The plasma pharmacokinetics of 9-aminocamptothecin (AC; NSC 603071), a potent toposomerase I inhibitor, was characterized in conjunction with efficacy studies against subcutaneous (s.c.) xenografts of human HT-29 colon adenocarcinoma in mice. These studies were conducted with the objective of developing a pharmacologically guided dosing regimen for the initial clinical evaluation of AC in cancer patients. When s.c. bolus injections of 4 mg/kg were given to tumored mice on a Q4Dx8 schedule, a solution of the drug provided only marginal activity, whereas a suspension afforded complete tumor regression. Partial activity with the solubilized formulation of AC was retrieved by increasing the frequency of administration. Systemic drug absorption from the s.c. solution was rapid, providing a peak plasma concentration of 1.6 fM at 30 min for the active lactone form of AC. However, its elimination was also fast, as evidenced an apparent biological half-life of 1.6 hr . The inactive opened lactone carboxylate form of AC accounted for 35% of the total drug AUC. Formulating the compound as a suspension effected a marked prolongation in the systemic duration of AC. With an apparent terminal half-life of 17.5 hr, two days were required for AC lactone plasma levels to decay from a peak of 246 nM (15 min) to 10 nM. Furthermore, only 17% of the agent was present in plasma as the inactive carboxylate. Whole body autoradiography revealed that, when delivered as a suspension, the drug remained in a depot at the s.c. injection site and a considerable amount of the dose was still evident after 4 days. These studies indicate that maintaining the AC lactone plasma concentration above a threshold level for a prolonged time period is required for optimal therapeutic effects. A 3-5 day continuous i.v. infusion schedule for the inaugural phase I trials is therefore recommended.
