Lessons Learned From the Development of Oral Calcitonin: The First Tablet Formulation of a Protein in Phase III Clinical Trials

Abstract

Oral delivery of proteins has been hampered by an array of difficulties. However, promising novel oral delivery systems have been developed. 5-CNAC, formulated with the peptide salmon calcitonin, is in phase III clinical trials for the treatment of osteoporosis or osteoarthritis and could become the first marketed oral peptide. This article reviews key findings and implications from studies undertaken to date with this oral formulation. Findings include these: (1) the optimal calcitonin tablet dose is 0.8 mg; (2) 0.8 mg of oral calcitonin is rapidly absorbed, reaching maximum concentration in 15 to 30 minutes, and is eliminated from plasma with a short half-life-9 to 15 minutes; (3) the 0.8-mg tablet is more highly absorbed than the marketed nasal formulation, with biomarker levels indicating significantly greater efficacy in suppression of bone resorption; (4) drug absorption is increased with dosing at least 10 minutes before a meal rather than postprandially and also with 50 mL of water; (5) the optimal timing of dosing for osteoporosis therapy is in the evening to mitigate the circadian peak in bone resorption; and (6) the oral formulations of synthetic and recombinant calcitonin have similar pharmacokinetic and pharmacodynamic properties. These key findings may aid researchers in the development of other oral formulations.

PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights

“…Due to its short terminal half-life (T½) following parenteral administration, regular injections are required and patient compliance is low. Although preferable to nasal, successful oral formulations of sCT have been elusive [10]. Longer-acting injections of sCT would have an obvious advantage over current injected formulations.…”

Coated minispheres of salmon calcitonin target rat intestinal regions to achieve systemic bioavailability: Comparison between intestinal instillation and oral gavage

“…Two other Phase I trials for enteric-coated preparations combining sCT with CA and either taurodeoxycholic acid or lauryl carnitine showed an average absolute F of 0.03% and 0.38%, respectively [56]. The Eligen ® carrier, 5-CNAC showed greater efficacy in suppression of bone resorption compared to a marketed nasal formulation, but it still failed the primary endpoint in Phase III trial for osteoporosis [57]. No oral formulation of sCT has yet been approved by the FDA.…”

Physicochemical and Formulation Developability Assessment for Therapeutic Peptide Delivery—A Primer

“…Compounds that display permeability-limited absorption are more prone to exhibiting a negative food effect (76). Therefore, not surprisingly, the systemic exposure of calcitonin when delivered orally was reduced by as much as 75% in a fed state relative to a fasted state in clinical trials (77). Thus, additional developability criteria must be established to evaluate food effects.…”

“…A noteworthy example is an oral tablet formulation of salmon calcitonin (sCT) which progressed to phase III studies after demonstrating a 10× increase in exposure and improved efficacy over the marketed nasal spray with approximately 24× the dose. In this case, the dosage form contained (8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid), an N-acetylated amino acid that reversibly complexes with sCT to facilitate passive transcellular permeation of the compound (77).…”