Interpatient variability in bioavailability of the intravenous formulationof topotecan given orally to children with recurrent solid tumors

Purpose: Evaluation of inter- and intrapatient variability of topotecan ora l bioavailability and disposition was performed in children with malignant solid tumors. Patients and methods: Topotecan i.v. formulation was given or ally on schedules of daily for 21 consecutive days (d x 21) or daily for 5 days per week for 3 weeks [(d x 5)3], in both cases repeated every 28 days. Topotecan doses of 0.8 and 1.1 mg/m(2) per day were evaluated on; both sch edules. Serial plasma samples were obtained after oral and i.v. administrat ion of topotecan at the beginning and end of the first course of therapy. T opotecan lactone and total concentrations were measured by a high-performan ce liquid chromatography (HPLC) assay, and a one-or two-compartment model w as fit to the plasma concentration-time data after oral or i.v. administrat ion, respectively. Topotecan oral bioavailability (F) was calculated as the ratio of the AUC determined after oral treatment (AUC(po)) divided by the AUC calculated after i.v. administration. Results: Pharmacokinetics studies were performed on 15 and 11 patients receiving 0.8 and 1.1 mg/m(2) per day , respectively. After oral administration the topotecan lactone AUC(po) and F determined for 0.8 and 1.1 mg/m(2) per day were 13.6 +/- 5.8 and 25.1 +/ - 12.9 ng ml(-1) h and 0.34 +/- 0.14 and 0.34 +/- 0.16, respectively. The w ithin-patient variance for AUG,, and F was much smaller than the between-pa tient variance. The ratio of topotecan lactone to total concentration was c onsistently higher after oral as compared with i.v. administration. Conclus ions: Large interpatient variability was noted in topotecan pharmacokinetic s, whereas intrapatient variability was relatively small. Further studies o f oral topotecan are warranted to evaluate the tolerance of shorter courses and to define further the interpatient variability.