ABSTRACT
Evocalcet is a novel calcimimetic agent for the treatment of secondary hyperparathyroidism (SHPT). This study evaluated the effects of evocalcet on inhibition and induction of cytochrome P450 (CYP) isozymes. Although drug interactions arising from reversible inhibition of CYP isozymes by evocalcet were considered unlikely based on the results of in vitro studies and static model analyses, the potential for evocalcet to cause time-dependent inhibition of CYP3A or induction of several CYP isozymes could not be ruled out. Therefore, a clinical drug-drug interaction (DDI) study to evaluate the effects of evocalcet on the pharmacokinetics (PKs) of probe substrates for CYP isozymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP3A) was conducted in healthy male volunteers using a novel cocktail combination. Evocalcet did not significantly affect the PKs of the probe substrates, confirming that CYP-mediated interactions were unlikely.
Subject(s)
Calcimimetic Agents/pharmacokinetics , Cytochrome P-450 Enzyme Inhibitors/pharmacokinetics , Cytochrome P-450 Enzyme System/metabolism , Naphthalenes/pharmacokinetics , Pyrrolidines/pharmacokinetics , Administration, Oral , Adult , Alkynes , Benzoxazines/administration & dosage , Benzoxazines/pharmacokinetics , Calcimimetic Agents/administration & dosage , Carbamates/administration & dosage , Carbamates/pharmacokinetics , Cells, Cultured , Cyclopropanes , Cytochrome P-450 Enzyme Inhibitors/administration & dosage , Drug Interactions , Healthy Volunteers , Hepatocytes , Humans , Hyperparathyroidism, Secondary/drug therapy , Inhibitory Concentration 50 , Isoenzymes/metabolism , Male , Naphthalenes/administration & dosage , Oxidation-Reduction/drug effects , Piperidines/administration & dosage , Piperidines/pharmacokinetics , Primary Cell Culture , Pyrrolidines/administration & dosage , Theophylline/administration & dosage , Theophylline/pharmacokinetics , Young AdultABSTRACT
The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and regulating parathyroid hormone secretion by parathyroid gland cells, and the receptor is a suitable target for the treatment of hyperparathyroidism. Cinacalcet hydrochloride is a representative CaSR agonist which widely used for the hyperparathyroidism. However, it has several issues to clinical use, such as nausea/vomiting and strong inhibition of CYP2D6. We tried to improve these issues of cinacalcet for a new pharmaceutical agent as a preferable CaSR agonist. Optimization from cinacalcet resulted in the identification of pyrrolidine compounds and successfully led to the discovery of evocalcet as an oral allosteric CaSR agonist. Evocalcet, which exhibited highly favorable profiles such as CaSR agonistic activity and good DMPK profiles, will provide a novel therapeutic option for secondary hyperparathyroidism.
Subject(s)
Cytochrome P-450 Enzyme Inhibitors/pharmacology , Cytochrome P-450 Enzyme System/metabolism , Drug Discovery , Hyperparathyroidism/drug therapy , Pyrrolidines/pharmacology , Receptors, Calcium-Sensing/agonists , Animals , Cytochrome P-450 Enzyme Inhibitors/chemical synthesis , Cytochrome P-450 Enzyme Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
BACKGROUND: Central substance P receptors, termed NK-1 receptors, have been considered as therapeutic targets in the development of drugs against diverse conditions, including emesis, overactive bladder, and depression. METHODS: Here, we applied small animal positron emission tomography (PET) and a radioligand for NK-1 receptors ([(18)F]FE-SPA-RQ) for measuring occupancies of these receptors by a selective antagonist (aprepitant) in order to examine the validity of this in vivo imaging system for preclinical characterization of candidate agents acting on NK-1 receptors, and as a tool for predicting optimal doses in humans. RESULTS: PET in gerbils depicted high uptake in the striatum and dose-dependent displacement with increasing doses of aprepitant. Occupancies increased as a function of aprepitant plasma concentrations according to a one-site competition model, which agrees with reported occupancy-concentration relationships in clinical studies after correction for species differences in plasma protein-unbound aprepitant fractions. These occupancy data were further supported by ex vivo autoradiography of brain samples from aprepitant-treated gerbils. In a pilot study of a marmoset, we obtained more accurate determinations of NK-1 receptor occupancy, less affected by spillover of signals from extracranial tissues than in gerbil experiments. CONCLUSIONS: These findings support the utility of small animals and quantitative PET in the development of drugs targeting NK-1 receptors.