BIOAVAILABILITY AND PHARMACOKINETICS OF ORAL TOPOTECAN - A NEW TOPOISOMERASE-I INHIBITOR

The results of preclinical and clinical studies indicate enhanced anti neoplastic activity of topotecan (SKF 104864-A) when administered as a chronic treatment. We determined the apparent bioavailability and pha rmacokinetics of topotecan administered orally to 12 patients with sol id rumours in a two-part crossover study. The oral dose of 1.5 mg m(-2 ) was administered as a drinking solution of 200 ml on day 1. The i.v. dose of 1.5 mg m(-2) was administered as a 30 min continuous infusion on day 2. The bioavailability was calculated as the ratio of the oral to i.v. area under the curve (AUG) calculated up to the last measured time point, The oral drinking solution was well tolerated. The bioava ilability revealed moderate inter-patient variation and was 30%+/-7.7% (range 21-45%). The time to maximum plasma concentration after oral a dministration (T-max) was 0.78 h (median: range 0.33-2.5). Total i.v. plasma clearance of topotecan was 824+/-154 ml min(-1) (range 535-1068 ml min(-1)). The AUC ratio of topotecan and the lactone ring-opened h ydrolysis product (hydroxy acid) was of the same order after oral (0.3 4-1.13) and i.v. (0.47-0.98) administration. The bioavailability of to potecan after oral administration illustrates significant systemic exp osure to the drug which may enable chronic oral treatment.