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Pharmacokinetics of oral cyanocobalamin formulated with sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC): an open-label, randomized, single-dose, parallel-group study in healthy male subjects.
Clin Ther. 2011 Jul; 33(7):934-45.CT

Abstract

BACKGROUND

Vitamin B12 (cobalamin) deficiency may be caused by inadequate dietary intake of B12 or by conditions that result in malabsorption of the vitamin. Crystalline vitamin B12, usually in the form of cyanocobalamin, is administered parenterally (ie, intramuscularly) or orally for treating deficiency states. Intramuscular administration is widely accepted as a treatment method. Oral B12 supplementation is also used, but it is considered to be less reliable.

OBJECTIVE

This study was conducted to compare the pharmacokinetics and tolerability of 2 oral formulations of cyanocobalamin-a marketed cyanocobalamin tablet (immediate-release B12 5 mg) and cyanocobalamin formulated with a proprietary carrier, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC)-to establish the feasibility of using an absorption enhancer with B12 to improve uptake of the vitamin. This was the first clinical study conducted with the cyanocobalamin/SNAC coformulation.

METHODS

An open-label, randomized, single-dose, parallel-group study was conducted in healthy male subjects. Subjects were randomly assigned to 1 of 4 treatment groups: Treatment A subjects (n = 4) received 2 tablets of 5-mg cyanocobalamin formulated with 100-mg SNAC as part of a dose range-finding arm included to determine a dose to provide a measurable concentration of vitamin B12 at all time points when tested with the available vitamin B12 assay; treatment B subjects (n = 6) received 1 tablet of 5-mg cyanocobalamin formulated with 100-mg SNAC; treatment C subjects (n = 6) received 1 commercially available 5-mg cyanocobalamin tablet; and treatment D subjects (n = 4) received commercially available 1-mg cyanocobalamin IV. Treatment A was completed 3 weeks before treatments B, C, and D were studied. Human serum B12 was analyzed by chemiluminescence assay method. Validation procedures established that samples could be diluted up to 100 times without any effects on accuracy and precision. The pharmacokinetic properties of vitamin B12 were characterized by noncompartmental analysis. Vitamin B12 absolute bioavailability estimates were calculated between the oral (A, B, and C) and IV (D) treatments using non-baseline-adjusted vitamin B12 concentrations as well as baseline-adjusted vitamin B12 concentrations, with or without body weight adjustments. Tolerability was evaluated through review or monitoring of medical history, physical examination findings, concomitant medications, vital signs, laboratory tests (hematology, serum chemistry, and urinalysis values), electrocardiography, adverse events, and serious adverse events.

RESULTS

Twenty healthy male subjects, aged 20 to 45 years, participated in this study. Based on data from treatment A, a 5-mg cyanocobalamin dose was selected for use with treatments B and C. The oral cyanocobalamin formulation containing SNAC had greater mean absolute bioavailability than the commercial oral formulation (5.09% vs 2.16%, respectively), calculated on AUC(0-last) values uncorrected for baseline, weight, or body mass index. It also had a reduced T(max) compared with the commercial formulation (0.5 hours vs 6.83 hours, respectively). The K(e) was similar between treatments (0.028 1/h vs 0.025 1/h). Comparable results were achieved using corrected values. The cyanocobalamin/SNAC formulation was well tolerated, and there were no reported adverse events.

CONCLUSIONS

An oral formulation of 5-mg cyanocobalamin containing 100-mg SNAC, an absorption enhancer, provided significantly improved bioavailability and a significant decrease in T(max) for B12 in a small study of normal healthy subjects compared with a commercially available 5-mg cyanocobalamin oral formulation. Both oral formulations and commercial 1-mg cyanocobalamin IV were well tolerated.

Authors+Show Affiliations

Emisphere Technologies, Cedar Knolls, New Jersey 07927, USA. ccastelli@emisphere.comNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21722960

