Clinical Pharmacology of 9‐Aminocamptothecin

Abstract

The clinical pharmacology of the new topoisomerase I inhibitor, 9-aminocamptothecin (9-AC), administered over the dose range of 5 to 47 pg/m2/h was analyzed in a Phase I trial' in 44 adult cancer patients with solid tumors. Steady-state 9-AC lactone and total (lactone + carboxylate) plasma concentrations (Css) were measured in all patients using a high-performance liquid chromatography assay.2 Thirteen patients also underwent extended blood sampling to determine the distribution and elimination kinetics of 9-AC.At steady-state, the percent of the total drug circulating in plasma as the active 9-AC lactone was relatively low, only 8.7 ? 4.7% (mean t SD). Total body clearance of 9-AC was uniform over the entire dose range (24.5 * 7.3 Lihim'); however, the clearance of total 9-AC was non-linear, increasing from 1.04 to 2.84 L/h/m2 over the dose range examined (TABLE 1). The volume of distribution at steady-state (Vss) for 9-AC lactone was large, 195

Campthotecin Design and Delivery Approaches for Elevating Anti‐Topoisomerase I Activities in Vivo

“…The interspecies variations in albumin binding noted for these camptothecins may in part explain why 9-aminocamptothecin (9-AC) was highly effective against human cancer in xenograft models 5 but has performed poorly in humans trials. 19,20 In addition to modulating human blood stability, the presence of physiologically relevant concentrations of HSA can greatly attenuate (by orders of magnitudes) the anticancer activities (IC 50 values) of these agents. 21,22 In humans it appears that protein binding interactions make it difficult to achieve therapeutically effective unbound lactone levels of these agents, particularly when we consider that continuous exposures (for tumors cells to cycle through S-phase) of the active lactone form are requisite for efficacy purposes.…”

“…Perhaps as a result of these species‐specific interactions, the clinical translation of the impressive biological activities observed in murine models has been very difficult to achieve. The interspecies variations in albumin binding noted for these camptothecins may in part explain why 9‐aminocamptothecin (9‐AC) was highly effective against human cancer in xenograft models5 but has performed poorly in humans trials 19,20. In addition to modulating human blood stability, the presence of physiologically relevant concentrations of HSA can greatly attenuate (by orders of magnitudes) the anticancer activities (IC 50 values) of these agents 21,22.…”

The Clinical Development of 9‐Aminocamptothecin

“…However, hepatic metabolites of 9-AC have not been identified. 31 An alternative explanation may be the induction of transport proteins by these same agents that could lead to increased 9-AC clearance and biliary secretion in these patients. 32 In pharmacodynamic studies, 9-AC steady-state plasma concentrations 28,32 and AUC 18,19,33 correlated with the dose-limiting toxicity of neutropenia.…”

“…This may be due to increased metabolic clearance of 9‐AC in patients receiving hepatic enzyme‐inducing antiepileptic agents, such as phenytoin, carbamazepine, phenobarbital, primidone, felbamate, and valproic acid. However, hepatic metabolites of 9‐AC have not been identified 31. An alternative explanation may be the induction of transport proteins by these same agents that could lead to increased 9‐AC clearance and biliary secretion in these patients 32.…”