A Pharmacokinetic Study of Single Oral Doses of Six Different Vitamin C Product Forms

A Randomized, Crossover, Pharmacokinetic Assessment of Single Oral Doses of Six Different Vitamin C Product Forms

Vitamin C (ascorbic acid) is an essential nutrient linked to many aspects of basic human physiology. It is a potent antioxidant and involved as a cofactor for many human enzymes, and its extreme deficiency can lead to a fatal disease known as scurvy and reduce immune function. Relatively less serious deficiency over a longer period of time may also increase cardiovascular disease and cancer risk. Deficiency is common amongst the Canadian general population, with around 5.5% being found to possess deficient plasma concentrations. Moreover, amongst many industrialized countries, rates of deficiency can be as high as 15% of the general population. Potential vitamin C overdose is not considered to be serious, but symptoms can include nausea, vomiting, headache, rash, and asthenia.

The pharmacokinetic profiles of vitamin C supplements are influenced by their formulation, impacting safety and efficacy. The study will compare the PK properties of six different vitamin C formulations, each over a 24 h test period.

Study Overview

• Status: Completed
• Conditions: Healthy; Pharmacokinetic
• Intervention / Treatment: Dietary supplement: TP1; Dietary supplement: TP2; Dietary supplement: TP3; Dietary supplement: TP4; Dietary supplement: CP; Dietary supplement: RP

Detailed Description

This is a randomized, 6-way crossover pharmacokinetic study to assess 6 different vitamin C formulations in healthy adults.

There is 1 comparator product (CP), 1 reference product (RP), and 4 test products (TP: TP1, TP2, TP3, TP4):

• TP1 (Vitamin C formulation 1, 1000 mg)
• TP2 (Vitamin C formulation 2, 1000 mg)
• TP3 (Vitamin C formulation 3, 1000 mg)
• TP4 (regular Vitamin C mega dose, 3000 mg)
• CP (Vitamin C formulation 4, 1000 mg)
• RP (regular Vitamin C, 1000 mg)

Each sequence will have 9 participants for a total of 27 participants.

• Sequence 1: TP1 → TP2 → TP3 → TP4 → CP → RP
• Sequence 2: RP → TP1 → TP2 → TP3 → TP4 → CP
• Sequence 3: CP → RP → TP1 → TP2 → TP3 → TP4

Pharmacokinetic blood sampling will occur pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 10 and 24 h post dose. Blood samples collected will be used to assess the PK profiles of all 6 formulations. PK parameters measured will include AUC0-24, Cmax, Tmax, AUCinf, T1/2, and Kel for L-ascorbic acid. L-ascorbic acid concentrations will be measured in urine to compare excretion during 0-4 h, 4-8 h, 8-10 h, and 10-24 h post-dose between all 6 formulations. L-ascorbic acid will also be measured in peripheral blood mononuclear cells at 8 h and 24 h post-dose to compare uptake and maintenance between all 6 formulations.

Gastrointestinal symptom questionnaire scores and total antioxidant capacity in plasma at 24 hours post-dose will also be compared between all 6 formulations.

Safety endpoints will be assessed throughout the study and will include reports of adverse events, vital signs, and safety laboratory assessments.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Guelph, Ontario, Canada, N1G 0B4
      • Nutrasource Site (Apex Trials)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• In good general health (i.e., no uncontrolled diseases or conditions) as deemed by the investigator.
• Are able to swallow the study products, in whole.
• Have a body mass index (BMI) between 18.0 to 29.9 kg/m2 (inclusive).
• Must have suitable veins for repeated venipuncture.
• No nicotine and/or nicotine products, including smoking or vaping of any kind (e.g., cigarettes) for at least 3 months before screening.
• Have maintained consistent dietary habits (including supplement intake) and lifestyle for the last 3 months before screening. Participants must be willing to maintain these habits throughout the duration of the study, with the exception of changes required by the vitamin C dietary restrictions.
• Willing to comply with the vitamin C dietary restrictions, 2 weeks prior to the baseline and throughout the duration of the study until the last study visit.
• Agree to follow the restrictions on concomitant treatments as listed in the protocol.
• Agree to follow the restrictions on lifestyle as listed in the protocol.
• Agree to use acceptable contraceptive methods as listed in the protocol.
• Willing and able to agree to the requirements of this study, willing to give voluntary consent, able to understand and read the questionnaires, and carry out all study-related procedures.
• Agrees not to donate blood until 3 months after study completion
• Must weigh ≥ 58.9 kg (130 lbs) at screening

