Trans-arterial micro perfusion (TAMP)–mediated localized intra-arterial gemcitabine delivery produced lower systemic gemcitabine exposure and higher exposure to the inactive metabolite difluorodeoxyuridine compared with systemic intravenous (IV) gemcitabine in patients with locally advanced pancreatic cancer, according to a pharmacokinetic and pharmacodynamic sub-study of the phase 3 TIGeR-PaC trial (NCT03257033) published in Cancer Chemotherapy and Pharmacology.¹
Among 16 sub-study patients (intra-arterial gemcitabine arm, n = 11; IV gemcitabine arm, n = 5), the mean gemcitabine area under the concentration-time curve from time 0 to the last measurable concentration (AUC0-t) was 4.9 h*mcg/mL (standard error [SE], 0.94) with intra-arterial gemcitabine vs 8.8 h*mcg/mL (SE, 0.99) with IV gemcitabine (P = .018). Conversely, the mean difluorodeoxyuridine maximum concentration (Cmax) was higher with intra-arterial gemcitabine, at 48.3 mcg/mL (SE, 5.61) vs 30.6 mcg/mL (SE, 2.20) with IV gemcitabine (P = .012), consistent with more rapid local conversion of gemcitabine to its inactive metabolite.
Increased difluorodeoxyuridine AUC0-t correlated with a pre- to post-treatment reduction in CA 19-9 tumor marker levels among intra-arterial gemcitabine–treated patients (Pearson r = –0.75; P = .034). However, the correlation between reduced CA 19-9 levels and systemic gemcitabine exposure was modest and did not reach statistical significance (Pearson r = –0.39; P = .334).
“In addition to providing increased local potency, the intra-arterial gemcitabine approach, in which gemcitabine is rapidly converted to its inactive metabolite difluorodeoxyuridine, may also be beneficial in decreasing gemcitabine-related systemic [adverse] effects [and provide] improved outcomes in patients with locally advanced pancreatic cancer,” the study authors wrote.
How was the TIGeR-PaC pharmacokinetic sub-study conducted?
The sub-study enrolled 16 patients across 6 TIGeR-PaC study sites who had histologically or cytologically confirmed locally advanced pancreatic cancer and an ECOG performance status of 0 or 1. Patients were randomly assigned as part of the parent trial to receive intra-arterial gemcitabine or IV gemcitabine. Patients in the intra-arterial gemcitabine group received localized infusions of gemcitabine at 1000 mg/m² over 20 minutes via TAMP using a double-balloon endovascular catheter, whereas those in the IV gemcitabine group received systemic gemcitabine at 1000 mg/m² over 30 minutes.
Blood samples for pharmacokinetic analysis were drawn immediately before, during, and after infusion. Gemcitabine and difluorodeoxyuridine were quantified by liquid chromatography/mass spectrometry. CA 19-9 levels were measured before treatment and 2 weeks afterward as a surrogate for tumor response. In the intra-arterial gemcitabine group, the mean age was 63.1 years (range, 43-84) vs 67.8 years (range, 65-70) in the IV gemcitabine group; all 11 patients in the intra-arterial gemcitabine arm had received prior stereotactic body radiation therapy; localized delivery was performed via the celiac axis in 5 patients and the superior mesenteric artery in 6 patients.
TAMP-Mediated Intra-Arterial Gemcitabine Delivery in Locally Advanced Pancreatic Cancer: Pharmacokinetic Highlights
- Gemcitabine Cmax and AUC0-t were lower with intra-arterial gemcitabine than with IV gemcitabine, whereas difluorodeoxyuridine Cmax and AUC0-t were higher, consistent with rapid local conversion to the inactive metabolite.
- The targeted extraction ratio was 0.511, indicating that approximately 51% of intra-arterial–delivered gemcitabine was extracted at the tumor site before reaching systemic circulation.
- Difluorodeoxyuridine exposure correlated with CA 19-9 level reduction, whereas systemic gemcitabine exposure did not.
What additional findings did the pharmacokinetic and pharmacodynamic TIGeR-PaC analyses show?
Gemcitabine was rapidly metabolized following both routes, but peak plasma concentration and total systemic exposure of the parent drug were markedly lower with intra-arterial gemcitabine despite a 50% higher concentration during infusion. The absolute bioavailability of intra-arterial–delivered gemcitabine relative to the IV approach was 0.489, yielding a targeted extraction ratio of 0.511 and indicating that approximately half of the intra-arterial–delivered dose was extracted at the tumor site before reaching systemic circulation. No differences in Cmax or AUC0-t for gemcitabine or difluorodeoxyuridine were observed between delivery via the superior mesenteric artery and the celiac axis.
Investigators observed a CA 19-9 level reduction of up to 40% after a single intra-arterial gemcitabine treatment and noted that difluorodeoxyuridine, given its longer half-life and renal excretion, may serve as a better marker of localized tumor drug delivery than serum gemcitabine.
What are the implications and limitations of the pharmacokinetic findings with TAMP-mediated gemcitabine in pancreatic cancer?
Locally advanced pancreatic cancer accounts for approximately half of new pancreatic cancer diagnoses and carries a median overall survival of 11 to 16 months with systemic chemotherapy. Recent regulatory activity in pancreatic cancer has largely centered on targeted agents in the metastatic setting, most notably the August 2026 FDA approval of daraxonrasib (Rasonque) for the treatment of adult patients with metastatic pancreatic adenocarcinoma who have received 1 or more prior systemic therapies or are not candidates for multi-agent systemic therapy.² However, overall, the gemcitabine sub-study authors noted that the pancreatic cancer treatment paradigm is in need of more effective and tolerable treatment options.
The authors framed the reduced systemic exposure of active gemcitabine with intra-arterial gemcitabine as a signal that could translate into fewer systemic toxicities when the standard 1000-mg/m² dose is delivered locally rather than intravenously, though the sub-study did not formally assess safety.
This analysis was limited by a small cohort of 16 patients, a clear outlier in the intra-arterial gemcitabine dataset with high gemcitabine Cmax and AUC0-t, and reliance on single-timepoint measurements and CA 19-9 level as a response surrogate.
“Results of the ongoing TIGeR-PaC study will help determine whether [these sub-study findings translate] into improved survival and reduced toxicity with intra-arterial gemcitabine vs IV gemcitabine.
References
- Novelli PM, Zervos EE, Zureikat AH, et al. Pharmacokinetic and pharmacodynamic sub-study of trans-arterial vs. intravenous gemcitabine in the TIGeR-PaC phase 3 clinical trial. Cancer Chemother Pharmacol. 2026;96(1):91. doi:10.1007/s00280-026-04939-0
- FDA approves first in class targeted therapy for metastatic pancreatic cancer. FDA. August 26, 2026. Accessed August 26, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-class-targeted-therapy-metastatic-pancreatic-cancer?utm_medium=email&utm_source=govdelivery
