Introduction We evaluated the pharmacokinetics, tissue concentrations, and toxicities of gemcitabine during rotational intraperitoneal pressurized aerosol chemotherapy (RIPAC) in pigs.
Methods We sprayed gemcitabine of 10% and 30% of doses for intravenous chemotherapy in six pigs (cohort 1, n=3, 300 mg/m2; cohort 2, n=3, 1,000 mg/m2). We evaluated the time-dependent plasma concentrations of gemcitabine before RIPAC to 120 hr for the pharmacokinetics, tissue concentrations in twelve peritoneal regions, and hepatic and renal functions before RIPAC to 120 hr in the two cohorts.
Results Mean values of the peak plasma concentration (Cmax), the time to Cmax (Tmax), the time taken for Cmax to drop in half (T1/2), and the area under the curve from time zero to the time of last quantifiable concentration (AUClast) were 1,320 and 7,476 ng/ml, 1.92 and 1.83 hr, 1.52 and 1.96 hr, and 4,718 and 26,347 ng·hr/ml in cohorts 1 and 2, respectively. Mean values of tissue concentrations were 1.3 to 11.2 times higher than in cohort 2 and in cohort 1 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. Cohort 2 showed the change of hepatic function after RIPAC, whereas there were no changes of hepatic and renal functions in cohort 1.
Conclusion/Implications Considering the change of hepatic function in gemcitabine of 1,000 mg/m2, gemcitabine of 300 mg/m2 can be considered as the stating dose for RIPAC in a phase 1 trial.
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