Effect of calcimimetic agent, KRN568, on gastrin secretion in healthy subjects

KRN568 is a calcimimetic compound which acts on the calcium sensing recepto rs (CaR) on the parathyroid gland to suppress secretion of PTH. A recent re port has demonstrated that CaRs are expressed on cultured human antral gast rin cells and that gastrin secretion is stimulated by an increase in extrac ellular calcium level. However, the effect of KRN568 on serum gastrin level s has yet to be clinically assessed. We therefore studied the effect of thi s calcimimetic on gastrin secretion in healthy subjects enrolled in the pha se 1 study for KRN568 currently carried out in Japan. Single doses of KRN56 8, ranging from 25 mg to 400 mg, were orally administered to 6 healthy male volunteers at fasting and after meal. One subject proved to be a poor meta bolizer (PM) for this compound and showed more than 10-fold high concentrat ions of plasma KRN568 (fasting Cmax 90.8 and non-fasting 83.8 ng/ml) compar ed to the other 5 individuals (Cmax 6.5 +/- 2.2 and 7.4 +/- 1.6 ng/ml, resp ectively). Plasma gastrin levels showed mild but apparent increase (from 30 to 125 pg/ml) in this particular subject, while there were no significant increases in the other five people (from 34+/-6 to 63+/-3 pg/ml) after oral administration of 400 mg KRN568 at fasting. In the PM, administration of K RN568 resulted in extraordinarily high serum drug levels associated with tr ansient increase of gastrin levels. This observation suggested that calcium -induced stimulation of gastrin secretion in human was mediated by a mechan ism involving CaR. Potential side effects related to the increased gastrin secretion may be warranted in the practical use of this compound.