Intra-arterial gemcitabine versus intravenous gemcitabine: Pharmacokinetic sub-study of the TIGeR-PaC phase 3 clinical trial.

Abstract

719 Background: Localized, dual balloon catheter-mediated, intra-arterial delivery of gemcitabine (IAG) targeted to tumors/tissue can provide higher local drug potency (1). Furthermore, IAG may result in a decreased systemic drug concentration and associated side effects. In patients with locally advanced pancreatic cancer (LAPC), this approach is currently being tested in the TIGeR-PaC Phase 3 clinical trial. Herein we report the results of a 19-patient pharmacokinetics (PK) sub-study analysis within TIGeR-PaC. Methods: PK analyses were performed for a total of 19 participants across 6 TIGeR-PaC study sites; 11 participants received IAG with the RenovoCath dual balloon catheter at 1000 mg/m 2 over 20 minutes and 8 participants received intravenous gemcitabine (IVG) (5 at 1000 mg/m 2 , 2 at 800 mg/m 2 , 1 at 500 mg/m 2 ) over 30 minutes. IAG target treatment arteries were either the superior mesenteric artery (SMA) (n=5) or branches of the celiac axis (n=6). At T = -5, 10, 15, 20, 30, 40, 60, and 90 minutes from the onset of infusion, 2 mL of blood was collected in heparinized tubing containing 25 mcg/mL of tetrahydrouridine. Plasma from each sample was frozen and shipped to a reference lab for gemcitabine assays. Maximum plasma drug concentration (C max ) and the area under the drug plasma concentration curve (AUC) based on the terminal phase were compared between the two groups; for these dose-dependent parameters, only participants who received 1000 mg/m 2 gemcitabine (IAG, N=11; IVG, N=5) were included in the comparison analysis. Results: As shown in the table, AUC was significantly lower with IAG (4.99) compared to IVG (9.97) ( P = 0.019). Peak plasma gemcitabine concentrations were also lower with IAG (12.9 mcg/mL) vs. IVG (14.6 mcg/mL) despite a 50% higher drug concentration during IAG vs. IVG (1000 mg/m 2 infused over 20 minutes vs. 30 minutes, respectively). There was no difference in plasma levels between IAG treatment sites (SMA vs. celiac axis). Conclusions: In this analysis, localized, dual-balloon catheter-mediated IAG resulted in decreased systemic levels of gemcitabine compared to IVG. Thus, in addition to providing increased local potency, the IAG approach may also be beneficial in decreasing gemcitabine-related systemic side effects. 1. Farsad K, et al. 2024. JVIR 35:1043-48 e3. Clinical trial information: NCT03257033 . Effects of treatment mode on mean pharmacokinetic parameters for gemcitabine. PK parameter IAG Group(N=11) IVG Group(N=5) C max (mcg/mL), Mean (SE) 12.9 (±2.4) 14.6 (±1.2) AUC (hr ⋅ mcg/mL), Mean (SE) 4.99 (±0.96) 9.97 (±1.9) AUC = area under the curve; C max = maximum serum concentration; IAG = intra-arterial gemcitabine; IVG = intravenous gemcitabine; PK = pharmacokinetic; SE = standard error.