A comparison of clinical pharmacodynamics of different administration schedules of oral topotecan (hycamtin)

Prolonged exposure to topotecan in in vitro and irt vivo experiments has yi elded the highest antitumor efficacy. An oral formulation of topotecan with a bioavailability of 32-44% in humans enables convenient prolonged adminis tration. Pharmacokinetic/pharmacodynamic relationships from four Phase I st udies with different schedules of administration of oral topotecan in 99 ad ult patients with malignant solid tumors refractory to standard forms of ch emotherapy were compared. Topotecan was administered as follows: (a) once d aily (o.d.) for 5 days every 21 days (29 patients); (b) o.d. for 10 days ev ery 21 days (19 patients); (c) twice daily (b.i.d.) for 10 days every 21 da ys (20 patients); and (d) b.i.d. for 21 days every 28 days (31 patients), P harmacokinetic analysis was performed in 55 patients using a validated high -performance liquid chromatographic assay and noncompartmental pharmacokine tic 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-d ay schedules, and only diarrhea in the 21-day schedule. Pharmacokinetics re vealed a substantial variation of the area under curve (AUC) of topotecan l actone in all of the dose schedules with a mean intrapatient variation of 2 5.4 +/- 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 ob served between myelotoxicity parameters and AUC(t) day I and AUC(t) per cou rse of topotecan lactone, In all of the studies, similar sigmoidal relation ships could be established between AUC(t) per course and the percentage dec rease of WBCs, At maximum-tolerated dose level, no significant difference i n AUC(t) per course was found [AUC(I) per course was 107.3 +/- 33.7 ng.h/ml (o.d. x 5), 145.3 +/- 23.8 ng.h/ml (o.d. x 10), 100.0 +/- 41.5 ng.h/ml (b. i.d. x 10), and 164.9 +/- 92.2 ng/h/ml (b.i.d. x 21), respectively.] For or al topotecan, the schedule rather than the AUC(t)-per-course seemed to be r elated to the type of toxicity. Prolonged oral administration resulted in i ntestinal side effects as a dose-limiting toxicity, and short-term administ ration resulted in granulocytopenia. On the basis of this pharmacokinetic s tudy, no schedule preference could be expressed, but based on patient conve nience, administration once daily for 5 days could be favored.