title: A semimechanistic model of the time-course of release of PTH into plasma following administration of the calcilytic JTT-305/MK-5442 in humans.
abstract: JTT-305/MK-5442 is a calcium-sensing receptor (CaSR) allosteric antagonist being investigated for the treatment of osteoporosis. JTT-305/MK-5442 binds to CaSRs, thus preventing receptor activation by Ca(2+) . In the parathyroid gland, this results in the release of parathyroid hormone (PTH). Sharp spikes in PTH secretion followed by rapid returns to baseline are associated with bone formation, whereas sustained elevation in PTH is associated with bone resorption. We have developed a semimechanistic, nonpopulation model of the time-course relationship between JTT-305/MK-5442 and whole plasma PTH concentrations to describe both the secretion of PTH and the kinetics of its return to baseline levels. We obtained mean concentration data for JTT-305/MK-5442 and whole PTH from a multiple dose study in U.S. postmenopausal women at doses of 5, 10, 15, and 20 mg. We hypothesized that PTH is released from two separate sources: a reservoir that is released rapidly (within minutes) in response to reduction in Ca(2+) binding, and a second source released more slowly following hours of reduced Ca(2+) binding. We modeled the release rates of these reservoirs as maximum pharmacologic effect (Emax ) functions of JTT-305/MK-5442 concentration. Our model describes both the dose-dependence of PTH time of occurrence for maximum drug concentration (Tmax ) and maximum concentration of drug (Cmax ), and the extent and duration of the observed nonmonotonic return of PTH to baseline levels following JTT-305/MK-5442 administration.
authors: Early Stage Development ESD - Modeling and Simulations, Merck and Co., Upper Gwynedd, PA, USA.
authors: Antonio
authors: A
authors: Cabal
authors: Khamir
authors: K
authors: Mehta
authors: David S
authors: DS
authors: Ross
authors: Rajiv P
authors: RP
authors: Shrestha
authors: Wendy
authors: W
authors: Comisar
authors: Andrew
authors: A
authors: Denker
authors: Sudhakar M
authors: SM
authors: Pai
authors: Tomohiro
authors: T
authors: Ishikawa
mesh_terms: D001565:Benzoates / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008954:Models, Biological; D010281:Parathyroid Hormone / Q000097:blood* / Q000493:pharmacokinetics*; D011412:Propanolamines / Q000008:administration & dosage*; D013997:Time Factors
chemical_list: D001565:Benzoates; C568849:JTT 305; D010281:Parathyroid Hormone; D011412:Propanolamines
keywords: CALCILYTIC; JTT-305/MK-5442; MECHANISTIC PK/PD; MODELING; OSTEOPOROSIS