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.

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.

Comparing the efficacy and tolerability of a new daily oral vitamin B12 formulation and intermittent intramuscular vitamin B12 in normalizing low cobalamin levels: a randomized, open-label, parallel-group study.

BACKGROUND: Vitamin B(12) deficiency is routinely treated with parenteral dosing and less often with high-dose oral vitamin B(12). Oral vitamin B(12) formulations have low bioavailability in patients with malabsorption and are considered less reliable than parenteral treatments. OBJECTIVE: The objective of this study was to compare the efficacy and safety profile of a new proprietary oral vitamin B(12) formulation (oral B(12)) with intramuscular (IM) vitamin B(12) (IM B(12)) in restoring normal serum B(12) concentrations in patients with low cobalamin levels (<350 pg/mL). METHODS: Patients were recruited from 5 centers and randomly assigned to receive oral B(12) 1000 µg, taken daily for 90 days, or IM B(12) 1000 µg, given on study days 1, 3, 7, 10, 14, 21, 30, 60, and 90. The patients were aged ≥60 years or aged ≥18 years and had gastrointestinal abnormalities or were on a restricted diet. The primary efficacy outcome compared the proportion of patients in each treatment arm in whom cobalamin levels were normalized (≥350 ng/mL) following 60 days of treatment. Secondary objectives included comparing the efficacy of the 2 formulations after 90 days of treatment, assessing time to normalization of B(12) levels, and evaluating the changes in the levels of biomarkers methylmalonic acid (MMA) and homocysteine (HC). The effect on holotranscobalamin II (active B(12)) levels was assessed as an exploratory end point and correlated to serum cobalamin levels in both treatment groups. Blood samples were collected at baseline (day 1) and on days 15, 31, 61, and 91. RESULTS: Fifty patients were recruited. Forty-eight patients (96.0%) completed the study (22 patients [91.7%] in the oral B(12) group and 26 patients [100%] in the IM B(12) group). All patients (100%) in both treatment groups and in both populations had a cobalamin level ≥350 pg/mL on day 61 and maintained it on day 91. The difference between the IM and oral treatment groups did not reach the planned level of statistical significance (P < 0.05) for mean percent change from baseline (PCFB) in serum cobalamin levels on day 61 and day 91. The difference between the IM and oral treatment groups did not reach the planned level of statistical significance for mean PCFB in serum MMA levels on day 61. There was a statistical difference between the IM and oral treatment groups for mean PCFB in serum MMA levels on day 91 (P = 0.033), with lower values in the oral B(12) group. The difference between the IM and oral treatment groups did not reach the planned level of statistical significance for mean PCFB in plasma HC levels on day 61 and day 91. All patients in each treatment group achieved normalization of serum cobalamin levels by day 15. All patients in both treatment groups and in both populations had plasma holotranscobalamin levels ≥40 pmol/L on day 61 and on day 91. No statistical analysis was planned or performed for safety end points, which were reported only descriptively. Most observed adverse effects were considered mild or moderate in intensity. All adverse effects that were considered severe in intensity were also considered by the investigator to be not related to the study drug. CONCLUSIONS: In this selected study population comprising individuals with low cobalamin levels but who otherwise were in good health, patients received oral B(12) (1000 µg/d) or IM B(12) (1000 µg in 9 injections over 3 months) for a total of 3 months. Both the oral and IM formulations were effective in restoring normal levels of serum cobalamin in all patients studied (100%). Both formulations used in this study were well tolerated at the dose studied. ClinicalTrials.gov identifier: NCT01312831.

Peri- and postnatal developmental toxicity of salcaprozate sodium (SNAC) in Sprague-Dawley rats.

Salcaprozate sodium (SNAC) (sodium 8-((2-hydroxybenzoyl) amino) octanoate, CAS RN 203787-91-1) is classified as an oral absorption promoter and may be a useful means for improving the absorption of certain nutrients and pharmaceutical agents. Presented herein is a subset of data from a larger study evaluating the potential effects of SNAC on the gestation, parturition, lactation, maternal behavior, and offspring development of rats. Pregnant Crl:CD BR VAF/Plus female rats (F(0); n = 25) received SNAC at 1000 mg/kg/d orally (gavage) from implantation through lactation and weaning. F(1) pups were exposed in utero and potentially through maternal milk; observations continued through sexual maturity. The study concluded with Caesarean sectioning of F(1) dams for litter observations and fetal evaluations. No deaths, abortions, premature deliveries, or gross lesions occurred in (F(0)) dams. Excess salivation, red perivaginal substance, and slight reductions in body weights, body weight gains, and/or feed intake were noted in late gestation/early lactation. SNAC was associated with a prolonged gestation period, leading to a greater number of dams with stillborn pups, higher number of stillborn pups, and reduced live litter size. Offspring body weights/gains, feed consumption, age of sexual maturation, mating, fertility, behavioral parameters, and organ weights at necropsy were unaffected by SNAC. No gross external changes were observed in F(1) or F(2) pups. In summary, SNAC administered orally at 1000 mg/kg/d to pregnant rats from gestation to weaning resulted in a slight decrease in maternal body weights (-3.8%) and prolonged gestation, along with an increase in stillbirths, but had no effects on growth and development in surviving offspring.

Subchronic oral toxicity of salcaprozate sodium (SNAC) in Sprague-Dawley and Wistar rats.

Salcaprozate sodium (SNAC) (sodium 8-((2-hydroxybenzoyl) amino) octanoate, CAS RN 203787-91-1) is classified as an oral absorption promoter, and its potential therapeutic applications as a delivery agent for oral forms of heparin and insulin have been explored in a number of clinical investigations. However, limited information about its nonclinical safety is available in the published scientific literature. As part of a larger study exploring the safety of SNAC in combination with heparin, Sprague-Dawley (SD) rats (20/sex/group) received SNAC alone at 2000 mg/kg/d orally (gavage) for 13 weeks (females were terminated after 10 weeks). In a separate study assessing the safety of SNAC in combination with ibandronate, Wistar rats (10/sex/group) received SNAC alone at levels of 100, 500, or 1000 mg/kg/d orally for 13 weeks. SNAC-related mortality was evident only at the 2000-mg/kg/d level, 20% among males and 50% among females; no clear cause of death was evident. No mortality was seen in the Wistar rat study at doses up to 1000 mg/kg/d. Some differences in clinical pathology parameters, including slightly altered electrolyte levels and lower globulin levels, were seen in SD and Wistar rats. Although these differences reached statistical significance, parameters were within historical control ranges. Liver and kidney weights were slightly higher in SNAC-treated animals of both strains, with no corresponding histopathological changes. These changes may therefore constitute an adaptive response. Histopathological changes were seen in the stomach in both studies, probably secondary to irritation caused by the dosing method. Based on the results of these studies, a no-observed-adverse-effect level (NOAEL) cannot be given for SD rats. The NOAEL for SNAC in Wistar rats was considered to be 1000 mg/kg/d.