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Gender-dependent pharmacokinetics of topotecan in adult patients

Gender-dependent differences in the clinical pharmacokinetic behavior of various drugs have been documented previously. Most commonly, these differences are associated with differences in body composition, renal elimination, drug absorption or hepatic metabolism. Gender-dependent differences in the pharmacokinetics of topotecan (Hycamtin®) have not yet been described. In this report, pharmacokinetic data of the lactone and carboxylate forms of topotecan were derived from clinical studies in which topotecan was administered either orally or i.v. to a total of 55 males and 37 females. A significant difference (p=0.0082) of 38% was found between the apparent clearance of topotecan lactone after oral administration in males (237±105 l/h) and females (163±62.5 l/h). When adjusted for body surface area, this difference remained significant (p=0.031). Similarly, differences were noted in the percentage of topotecan in the lactone form (37.1±5.32 versus 41.7±6.51%, p=0.0076). Statistical analysis revealed that individual hematocrit values, which were consistently lower in females (p<0.023), were a significant predictor of the apparent topotecan lactone clearance. This was confirmed experimentally in in vitro incubation studies in whole blood using artificially altered hematocrit values and in blood samples from both male and female volunteers. Topotecan is thus subject to significant gender-dependent differences in pharmacokinetics that arise as a result of a physiological difference in hematocrit values between males and females. This finding may have significant implications for the interpretation of the relationships between pharmacokinetics and pharmacodynamic outcome of topotecan treatment, and may provide a basis for the development and refinement of future clinical protocols.