title: Continuous infusion of low-dose topotecan: pharmacokinetics and pharmacodynamics during a phase II study in patients with small cell lung cancer.
abstract: Preclinical schedule dependency suggests that prolonged maintenance of low plasma levels of topotecan, a specific inhibitor of the nuclear enzyme topoisomerase I, results in optimal antitumor activity. The pharmacokinetics and pharmacodynamics of topotecan, administered as single agent in second-line therapy as a continuous low-dose infusion for 21 days, were evaluated in nine patients with small cell lung cancer (SCLC). Topotecan was administered i.v. as a 21 day continuous infusion every 28 days via an ambulatory pump. Dosages ranged from 0.4 to 0.6 mg/m2/day. Plasma levels of topotecan, the sum of topotecan, and its hydroxy acid congener and the N-desmethyl metabolite were determined at 1, 7, 14 and 21 days during infusion, using a validated high-performance liquid chromatography method with fluorescence detection. Myelosuppression was the most important toxicity. All patients experienced anemia, being severe (grade 3/4) in 55% of all courses. Other adverse effects were relatively mild and reversible, and included nausea, vomiting, diarrhea and fatigue. Three patients achieved a partial response. Mean steady-state concentrations of topotecan (C(ss)) in the first course were 0.46+/-0.17 and 0.47+/-0.19 ng/ml after doses of 0.4 and 0.5 mg/m2/day, respectively. Steady-state levels of the total of topotecan and hydroxy acid (C(ss,tot)) were 1.28+/-0.25 (range 0.93-1.58) and 1.57+/-0.19 (range 1.43-1.70) ng/ml at doses of 0.4 and 0.5 mg/m2/day, respectively. The percentage of the administered topotecan dose excreted in the urine within 24 h was 40+/-14 and 1.2+/-1.0% for total topotecan and N-desmethyltopotecan, respectively. During the second course, C(ss,tot) was significantly higher (p=0.032, paired t-test), which suggests altered topotecan disposition. A sigmoidal relationship was found between C(ss,tot) and the percent decrease in platelets (r=0.76, p=0.018). We conclude that topotecan administered as a 21 day continuous low-dose infusion has activity as single-agent, second-line therapy in patients with SCLC. There was considerable interpatient and intrapatient variability in systemic exposure to topotecan. Differences in organ function might contribute to this variation. Serum aspartate aminotransferase and albumin levels were predictive of topotecan pharmacokinetics.
authors.affiliation: Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Amsterdam.
authors.forename: V M
authors.initials: VM
authors.lastname: Herben
authors.forename: W W
authors.initials: WW
authors.lastname: ten Bokkel Huinink
authors.forename: M E
authors.initials: ME
authors.lastname: Schot
authors.forename: I
authors.initials: I
authors.lastname: Hudson
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007970:Leukopenia / Q000139:chemically induced; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D019772:Topotecan / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D019772:Topotecan