Topotecan (Hycamtin), a semisynthetic water-soluble derivative of camptothecin, is a potent inhibitor of DNA topoisomerase I in vitro and has demonstrated encouraging antitumour activity in a wide variety of tumours, including ovarian cancer and small cell lung cancer. Now approved in the US, topotecan has completed single-agent phase I testing; phase II/III trials are ongoing. Under physiological conditions the lactone moiety of topotecan undergoes a rapid and reversible pH-dependent conversion to a carboxylated open-ring form, which lacks topoisomerase I inhibiting activity. At equilibrium at pH 7.4 the open-ring form predominates. Topotecan is stable in infusion fluids in the presence of tartaric acid (pH < 4.0), but is unstable in plasma, requiring immediate deproteinisation with cold methanol after blood sampling and storage of the extract at -30 degrees C to preserve the lactone form. Topotecan has been administered in phase I trials in several infusion schedules ranging from 30 minutes to 21 days. The plasma decay of topotecan concentrations usually fits a 2-compartment model. Rapid hydrolysis of topotecan lactone results in plasma carboxylate levels exceeding lactone levels as early as 45 minutes after the start of a 30-minute infusion. The peak plasma concentrations and the area under the plasma concentration-versus-time curves (AUC) show linear relationship with increasing dosages. No evidence of drug accumulation is seen with daily 30-minute infusions for 5 consecutive days. Topotecan lactone is widely distributed into the peripheral space, with a mean volume of distribution (Vd) at steady-state of 75 L/m2. The mean total body clearance of the lactone form is 30 L/h/m2, with a mean elimination half-life (t1/2 beta) of 3 hours; renal clearance accounts for approximately 40% of the administered dose with a large interindividual variability. The oral bioavailablity of topotecan is approximately 35%. The low bioavailability may be caused by hydrolysis of topotecan lactone in the gut, yielding substantial amounts of the open-ring form, which is poorly absorbed. Renal dysfunction may decrease topotecan plasma clearance. Creatinine clearance is significantly, but poorly, correlated with topotecan clearance. Hepatic impairment does not influence topotecan disposition. Indices of systemic exposure (steady-state concentrations and AUC) are correlated with the extent of myelotoxicity. Sigmoidal functions adequately describe the relationships between systemic exposure and the percentage decrease in neutrophils.