Phase I pharmacokinetic study of high-dose vitamin C dosing regimens in patients with advanced hepatobiliary-pancreatic cancers.

Abstract

e15133 Background: High-dose vitamin C (HDVC) has demonstrated synergistic or sensitizing effects with chemotherapy and radiotherapy in preclinical studies. However, its clinical translation has been largely limited due to suboptimal pharmacokinetics, characterized by a short half-life and insufficient duration of effective plasma concentration. To investigate whether optimizing the dosing regimen can prolong the maintenance of effective plasma vitamin C concentrations in patients with advanced hepatobiliary and pancreatic malignancies, thereby providing a new strategy to enhance its clinical antitumor effects. Methods: 18 patients with advanced hepatobiliary and pancreatic malignancies were enrolled and assigned to three dosing cohorts: Cohort A (0.5 g/kg once daily, qd), Cohort B (0.5 g/kg every 12 hours, q12h), and Cohort C (0.75 g/kg every 12 hours, q12h), with 6 patients in each group. All patients received standard antitumor therapy concurrently with HDVC, administered via a central venous catheter for 7 consecutive days. Plasma vitamin C concentrations were measured by high-performance liquid chromatography (HPLC) at fixed time points daily. Results: No significant differences in baseline plasma vitamin C concentrations were observed among the three cohorts. Compared with the once-daily regimen (0.5 g/kg qd), the every-12-hour regimen (0.5 g/kg q12h) significantly enhanced the maintenance level of plasma vitamin C concentration. However, increasing the dose to 0.75 g/kg q12h did not further elevate the plasma concentration. Regarding safety, only one patient experienced nausea and discomfort, with no other significant adverse events observed. Conclusions: In patients with advanced hepatobiliary and pancreatic malignancies, increasing the dosing frequency (e.g., to every 12 hours) under the same total daily dose can more effectively maintain the plasma concentration of HDVC with a favorable safety profile. This provides a feasible dosing optimization approach to potentially improve its antitumor efficacy. A further dose increase to 0.75 g/kg q12h did not demonstrate additional pharmacokinetic benefits in this study. Clinical trial information: NCT07121036 .