title: An overview of the clinical pharmacology of topotecan.
abstract: Topotecan (Hycamtin; SmithKline Beecham Pharmaceuticals, Philadelphia, PA), a topoisomerase I inhibitor, is a semisynthetic camptothecin that has been structurally modified for increased water solubility. The closed lactone ring predominates at acidic pH, but the reverse reaction of the parent into the metabolite predominates at physiologic pH. The pharmacokinetic profile of topotecan is usually characterized by a two-compartment model and is linear in the dose range of 0.5 to 3.5 mg/m2. Following intravenous administration for 5 days at doses of 0.5 to 1.5 mg/m2/d as a 30-minute infusion, topotecan has a volume of distribution of approximately 130 L. Mean plasma clearance for topotecan (total) was approximately 1,000 mL/min with a plasma half-life of 2 to 3 hours. Renal clearance is an important determinant of topotecan elimination, with approximately 30% of the dose excreted in the urine. In three phase I studies in which the schedule of five daily doses every 21 or 28 days was investigated, all found 1.5 mg/m2/d to be the maximum tolerated dose. Neutropenia (reversible and noncumulative over time) was the major dose-limiting toxicity; fevers and infections were infrequently reported. The magnitude of topotecan exposure was correlated to the observed myelosuppression.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Dennis
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: L B
authors.initials: LB
authors.lastname: Grochow
authors.forename: L J
authors.initials: LJ
authors.lastname: van Warmerdam
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007262:Infusions, Intravenous; D007783:Lactones / Q000737:chemistry; D008657:Metabolic Clearance Rate; D008956:Models, Chemical; D009503:Neutropenia / Q000139:chemically induced; D012995:Solubility; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D014867:Water
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007783:Lactones; D059004:Topoisomerase I Inhibitors; D014867:Water; D019772:Topotecan; D002166:Camptothecin