The objective of this study was to determine the influence of pleural and ascitic fluid on the pharmacokinetics of the antitumor
camptothecin derivative
topotecan. Four patients with histological proof of malignant solid
tumor received
topotecan (0.45 or 1.5 mg/m2) p.o. on several occasions in both the presence and absence of third space volumes. Serial plasma and pleural or ascitic fluid samples were collected during each dosing and analyzed by high-performance liquid chromatography for both the intact
lactone form of
topotecan and its ring-opened carboxylate form. The apparent
topotecan clearance demonstrated substantial interpatient variability but remained unchanged within the same patient in the presence [110 +/- 55.6 liters/ h/m2 (mean +/- SD of eight courses)] or absence of pleural and ascitic fluid [118 +/- 31.1 liters/h/m2 (mean +/- SD of seven courses)]. Similarly, terminal half-lives and area under the concentration-time curve ratios of
lactone:total
drug in plasma were similar between courses within each patient.
Topotecan penetration into pleural and ascitic fluid demonstrated a mean lag time of 1.61 h (range, 1.37-1.86 h), and ratios with plasma concentration increased with time after dosing in all patients. The mean ratio of third space
topotecan total
drug area under the concentration-time curve to that in plasma was 0.55 (range, 0.26-0.87). These data indicate that
topotecan can be safely administered to patients with
pleural effusions or
ascites and that there is substantial penetration of
topotecan into these third spaces, which may prove beneficial for local antitumor effects.