Evaluation of potentially excessive plasma gemcitabine (dFdC) concentrations produced by 30-minute dFdC infusions

Abstract

2019 Background: The phosphorylation of dFdC to active metabolites is saturable, whereas its deamination to the inactive metabolite, 2'2'-difluorodeoxyuridine (dFdU) is not. 30-min dFdC infusions produce plasma concentrations greater than the 10–15 μM that saturate intracellular phosphorylation. We utilized data from patients given 30-min infusions of dFdC to evaluate the percentage of plasma AUC associated with dFdC concentrations ≥ 10–15 μM. Methods: 31 patients with varying degrees of renal and hepatic function were enrolled in CALGB 9565 and underwent intensive pharmacokinetic sampling after being treated with 30-min dFdC infusions at doses of 650–950 mg/m2. Plasma concentrations of dFdC and dFdU were determined by HPLC. Plasma dFdC and dFdU concentration vs. time data were modeled using a 5-compartment model in ADAPT II and additional mathematical methods were developed using MATLAB. AUC was calculated using Simpson's rule and patient-specific pharmacokinetic parameters so as to calculate the total AUC (TAUC) and excessive AUC (EAUC). The fraction of each patient's dFdC AUC spent above 10 and 15 μM was then calculated from the ratio EAUC / TAUC. Results: 4 patients received 650 mg/m2, 17 patients received 800 mg/m2, and 10 patients received 950 mg/m2 of dFdC. The percentages of total dFdC AUC spent above the 10 μM threshold were 68 ± 16, 49 ± 15 and 57 ± 11% for doses of 650, 800, and 950 mg/m2, respectively. The percentages of total dFdC AUC spent above the 15 μM threshold were 58 ± 21, 35 ± 16, and 43 ± 13% for doses of 650, 800, and 950 mg/m2, respectively. Conclusions: Administering dFdC by 30-min infusion resulted in approximately half of the plasma drug exposure (as measured by AUC) occurring above dFdC concentrations that saturate its phosphorylation to active metabolites. This excessive drug may be clinically inconsequential because of its inactivation through deamination to dFdU. The data argue for studying additional patients with normal organ function and other schedules of dFdC delivery. Support: U10 CA44691, National Cancer Institute and a Whitaker Foundation Graduate Student Fellowship (JAF). Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eil Lilly Corp. Eli Lilly Corporation