Pharmacokinetic and pharmacodynamic sub-study of trans-arterial vs. intravenous gemcitabine in the TIGeR-PaC phase 3 clinical trial
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Key result
Localized intra-arterial gemcitabine cuts systemic exposure ~44% versus intravenous delivery.
- P=0.018
- n=16
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Why the study?
Localized intra-arterial delivery of gemcitabine may increase tissue concentration and decrease systemic dosing, potentially reducing systemic concentration and associated side effects.
Does localized intra-arterial gemcitabine alter systemic pharmacokinetics and correlate with tumor marker reduction compared to intravenous gemcitabine in patients with locally advanced pancreatic cancer?
Key Points
- To evaluate whether localized intra-arterial delivery of gemcitabine lowers systemic drug exposure and enhances tumor targeting compared to standard intravenous administration.
- Pharmacokinetic sub-study nested within the multicenter TIGeR-PaC phase 3 clinical trial (NCT03257033) analyzing N=16 participants across 6 study sites.
- Patients received either localized intra-arterial gemcitabine via targeted arterial micro-perfusion (n=11) or systemic intravenous gemcitabine (n=5).
- Plasma concentrations of gemcitabine and its inactive breakdown product difluorodeoxyuridine (dFdU) were measured alongside CA 19-9 tumor marker responses.
- Intra-arterial delivery resulted in lower peak gemcitabine concentrations and reduced systemic exposure compared to intravenous delivery (AUC0−t/dose geometric mean of 2.13 vs. 4.36; bioavailability F=0.489; targeted extraction ratio Etarget=0.511).
- Intra-arterial infusion produced higher plasma levels of the inactive metabolite dFdU than intravenous infusion, indicating rapid local drug breakdown.
- Higher dFdU exposure following intra-arterial treatment correlated significantly with reductions in CA 19-9 tumor marker levels (Pearson's r = -0.75; P = 0.034).
Study Design
Type
RCT (n=16)
Randomization
Randomized
Multicenter
Yes
Structured PICO
Does localized intra-arterial gemcitabine alter systemic pharmacokinetics and correlate with tumor marker reduction compared to intravenous gemcitabine in patients with locally advanced pancreatic cancer?
P
Population
16 adults with locally advanced pancreatic cancer participated in a pharmacokinetic sub-study comparing intra-arterial versus intravenous gemcitabine.
I
Intervention
Localized intra-arterial gemcitabine (IAG) via trans-arterial micro perfusion (TAMP) at 1000 mg/m2 over 20 minutes.
C
Comparator
Systemic intravenous gemcitabine (IVG) at 1000 mg/m2 over 30 minutes.
O
Outcome
Maximum plasma drug concentration (Cmax) and area under the drug plasma concentration curve (AUC0-t) of gemcitabine and its metabolite dFdU.surrogate
Main Result
Absolute Event Rate: 4.9% vs 8.8%
p-value: p=0.018
Intra-arterial delivery of gemcitabine reduces systemic exposure to the active drug while increasing local conversion to its inactive metabolite, which correlates with reductions in the CA 19-9 tumor marker.
Limitations
- Small sample size (n=16)
- Presence of an obvious outlier in the IAG group with high gemcitabine Cmax and AUC0-t levels
- Systemic gemcitabine levels with IA delivery may represent systemic escape of the drug into the circulation via the microvasculature despite localized delivery
- Small sample size
- Presence of a clear outlier in the IAG dataset
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“New Paper on Pharmacokinetics and Pharmacodynamics of localized intra-arterial Gemcitabine. Advantages: Increased tissue concentration. Decreased systemic dosing/toxicity. More pertinent in an era of better systemic.”
“The findings from this PK/PD study provide additional meaningful mechanistic support for our TAMP platform's targeted drug-delivery approach. The results provide direct pharmacokinetic evidence supporting TAMP's potential to deliver chemotherapy more selectively to the tumor while limiting systemic exposure. These findings strengthen TAMP, enabled by our RenovoCath device, as a differentiated approach to improving the therapeutic index of chemotherapy in patients with LAPC.”
Implication
May reduce gemcitabine toxicity risk; hypothesis-generating for therapeutic index in targeted cancers.
Abstract
Purpose Localized intra-arterial delivery of gemcitabine (IAG) may provide advantages in terms of increased tissue concentration and decreased systemic dosing. We hypothesized IAG may result in decreased systemic gemcitabine concentration and associated side effects due to intracellular delivery prior to conversion to gemcitabine’s inactive metabolite, difluorodeoxyuridine (dFdU). Here we report the results of a pharmacokinetics and pharmacodynamics sub-study within the TIGeR-PaC phase 3 clinical trial (NCT03257033). Methods Analyses were performed for 16 participants across 6 TIGeR-PaC study sites; 11 participants received localized IAG and 5 participants received systemic intravenous gemcitabine (IVG). Gemcitabine and dFdU assays were performed on blood samples collected immediately before, during, and after infusion. CA 19 − 9 levels were measured prior to and 2 weeks after IAG treatment. Maximum plasma drug concentration (C max ) and the area under the drug plasma concentration curve (AUC 0−t ) were compared between treatment groups. Pearson’s correlation for AUC 0−t and the percent change in CA 19 − 9 levels was calculated for the IAG group. Results IAG resulted in lower gemcitabine C max and AUC 0−t and higher dFdU C max and AUC 0−t compared to IVG, consistent with a more rapid conversion of gemcitabine to dFdU with IAG versus IVG. With IAG, there was a significant correlation between increased dFdU levels and a pre- to post-treatment reduction in CA 19 − 9 levels (Pearson’s r = -0.75; P = 0.034). Conclusion In addition to providing increased local potency, localized IAG, in which gemcitabine is rapidly converted to its inactive metabolite dFdU, may also be beneficial in decreasing gemcitabine-related systemic side effects.
Discussion
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Cite This Study
Novelli et al. (2026) conducted an RCT in Locally advanced pancreatic cancer (LAPC) (n=16). Localized intra-arterial delivery of gemcitabine (IAG) via trans-arterial micro perfusion (TAMP) vs. Systemic intravenous gemcitabine (IVG) 1000 mg/m2 over 30 min was evaluated on Gemcitabine systemic exposure (AUC0-t in h*mcg/mL) (p=0.018). Localized intra-arterial delivery of gemcitabine significantly reduced systemic gemcitabine exposure (AUC0-t 4.9 vs 8.8 h*mcg/mL, p=0.018) compared to intravenous administration.
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