title: 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.
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730 Herlev, Denmark. mk@nordicbioscience.com
authors.forename: M A
authors.initials: MA
authors.lastname: Karsdal
authors.forename: K
authors.initials: K
authors.lastname: Henriksen
authors.forename: A C
authors.initials: AC
authors.lastname: Bay-Jensen
authors.forename: B
authors.initials: B
authors.lastname: Molloy
authors.forename: M
authors.initials: M
authors.lastname: Arnold
authors.forename: M R
authors.initials: MR
authors.lastname: John
authors.forename: I
authors.initials: I
authors.lastname: Byrjalsen
authors.forename: M
authors.initials: M
authors.lastname: Azria
authors.forename: B J
authors.initials: BJ
authors.lastname: Riis
authors.forename: P
authors.initials: P
authors.lastname: Qvist
authors.forename: C
authors.initials: C
authors.lastname: Christiansen
mesh_terms: D000284:Administration, Oral; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001862:Bone Resorption / Q000188:drug therapy; D002116:Calcitonin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018565:Food-Drug Interactions; D005746:Gastric Emptying / Q000187:drug effects; D006801:Humans; D010024:Osteoporosis / Q000188:drug therapy* / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000493:pharmacokinetics; D013607:Tablets / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D050071:Bone Density Conservation Agents; D010446:Peptide Fragments; D013607:Tablets; C028815:salmon calcitonin; D002116:Calcitonin