Pharmacokinetics, toxicities, and tissue concentrations of belotecan sprayed by rotational intraperitoneal pressurized aerosol chemotherapy in a pig model

Abstract

Objective: We evaluated the pharmacokinetics, tissue concentrations, and toxicities of belotecan during rotational intraperitoneal pressurized aerosol chemotherapy (RIPAC) in pigs.

Methods: We sprayed belotecan in 10% and 30% of doses for intravenous chemotherapy in six pigs (cohort 1, n=3, 0.50 mg/m²; cohort 2, n=3, 1.5 mg/m²). We evaluated the time-dependent plasma concentrations of belotecan before RIPAC to 120 hours for the pharmacokinetics, tissue concentrations in twelve peritoneal regions, and hepatic and renal functions before RIPAC to 120 hours in the 2 cohorts.

Results: Mean values of the peak plasma concentration (C_max), the time to C_max, the time taken for C_max to drop in half, and the area under the curve from time zero to the time of last quantifiable concentration were 905 and 3,700 ng/mL, 1.42 and 1.50 hours, 3.64 and 5.60 hours, and 2,260 and 17,900 pg·hr/mL in cohorts 1 and 2, respectively. Mean values of tissue concentrations were 1.5 to 15.3 times higher in cohort 1 than in cohort 2 despite the similar ratio of tissue to plasma concentration, and tissue concentrations in the two cohorts were higher in the parietal peritoneum than in the visceral peritoneum. However, hepatic and renal functions were not different before RIPAC to 120 hours in the two cohorts.

Conclusion: RIPAC using belotecan of 0.5 mg/m² and 1.5 mg/m² may be feasible with fewer hepatic and renal toxicities in pigs. Thus, belotecan of 1.5 mg/m² may be considered as the starting dose for RIPAC in a phase 1 trial.

Keywords: Aerosols; Drug Therapy; Pharmacokinetics; Swine; Tissues.

Fig. 1. The plasma concentration-time curve of belotecan used in rotational intraperitoneal pressurized aerosol chemotherapy: (A) belotecan of 0.5 mg/m²; (B) belotecan of 1.5 mg/m².

Fig. 2. Tissue concentrations of belotecan used in rotational intraperitoneal pressurized aerosol chemotherapy based on the modified peritoneal cancer index: (A) belotecan of 0.5 mg/m²; (B) belotecan of 1.5 mg/m².