Citation

Castelli, M Cristina, et al. "Pharmacokinetics of Oral Cyanocobalamin Formulated With Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC): an Open-label, Randomized, Single-dose, Parallel-group Study in Healthy Male Subjects." Clinical Therapeutics, vol. 33, no. 7, 2011, pp. 934-45.
Castelli MC, Wong DF, Friedman K, et al. Pharmacokinetics of oral cyanocobalamin formulated with sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC): an open-label, randomized, single-dose, parallel-group study in healthy male subjects. Clin Ther. 2011;33(7):934-45.
Castelli, M. C., Wong, D. F., Friedman, K., & Riley, M. G. (2011). Pharmacokinetics of oral cyanocobalamin formulated with sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC): an open-label, randomized, single-dose, parallel-group study in healthy male subjects. Clinical Therapeutics, 33(7), 934-45. https://doi.org/10.1016/j.clinthera.2011.05.088
Castelli MC, et al. Pharmacokinetics of Oral Cyanocobalamin Formulated With Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC): an Open-label, Randomized, Single-dose, Parallel-group Study in Healthy Male Subjects. Clin Ther. 2011;33(7):934-45. PubMed PMID: 21722960.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetics of oral cyanocobalamin formulated with sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC): an open-label, randomized, single-dose, parallel-group study in healthy male subjects. AU - Castelli,M Cristina, AU - Wong,Diane F, AU - Friedman,Kristen, AU - Riley,M Gary I, Y1 - 2011/07/01/ PY - 2011/5/24/accepted PY - 2011/7/5/entrez PY - 2011/7/5/pubmed PY - 2011/12/13/medline SP - 934 EP - 45 JF - Clinical therapeutics JO - Clin Ther VL - 33 IS - 7 N2 - BACKGROUND: Vitamin B12 (cobalamin) deficiency may be caused by inadequate dietary intake of B12 or by conditions that result in malabsorption of the vitamin. Crystalline vitamin B12, usually in the form of cyanocobalamin, is administered parenterally (ie, intramuscularly) or orally for treating deficiency states. Intramuscular administration is widely accepted as a treatment method. Oral B12 supplementation is also used, but it is considered to be less reliable. OBJECTIVE: This study was conducted to compare the pharmacokinetics and tolerability of 2 oral formulations of cyanocobalamin-a marketed cyanocobalamin tablet (immediate-release B12 5 mg) and cyanocobalamin formulated with a proprietary carrier, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC)-to establish the feasibility of using an absorption enhancer with B12 to improve uptake of the vitamin. This was the first clinical study conducted with the cyanocobalamin/SNAC coformulation. METHODS: An open-label, randomized, single-dose, parallel-group study was conducted in healthy male subjects. Subjects were randomly assigned to 1 of 4 treatment groups: Treatment A subjects (n = 4) received 2 tablets of 5-mg cyanocobalamin formulated with 100-mg SNAC as part of a dose range-finding arm included to determine a dose to provide a measurable concentration of vitamin B12 at all time points when tested with the available vitamin B12 assay; treatment B subjects (n = 6) received 1 tablet of 5-mg cyanocobalamin formulated with 100-mg SNAC; treatment C subjects (n = 6) received 1 commercially available 5-mg cyanocobalamin tablet; and treatment D subjects (n = 4) received commercially available 1-mg cyanocobalamin IV. Treatment A was completed 3 weeks before treatments B, C, and D were studied. Human serum B12 was analyzed by chemiluminescence assay method. Validation procedures established that samples could be diluted up to 100 times without any effects on accuracy and precision. The pharmacokinetic properties of vitamin B12 were characterized by noncompartmental analysis. Vitamin B12 absolute bioavailability estimates were calculated between the oral (A, B, and C) and IV (D) treatments using non-baseline-adjusted vitamin B12 concentrations as well as baseline-adjusted vitamin B12 concentrations, with or without body weight adjustments. Tolerability was evaluated through review or monitoring of medical history, physical examination findings, concomitant medications, vital signs, laboratory tests (hematology, serum chemistry, and urinalysis values), electrocardiography, adverse events, and serious adverse events. RESULTS: Twenty healthy male subjects, aged 20 to 45 years, participated in this study. Based on data from treatment A, a 5-mg cyanocobalamin dose was selected for use with treatments B and C. The oral cyanocobalamin formulation containing SNAC had greater mean absolute bioavailability than the commercial oral formulation (5.09% vs 2.16%, respectively), calculated on AUC(0-last) values uncorrected for baseline, weight, or body mass index. It also had a reduced T(max) compared with the commercial formulation (0.5 hours vs 6.83 hours, respectively). The K(e) was similar between treatments (0.028 1/h vs 0.025 1/h). Comparable results were achieved using corrected values. The cyanocobalamin/SNAC formulation was well tolerated, and there were no reported adverse events. CONCLUSIONS: An oral formulation of 5-mg cyanocobalamin containing 100-mg SNAC, an absorption enhancer, provided significantly improved bioavailability and a significant decrease in T(max) for B12 in a small study of normal healthy subjects compared with a commercially available 5-mg cyanocobalamin oral formulation. Both oral formulations and commercial 1-mg cyanocobalamin IV were well tolerated. SN - 1879-114X UR - https://www.unboundmedicine.com/medline/citation/21722960/Pharmacokinetics_of_oral_cyanocobalamin_formulated_with_sodium_N_[8__2_hydroxybenzoyl_amino]caprylate__SNAC_:_an_open_label_randomized_single_dose_parallel_group_study_in_healthy_male_subjects_ DB - PRIME DP - Unbound Medicine ER -