A Pharmacokinetic Study of High‐Dose Intravenous Vitamin C in Healthy Volunteers and Oncological Patients

Abstract

Purpose : High-dose intravenous vitamin C (IVC) is used in a variety of disorders and clinical trials (e.g. cancer, sepsis, burn, infection, fatigue, chelation). However, reliable pharmacokinetic (PK) data is limited and misinformation exists in clinical applications of vitamin C. Here we conducted a study in healthy volunteers and cancer patients to detail the PK of escalating doses of IVC from 1 to 100 g. Methods : A single-site standard PK study was conducted in 12 healthy volunteers and 12 cancer patients. Healthy subjects received a single-dose IVC infusion at 1, 5, 10, 25, 50, or 75 g, while the 100 g was administered as 4-dose infusions separated by 1-week; oncology subjects received 25, 50, 75, or 100 g of IVC with 4-dose infusions at each dose level separated by 1-week. Blood and urine samples were collected pre-infusion and at various time points within 24 hours post-infusion. Complete blood counts, blood chemistry, metabolic parameters were measured. Urine oxalate, urate, and ascorbate were also detected. Pharmacokinetic parameters were computed using noncompartmental methods. Adverse events were monitored during the study. Results : In healthy subjects, ascorbate maximum plasma concentration (Cmax) and the area under the concentration-time curve over 24 hours (AUC0-24) increased proportionally with the IVC doses. Half-life (t1/2) of ascorbate was stable on these doses (1.8 ± 0.3 h). No saturation of clearance was observed. When receiving 100 g of IVC, oncology patients had significantly lower Cmax than healthy participants (oncology: 151 ± 42 mg/dL vs. healthy: 578 ± 58 mg/dL) and AUC0-24 (oncology: 942 ± 225 hr*mg/dL vs. healthy: 2499 ± 55 hr*mg/dL), but a longer half-life (oncology: 5.4 ± 2.6 hours vs. healthy: 1.8 ± 0.3 hours). Consequently, the 24-h total ascorbate excretion in urine was significantly lower in oncology subjects than healthy subjects at 100 g (oncology: 38.6 ± 10.0 g vs. healthy: 107.4 ± 1.9 g). No adverse events were observed except for Grade 1 chills in one oncology participant at 100 g. MTD was not reached. There were no significant changes in blood glucose or ECG tracings in all participants. The blood calcium decreased immediately after patients received the IVC at the high dose levels (75 and 100 g), but the change was temporary and likely related to osmolarity of the infuscate. IVC had no significant effect on blood counts or indicators of liver and kidney functions including ALT, AST, albumin-to-creatinine ratio and urea nitrogen. Conclusion : Intravenously administered ascorbate resulted in systemic pharmacological concentrations with Cmax linearly correlated with the dose. Disease conditions such as cancer may change the Cmax and t1/2, presumably because of tissue utilization. Ascorbate was exclusively excreted through urine. High does up to 100 g/infusion did not change blood counts or major blood chemistry, nor kidney or liver functions. This study is the first to report pharmacokinetics of escalating doses of IVC from 1 to 100 g with sampling over 24-hours in both healthy and oncology subjects. The data could be used to clarify existing misinformation and to guide future clinical trials.