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Keywords:

  • CALCILYTIC;
  • MECHANISTIC PK/PD;
  • MODELING;
  • JTT-305/MK-5442;
  • OSTEOPOROSIS

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 Ca2+. 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 Ca2+ binding, and a second source released more slowly following hours of reduced Ca2+ 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.