Topotecan lacks third space sequestration

The objective of this study was to determine the influence of pleural and a scitic fluid on the pharmacokinetics of the antitumor camptothecin derivati ve topotecan. Four patients with histological proof of malignant solid tumo r received topotecan (0.45 or 1.5 mg/m(2)) p.o. on several occasions in bot h the presence and absence of third space volumes. Serial plasma and pleura l or ascitic fluid samples were collected during each dosing and analyzed b y highperformance liquid chromatography for both the intact lactone form of topotecan and its ring-opened carboxylate farm. The apparent topotecan cle arance demonstrated substantial interpatient variability but remained uncha nged within the same patient in the presence [110 +/- 55.6 liters/ h/m(2) ( mean +/- SD of eight courses)] or absence of pleural and ascitic fluid [118 +/- 31.1 liters/h/m(2) (mean +/- SD of seven courses)]. Similarly, termina l half-lives and area under the concentration-time curve ratios of lactone: total drug in plasma were similar between courses within each patient. Topo tecan penetration into pleural and ascitic fluid demonstrated a mean lag ti me of 1.61 h (range, 1.37-1.86 h), and ratios with plasma concentration inc reased with time after dosing in all patients. The mean ratio of third spac e topotecan total drug area under the concentration-time curve to that in p lasma was 0.55 (range, 0.26-0.87). These data indicate that topotecan can b e safely administered to patients with pleural effusions or ascites and tha t there is substantial penetration of topotecan into these third spaces, wh ich may prove beneficial for local antitumor effects.