Exclusion Criteria:

• Individuals who are lactating, pregnant or planning to become pregnant during the study.
• Have a known sensitivity, intolerability, or allergy to any of the study products or their excipients.
• Have Type I diabetes, Type II diabetes, high blood pressure (≥140 systolic or ≥90 diastolic mmHg), or thyroid disease.
• Have medical condition(s) known to interfere with absorption, distribution, metabolism, or excretion of the study product (e.g., Crohn's disease, short bowel, acute or chronic pancreatitis, or pancreatic insufficiency).
• Have a history of heart disease, renal or hepatic impairment/disease, gout, hemochromatosis, glucose-6-phosphate dehydrogenase deficiency, immune disorders and/or immunocompromised (i.e., HIV/AIDS).
• Have a history of cancer (except localized skin cancer without metastases or in situ cervical cancer), unless a minimum of 5 years before the screening visit have elapsed since full recovery.
• Reports a clinically significant illness during the 28 days before the first dose of study product, including acute inflammatory conditions or viral infections (e.g., cold, flu, COVID-19), or any other condition that, in the opinion of the investigator, may be of a concern for the study.
• Participants must not exceed the ''high'' physical activity level as defined by the International Physical Activity Questionnaire-- Short Form (IPAQ-SF) in the week prior to baseline and agree to adhere to this requirement throughout the study duration. A 'high' physical activity level is defend as having engaged in vigorous-intensity physical activity on at least 3 days achieving a total of 1500 or more Metabolic Equivalent of Task (MET)-minutes per week; or, having engaged in any combination of walking, moderate-intensity, or vigorous-intensity physical activities on 7 or more days achieving a total of 3000 or more MET-minutes per week.
• Reports a significant blood loss or blood donation totaling between 101 mL to 449 mL of blood within 30 days prior to the first PK visit or a blood donation of more than 450 mL within 3 months prior to the first PK visit.
• Major surgery in 3 months before screening or planned major surgery during the study.
• Are receiving treatments for or have been hospitalized in the last 12 months for psychiatric disorders (e.g., depression, bipolar disorder, schizophrenia, etc.).
• Demonstrates a positive urine drug screen for compounds listed in the protocol, or positive breath alcohol test at screening or baseline.
• Have a history of alcohol or substance abuse in the 12 months before screening (including having been hospitalized for such in an in-patient or out-patient intervention program).
• Currently consumes, on average, more than 2 standard alcoholic beverages a day or has any habit of alcohol use that, to the opinion of the investigator, may be of a concern for the study. A standard alcoholic beverage is defined as 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of liquor.
• Current enrolment or past participation in another study with any product(s) with at least one active ingredient within 30 days before first dose of study product (or screening) or longer, if the previous test product is deemed by the investigator to have lasting effects that might influence the eligibility criteria or outcomes of current study.
• Any other medical condition/situation or use of medications/supplements/therapies that, in the opinion of the investigator, may adversely affect the participant's ability to participate in the study or its measures or pose a significant risk to the participant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: TP1 → TP2 → TP3 → TP4 → CP → RP; Each test period will consist of 2 in-clinic visits to assess the pharmacokinetics of one of the assigned study products. On Day 1 of each test period participants will provide a pre-dose blood sample within 90-minutes before a dose of study product, followed by PK blood sample collections for the next 10 h. Participants will return to the clinic the following day for the 24 h PK blood sample collection. Each test period will be separated by a washout period.	Dietary supplement: TP1; Vitamin C formulation 1, 1000 mg; Dietary supplement: TP2; Vitamin C formulation 2, 1000 mg; Dietary supplement: TP3; Vitamin C formulation 3, 1000 mg; Dietary supplement: TP4; regular Vitamin C, 3000 mg; Dietary supplement: CP; Vitamin C formulation 4, 1000 mg; Dietary supplement: RP; regular Vitamin C, 1000 mg
