A comparison of clinical pharmacodynamics of different administration schedules of oral topotecan (Hycamtin)
Prolonged exposure to topotecan in in vitro and in vivo experiments has yielded the highest antitumor efficacy. An oral formulation of topotecan with a bioavailability of 32-44% in humans enables convenient prolonged administration. Pharmacokinetic/pharmacodynamic relationships from four Phase I studies with different schedules of administration of oral topotecan in 99 adult patients with malignant solid tumors refractory to standard forms of chemotherapy were compared. Topotecan was administered as follows: (a) once daily (o.d.) for 5 days every 21 days (29 patients); (b) o.d. for 10 days every 21 days (19 patients); (c) twice daily (b.i.d.) for 10 days every 21 days (20 patients); and (d) b.i.d. for 21 days every 28 days (31 patients). Pharmacokinetic analysis was performed in 55 patients using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic methods. Totals of 109, 48, 64, and 59 courses were given, respectively. Dose-limiting toxicity consisted of granulocytopenia for the o.d. x 5-day dosage, a combination of myelosuppression and diarrhea in both of the 10-day schedules, and only diarrhea in the 21-day schedule. Pharmacokinetics revealed a substantial variation of the area under curve (AUC) of topotecan lactone in all of the dose schedules with a mean intrapatient variation of 25.4 +/- 31.0% (o.d. x 5), 34.5 +/- 25.0% (o.d. x 10), 96.5 +/- 70.1% (b.i.d. x 10), and 59.5 +/- 51.0% (b.i.d. x 21). Significant correlations were observed between myelotoxicity parameters and AUC(t) day 1 and AUC(t) per course of topotecan lactone. In all of the studies, similar sigmoidal relationships could be established between AUC(t) per course and the percentage decrease of WBCs. At maximum-tolerated dose level, no significant difference in AUC(t) per course was found [AUC(t) per course was 107.4 +/- 33.7 ng x h/ml (o.d. x 5), 145.3 +/- 23.8 ng x h/ml (o.d. x 10), 100.0 +/- 41.5 ng x h/ml (b.i.d. x 10), and 164.9 +/- 92.2 ng x h/ml (b.i.d. x 21), respectively.] For oral topotecan, the schedule rather than the AUC(t)-per-course seemed to be related to the type of toxicity. Prolonged oral administration resulted in intestinal side effects as a dose-limiting toxicity, and short-term administration resulted in granulocytopenia. On the basis of this pharmacokinetic study, no schedule preference could be expressed, but based on patient convenience, administration once daily for 5 days could be favored.
|Keywords||Administration, Oral, Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Agents/*administration & dosage/adverse effects/pharmacokinetics, Comparative Study, Diarrhea/chemically induced, Dose-Response Relationship, Drug, Drug Administration Schedule, Humans, Leukopenia/chemically induced, Middle Aged, Neoplasms/*drug therapy/metabolism, Topotecan/*administration & dosage/adverse effects/pharmacokinetics|
Gerrits, C.J.H., Hudson, I., Verweij, J., Von Hoff, D.D., Schellens, J.H., Burris, H., … van Beurden, V.. (1999). A comparison of clinical pharmacodynamics of different administration schedules of oral topotecan (Hycamtin). Clinical Cancer Research. Retrieved from http://hdl.handle.net/1765/9002