title: Oral topotecan given once or twice daily for ten days: a phase I pharmacology study in adult patients with solid tumors.
abstract: Prolonged exposure to topotecan (TPT) in in vitro experiments and in vivo studies in animals yielded the highest antitumor efficacy. An oral bioavailability of TPT of 32-44% enables convenient prolonged administration. Because of unpredictable diarrhea in the third week of the twice daily (b.i.d.) 21-day schedule of p.o. administered TPT and the finding of optimal down-regulation of topoisomerase I level after 10-14 days in mononuclear peripheral blood cells, a shorter period of administration (10 days) was chosen for Phase I and pharmacological studies of oral administration of TPT. Adult patients with malignant solid tumors that were refractory to standard forms of chemotherapy were entered. Two dose schedules were studied: once daily (o.d.) and b.i.d. administration for 10 days every 3 weeks. TPT o.d. for 10 days was studied at dose levels 1.0, 1.4, and 1.6 mg/m2/day, and dose levels were 0.5, 0.6, 0.7, and 0.8 mg/m2 with the 10-day b.i.d. schedule. Pharmacokinetics were performed on days 1 and 8 of the first course using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic methods. Nineteen patients were entered in the 10-day o.d. schedule, with a total of 48 courses given. Dose-limiting toxicity (DLT) was reached at 1.6 mg/m2/day and consisted of common toxicity criteria (CTC) grade IV thrombocytopenia and CTC grade III diarrhea. The maximum tolerated dose was 1.4 mg/m2/day. In the 10-day b.i.d. administration of TPT, a total of 64 courses were studied in 20 patients. DLT was reached at a dose of 0.8 mg/m2 b.i.d. and consisted of CTC grade IV myelosuppression and CTC grade IV diarrhea. The maximum tolerated dose was 0.7 mg/m2 b.i.d. Nonhematological toxicities with both schedules included mild nausea and vomiting, fatigue, and anorexia. Pharmacokinetics revealed a substantial variation of the area under the plasma concentration-time curve of TPT lactone in both schedules. Significant correlations were observed between the myelotoxicity parameters and the area under the plasma concentration-time curve at day 1 of TPT lactone o.d. and b.i.d. The DLT of 10 daily administrations of oral topotecan every 3 weeks consisted of a combination of myelosuppression and diarrhea for both schedules studied. The recommended doses for Phase II studies are 1.4 mg/m2/day for 10 days for the o.d. administration and 0.7 mg/m2 for the b.i.d. schedule.
authors.affiliation: Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, The Netherlands.
authors.forename: C J
authors.initials: CJ
authors.lastname: Gerrits
authors.forename: H
authors.initials: H
authors.lastname: Burris
authors.forename: J H
authors.initials: JH
authors.lastname: Schellens
authors.forename: J R
authors.initials: JR
authors.lastname: Eckardt
authors.forename: A S
authors.initials: AS
authors.lastname: Planting
authors.forename: M E
authors.initials: ME
authors.lastname: van der Burg
authors.forename: G I
authors.initials: GI
authors.lastname: Rodriguez
authors.forename: W J
authors.initials: WJ
authors.lastname: Loos
authors.forename: V
authors.initials: V
authors.lastname: van Beurden
authors.forename: I
authors.initials: I
authors.lastname: Hudson
authors.forename: S
authors.initials: S
authors.lastname: Fields
authors.forename: D D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: J
authors.initials: J
authors.lastname: Verweij
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D019772:Topotecan