Other: RP → TP1 → TP2 → TP3 → TP4 → CP; Each test period will consist of 2 in-clinic visits to assess the pharmacokinetics of one of the assigned study products. On Day 1 of each test period participants will provide a pre-dose blood sample within 90-minutes before a dose of study product, followed by PK blood sample collections for the next 10 h. Participants will return to the clinic the following day for the 24 h PK blood sample collection. Each test period will be separated by a washout period.	Dietary supplement: TP1; Vitamin C formulation 1, 1000 mg; Dietary supplement: TP2; Vitamin C formulation 2, 1000 mg; Dietary supplement: TP3; Vitamin C formulation 3, 1000 mg; Dietary supplement: TP4; regular Vitamin C, 3000 mg; Dietary supplement: CP; Vitamin C formulation 4, 1000 mg; Dietary supplement: RP; regular Vitamin C, 1000 mg
Other: CP → RP → TP1 → TP2 → TP3 → TP4; Each test period will consist of 2 in-clinic visits to assess the pharmacokinetics of one of the assigned study products. On Day 1 of each test period participants will provide a pre-dose blood sample within 90-minutes before a dose of study product, followed by PK blood sample collections for the next 10 h. Participants will return to the clinic the following day for the 24 h PK blood sample collection. Each test period will be separated by a washout period.	Dietary supplement: TP1; Vitamin C formulation 1, 1000 mg; Dietary supplement: TP2; Vitamin C formulation 2, 1000 mg; Dietary supplement: TP3; Vitamin C formulation 3, 1000 mg; Dietary supplement: TP4; regular Vitamin C, 3000 mg; Dietary supplement: CP; Vitamin C formulation 4, 1000 mg; Dietary supplement: RP; regular Vitamin C, 1000 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bioavailability of vitamin C compared between each of the liposomal formulations TP1 and TP2 to the traditional RP	Area under the plasma concentration-time curve over 24 h (AUC0-24) for L-ascorbic acid following single dose administration of TP1 and TP2 and RP.	0-24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics (PK) of single doses of six vitamin C formulations	Peak plasma concentration (Cmax)	0-24 hours
Pharmacokinetics (PK) of single doses of six vitamin C formulations	Time to reach Cmax (Tmax)	0-24 hours
Bioavailability of vitamin C compared between six different formulations.	AUC0-24 for L-ascorbic acid of six different vitamin C formulations.	0-24 hours
Excretion of vitamin C in urine over a 24 h period compared between six different formulations.	L-ascorbic acid excreted in urine over 24 h post-dose and at intervals 0 - 4 h, 4 - 8 h, 8 - 10 h, and 10 - 24 h post-dose	0-24 hours
Uptake and maintenance of vitamin C in peripheral blood mononuclear cells (PBMCs) between six different formulations.	L-ascorbic acid concentration in PBMCs normalized to cell count (10^8 cells) pre-dose, 8 h, and 24 h post-dose	0-24 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics (PK) of single doses of six vitamin C formulations.	Area under the plasma concentration time curve from time of dosing to infinity (AUCinf)	0-24 hours
Pharmacokinetics (PK) of single doses of six vitamin C formulations.	Half-life (T1/2)	0-24 hours
Pharmacokinetics (PK) of single doses of six vitamin C formulations.	Elimination rate constant (Kel)	0-24 hours
Gastrointestinal tolerability of single doses of six vitamin C formulations.	Gastrointestinal symptom questionnaire scores	0-24 hours
