Oral topotecan: bioavailability and effect of food co-administration

The aims of the study were twofold: (1) to evaluate the effect of food on the relative oral bioavailability of topotecan gelatin capsules in patients with solid tumours, and (2) to determine the absolute bioavailability of oral topotecan with reference to the intravenous (i.v.) formulation. The study had a randomized two-period cross-over design. On day 1 of the first treatment course patients were administered 2.3 mg m(−2) day(−1) of oral topotecan with or without a high-fat breakfast. They crossed over to receive the alternate regimen on day 2. In the second course (3 weeks later) fasted patients received topotecan orally (2.3 mg m(−2) day(−1)) or i.v. (1.5 mg m(−3) day). They crossed over to receive the alternate regimen on day 2. On days 3–5 of both treatment courses patients received oral topotecan. Plasma pharmacokinetics were performed on days 1 and 2 of the first and second course using a high-performance liquid chromatographic assay. Eighteen patients were enrolled in the study. The ratio of the area under the curve to infinity during fasted and high-fat treatment was 0.93 ± 0.23 (90% confidence interval (CI) 0.83–1.03). Maximal plasma concentrations of topotecan were similar after ingestion of the capsules with (10.6 ± 4.4 ng ml(−1)) or without food (9.2 ± 4.1 ng ml(−1)) (P = 0.130). The time needed to reach maximal plasma levels was significantly prolonged after food intake (median 3.1 h, range 2.8–6.1) compared to fasted conditions (2.0 h, range 1.1–8.1) (P = 0.013). The absolute bioavailability of topotecan averaged 42 ± 13% (90% CI 37– 47%). The apparent terminal half-life was significantly longer after administration of oral topotecan (3.9 ± 1.0 h) than after i.v. administration (2.7 ± 0.4 h) (P < 0.001). Topotecan demonstrates suitable bioavailability for oral treatment. Co-administration of the topotecan gelatin capsules with a high-fat breakfast leads to a small decrease in absorption rate but does not affect the extent of absorption. © 1999 Cancer Research Campaign