³ and haemoglobin levels recover to 9.0 g/dl (with transfusion if needed). May impair ability to drive or operate machinery.

Renal Impairment:

• Ovarian carcinoma, Small cell lung cancer: CrCl 20-30: Initial dose 0.75 mg/m².
• Cervical cancer: Treatment to be initiated only if serum creatinine ≤1.5 mg/dl.

Hepatic Impairment: Avoid

Cytotoxic Chemotherapy

Symptoms: Bone marrow supression.

Unopened vial: Store at 20-25°C; protect from light. Reconstituted solution: Stable for 24 hr at 20-25°C in ambient light.