Antioxidant effects of six different vitamin C formulations.	Total antioxidant capacity in plasma pre-dose and 24 h post-dose.	0-24 hours
Heart rate	Change from pre-dose to post-dose in heart rate (beats per minute)	0-24 hours
Incidence of adverse events	Number of participants with adverse events	up to 8 weeks
Whole blood hemoglobin	Change from pre-dose in whole blood hemoglobin (g/dL)	24 hours
Whole blood hematocrit	Change from pre-dose in whole blood hematocrit (%)	24 hours
Whole blood white blood cells	Change from pre-dose in whole blood white blood cells (x10^3/uL)	24 hours
Whole blood neutrophils	Change from pre-dose in whole blood neutrophils (cells/uL)	24 hours
Whole blood eosinophils	Change from pre-dose in whole blood eosinophils (cells/uL)	24 hours
Whole blood basophils	Change from pre-dose in whole blood basophils (cells/uL)	24 hours
Whole blood lymphocytes	Change from pre-dose in whole blood lymphocytes (cells/uL)	24 hours
Whole blood monocytes	Change from pre-dose in whole blood monocytes (cells/uL)	24 hours
Whole blood mean platelet volume	Change from pre-dose in whole blood mean platelet volume (fL)	24 hours
Whole blood platelet count	Change from pre-dose in whole blood platelet count (x10^9/L)	24 hours
Whole blood red blood cell count	Change from pre-dose in whole blood red blood cell count (x10^6/uL)	24 hours
Whole blood red blood cell distribution width	Change from pre-dose in whole blood red blood cell distribution width (%)	24 hours
Whole blood mean corpuscular volume	Change from pre-dose in whole blood mean corpuscular volume (fL)	24 hours
Whole blood mean corpuscular hemoglobin	Change from pre-dose in whole blood mean corpuscular hemoglobin (pg)	24 hours
Whole Blood Mean Corpuscular Hemoglobin Concentration	Change from pre-dose in whole blood mean corpuscular hemoglobin concentration (g/dL)	24 hours
Serum Sodium	Change from pre-dose in serum sodium (mmol/L)	24 hours
Serum Potassium	Change from pre-dose in serum potassium (mmol/L)	24 hours
Serum Chloride	Change from pre-dose in serum chloride (mmol/L)	24 hours
Serum Urea	Change from pre-dose in serum urea (mg/dL)	24 hours
Serum Creatinine	Change from pre-dose in serum creatinine (umol/L)	24 hours
Serum Estimated Glomerular Filtration	Change from pre-dose in serum estimated glomerular filtration rate (mL/min/1.73^2)	24 hours
Serum Total Protein	Change from pre-dose in serum total protein (g/dL)	24 hours
Serum Albumin	Change from pre-dose in serum albumin (g/dL)	24 hours
Serum Globulin	Change from pre-dose in serum globulin (g/dL)	24 hours
Serum Total Bilirubin	Change from pre-dose in serum total bilirubin (mg/dL)	24 hours
Serum Glucose	Change from pre-dose in serum glucose concentration (mg/dL)	24 hours
Serum Alanine Transaminase	Change from pre-dose in serum alanine transaminase concentration (U/L)	24 hours
Serum Aspartate Transaminase	Change from pre-dose in serum aspartate transaminase concentration (U/L)	24 hours
Serum Alkaline Phosphatase	Change from pre-dose in serum alkaline phosphatase concentration (U/L)	24 hours
Gamma Glutamyl Transferase	Change from pre-dose in serum gamma glutamyl transferase concentration (U/L)	24 hours
Systolic and diastolic blood pressure	Change from pre-dose to post-dose in blood pressure (mm Hg)	0-24 hours

Collaborators and Investigators

• Sponsor: DSM Nutritional Products, Inc.
• Collaborators: Nutrasource Pharmaceutical and Nutraceutical Services, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2024
• Primary Completion (Actual): September 16, 2024
• Study Completion (Actual): September 16, 2024

Study Registration Dates

• First Submitted: June 12, 2024
• First Submitted That Met QC Criteria: June 17, 2024
• First Posted (Actual): June 24, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 9, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Vitamin C; Ascorbic acid
• Other Study ID Numbers: T0052

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No