PLASMA AND CEREBROSPINAL-FLUID PHARMACOKINETICS OF 9-AMINOCAMPTOTHECIN (9-AC), IRINOTECAN (CPT-11), AND SN-38 IN NONHUMAN-PRIMATES

Purpose: The plasma and cerebrospinal fluid (CSF) pharmacokinetics of the camptothecin analogs, 9-aminocamptothecin (9-AC) and irinotecan, w ere studied in a nonhuman primate model to determine their CSF penetra tion. Methods: 9-AC, 0.2 mg/kg (4 mg/m(2)) or 0.5 mg/kg (10 mg/m(2)), was infused intravenously over 15 min and irinotecan, 4.8 mg/kg (96 mg /m(2)) or 11.6 mg/kg (225 mg/m(2)), was infused over 30 min. Plasma an d CSF samples were obtained at frequent intervals over 24 h. Lactone a nd total drug forms of 9-AC, irinotecan, and the active metabolite of irinotecan, SN-38, were quantified by reverse-phase HPLC. Results: 9-A C lactone had a clearance (CL) of 2.1 +/- 0.9 l/kg per h, a volume of distribution at steady state (Vd(ss)) of 1.6 +/- 0.7 l/kg and a half-l ife (t(1/2)) Of 3.2 +/- 0.8 h. The lactone form of 9-AC accounted for 26 +/- 7% of the total drug in plasma. The CSF penetration of 9-AC lac tone was limited. CSF 9-AC lactone concentration peaked 30 to 45 min a fter the dose at 11 to 21 nM (0.5 mg/kg dose), and the ratio of the ar eas under the CSF and plasma concentration-time curves (AUC(CSF): AUC( P)) was only 3.5 +/- 2.1%. For irinotecan, the CL was 3.4 +/- 0.4 l/kg per h, the Vd(ss) was 7.1 +/- 1.3 l/kg, and the t(1/2) was 4.9 +/- 2. 2 h. Plasma AUCs of the lactone form of SN-38 were only 2.0% to 2.4% o f the AUCs of irinotecan lactone. The lactone form of irinotecan accou nted for 26 +/- 5% of the total drug in plasma, and the lactone form o f SN-38 accounted for 55 +/- 6% of the total SN-38 in plasma. The AUC( CSF): AUC(P) ratio for irinotecan lactone was 14 +/- 3%. SN-38 lactone and carboxylate could not be measured (<1.0 nM) in CSF. The AUC(CSF): AUC(P) ratio for SN-38 lactone was estimated to be less than or equal to 8%. Conclusion: Despite their structural similarity, the CSF penet ration of 9-AC and SN-38 is substantially less than that of topotecan which we previously found to have an AUC(CSF): AUC(P) ratio of 32%.