Pharmacology: Pharmacodynamics: Mechanism of Action: All calcitonin structures consist of 32 amino acids in a single chain with a ring of seven amino-acid residues at the N-terminus that differs in sequence from species to species. Salmon calcitonin is more potent and longer acting than calcitonins from mammalian species due to its greater affinity for receptor binding sites.
By inhibiting osteoclast activity via its specific receptors, salmon calcitonin markedly reduces bone turnover to a normal level in conditions with an increased rate of bone resorption such as osteoporosis. Salmon calcitonin has also been shown both in animal models and in humans to have analgesic activity, probably primarily via a direct effect on the central nervous system.
Miacalcic produces a clinically relevant biological response in humans after only a single dose, as shown by an increase in the urinary excretion of calcium, phosphorus and sodium (by reducing their tubular re-uptake) and a decrease in the urinary excretion of hydroxyproline. Long-term administration of parenteral Miacalcic or Miacalcic nasal spray (up to 5 years of treatment) significantly suppresses biochemical markers of bone turnover such as serum C-telopeptides (sCTX) (for nasal spray only), pyridinoline-crosslinks (for injection only) and skeletal isoenzymes of alkaline phosphatase.
Administration of Miacalcic nasal spray 200 IU/day results in a statistically and clinically significant 36% decrease in the risk of developing new vertebral fractures relative to treatment with vitamin D and calcium alone (placebo). Additionally, the incidence of multiple new vertebral fractures is reduced by 35%, also compared to "placebo".
Calcitonin reduces gastric and exocrine pancreatic secretion.
Owing to these properties, Miacalcic injection has been shown to be beneficial in the medical treatment of acute pancreatitis.
Clinical Studies: Not applicable.
Pharmacokinetics: The absolute bioavailability of salmon calcitonin is about 70% after either intramuscular (i.m.) or subcutaneous (s.c.) injection. Peak plasma concentrations are attained within 1 hour. After subcutaneous administration, peak plasma levels are reached in about 23 minutes.The elimination half-life is about 1 hour for i.m. administration and 1 to 1.5 hours for s.c. administration. Salmon calcitonin and its metabolites are excreted up to 95% by the kidney, the fraction of parent drug being 2%. The apparent volume of distribution is 0.15 to 0.3 L/kg, and protein binding amounts to 30 to 40%.
Toxicology: Non-Clinical Safety Data: Conventional long-term toxicity, reproduction, mutagenicity and carcinogenicity studies have been performed in laboratory animals.
Minor effects in toxicity studies are attributable to the pharmacological action of salmon calcitonin. Salmon calcitonin is devoid of embryotoxic, teratogenic and mutagenic potential. Toxicity and carcinogenicity studies have shown that salmon calcitonin increases the incidence of pituitary tumors in rats at exposures lower than those likely from clinical use. However, further preclinical studies, particularly a mouse carcinogenicity study, in which the maximum exposure was more than 7,000 times greater than that in humans following a dose of 200 IU, suggested that pituitary tumor induction is specific to the rat.
Furthermore, there have been no reports of adverse events relating to pituitary tumors in patients
There is therefore enough evidence to conclude that pituitary tumor induction is a rat-specific event and that rat pituitary tumors have no relevance for the clinical use of Miacalcic.