Fractionated high-dose vitamin c sustains higher plasma trough concentrations in advanced solid tumors: a phase I clinical study

High-dose vitamin C (HDVC) has a short half‑life of approximately 2 h, and once‑daily dosing results in sub‑therapeutic plasma concentrations for most of the dosing interval, potentially limiting its pro‑oxidant antitumor activity. In this phase I study, 18 patients with advanced solid tumors were assigned to three cohorts (n = 6 each): Group A (0.5 g/kg once daily, total daily dose 0.5 g/kg), Group B (0.5 g/kg every 12 h, total daily dose 1.0 g/kg), and Group C (0.75 g/kg every 12 h, total daily dose 1.5 g/kg). Plasma trough concentrations were measured daily for 7 days. Compared to Group A, Group B exhibited significantly higher trough concentrations throughout the study (P < 0.05), demonstrating superior maintenance of therapeutic levels. Further dose escalation to 0.75 g/kg twice daily (Group C) provided no additional trough concentration benefit versus Group B (P > 0.05), consistent with the plateau in peak concentrations at single doses above approximately 70 g/m² (∼1.0 g/kg). All regimens were well tolerated, with only one mild nausea (5.6%) and no serious adverse events. Fractionated dosing (0.5 g/kg every 12 h) significantly improves trough concentration maintenance with good tolerability. This optimized regimen (total daily dose 1.0 g/kg) provides a rational pharmacokinetic basis for future phase II trials designed to evaluate whether sustained pro‑oxidant levels translate into enhanced clinical efficacy.