Topotecan hydrochloride

White Crystalline Solid

A DNA topoisomerase I inhibitor; semisynthetic analog of Camptothecin. Antineoplastic. Topotecan hydrochloride is a chemotherapy agent that is a topoisomerase 1 inhibitor.

Topotecan is supplied in 4-mg vials and administered IV forthe treatment of ovarian cancer, cervical cancer, and smallcell lung cancer in those patients who did not respond tofirst-line therapy. Following IV administration, the drug iswidely distributed with 10% to 35% of the agent bound toplasma proteins. There is evidence that the agent may crossthe blood-brain barrier to some extent. In plasma, an equilibriumis established between the lactone and the less activehydroxy acid with 20% of the drug present as the lactone 1hour after the infusion is complete. In contrast to irinotecan,both the lactone and the hydroxy acid bind equally well tohuman serum albumin. N-Demethylation of the tertiaryamine to give the secondary amine is mediated by CYP3A4and represents a minor route of metabolism. Glucuronidationof the parent and the phase I metabolites also occurs to a limited(10%) extent.Elimination occurs primarily in theurine, with 30% of the dose being recovered as unchangeddrug. The terminal elimination half-life is 2 to 3 hours. Themajor toxicity seen for topotecan is dose-limiting myelosuppression.Nausea and vomiting are seen in most (70%–80%)patients, along with diarrhea and abdominal pain. Other toxicitiesinclude headache myalgias, alopecia and elevation ofserum transaminases, alkaline phosphatases, and bilirubin.Microscopic hematuria (blood in the urine) may also be seen.

Topotecan elimination is biphasic, with a terminal half-life of 2.0 to 3.5 hours. Lactone hydrolysis is rapid, and binding to serum proteins is limited to between 25 and 40%. CYP3A4-mediated N-dealkylation to mono?and didealkylated metabolites occurs to a limited extent, and the O-glucuronides that form at multiple points along the metabolic path are excreted via the kidney.

This active camptothecin analogue is used by the IV route in the treatment of ovarian and small cell lung cancer that has not responded to first-line therapy.