Gemcitabine (G) plamsa and intracellular pharmacokinetics in E6201: Greater metabolite levels using fixed dosing rate (FDR) delivery

Abstract

2024 Background: Gemcitabine (G) is an antimetabolite which requires activation by the rate-limiting enzyme dCK to its active metabolite, dFdCTP. FDR delivery of G at 10 mg/m2/minute may allow greater formation of active metabolite and improved activity. E6201 randomly assigned first line pancreatic cancer patients to three arms: A (G 1000 mg/m2 over 30 minutes), B FDR G (1500 mg/m2 over 150 minutes), and C GemOx (1000 mg/m2 over 100 minutes with oxaliplatin 100 mg/m2). Methods: Investigators from 18 centers contributed 23 sample sets on the first dose of G. Five time points over 4 hrs were sampled (baseline, mid infusion, end infusion, 1–2 post and 4 hrs). Plasma fractionation along with the PBMC purification and subsequent perchloric acid extraction were conducted locally with THU 1 mg (cytidine deaminase inhibitor). Samples were shipped overnight to the central lab where G and its metabolite dFdU were quantified from deproteinized plasma by reverse phase HPLC. dFdCTP was quantified by ion-exchange HPLC in neutralized PBMC extracts after removal of ribonucleotide triphosphates. Data were fit to nonlinear models (WinNonLin, v4.1) and comparisons amongst dosing groups employed the non-parametric, 2-sided Mann-Whitney test. Results: For Arms A, B and C the plasma AUCs were respectively (median ± SD): 4542 ± 2472 (N=9), 8603 ± 2608 (N=8) and 9130 ± 8788 (N=6) ng/ml x hr. The difference between group A and B (p=0.003) and A and C (p=0.05) were statistically different. Intracellular dFdCTP AUCs for groups A, B, and C were: 1862 ± 794 (N=8); 3725 ± 7763 (N=8) and 5024 ± 2113 (N=5) and significantly different for both A vs. B (p=0.05) and borderline significant for A vs C (p=0.065). The latter comparison is limited by a small number of samples. Conclusions: When studied in a multi-centered, randomized cooperative group setting, FDR delivery of G results in higher plasma AUC, and increased intracellular levels of active metabolite dFdCTP. These data support the concept that fixed dose rate delivery of G results in greater intracellular metabolite production at similar and equitoxic doses. Supported by ECOG NYU620HH04–00, NCI CA16087, CA2115, and from Eli Lilly. No significant financial relationships to disclose.