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 2þ . 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 2þ binding, and a second source released more slowly following hours of reduced Ca 2þ binding. We modeled the release rates of these reservoirs as maximum pharmacologic effect (E max ) functions of JTT-305/MK-5442 concentration. Our model describes both the dose-dependence of PTH time of occurrence for maximum drug concentration (T max ) and maximum concentration of drug (C max ), and the extent and duration of the observed nonmonotonic return of PTH to baseline levels following JTT-305/MK-5442 administration.

Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-In Mice Mimicking Autosomal Dominant Hypocalcemia (ADH)

“…A pharmacokinetic/pharmacodynamic study with oral administration of JTT-305/ MK-5442 to postmenopausal women showed that endogenous PTH was secreted from two separate reservoirs, a rapid phase within minutes and a slower phase for hours by 15 to 20 mg JTT-305/MK-5442. (57) Because of these characteristics, there were no significant increases in BMD versus placebo after 6 months of treatment in a phase 2, randomized, placebo-controlled, doseranging study involving postmenopausal women with low bone mass. (58) We hypothesized that the disadvantage of JTT-305/MK-5442 with long plasma half-life due to the secretion of PTH from the second reservoir may be beneficial for ADH patients by providing long-term effect with once or twice daily administration.…”

Parathyroid hormone pulsatility: physiological and clinical aspects

“…24 Comparable anabolic effects may be produced by treatment with short-acting antagonists of calcium sensing receptor, the so-called calcilytics, which induce an acute stimulation of PTH secretion by the parathyroid gland mimicking a pulsatile secretory pattern which may lead to improvement of bone mineral density (BMD) and decrease in fracture risk. 25,26 Over the recent years, there has been convincing evidence that PTH exerts extra-skeletal effects, mainly on cardiovascular system and glucose metabolism. 27–29 However, it is still unknown whether and how the pulsatile PTH secretion may influence these extra-skeletal targets.…”

The osteocyte as a therapeutic target in the treatment of osteoporosis

“…Allosteric modulators of this calcium-sensing receptor can affect the secretion of PTH [Trivedi et al 2008; Riccardi, 2012]. Positive calcium-sensing receptor agonists, called calcimimetics, such as cinacalcet, can reduce PTH secretion in patients with hyperparathyroidism and renal disease [Li et al 2013; Tsuruta et al 2013], whereas negative antagonists of this receptor, called calcilytics, can inhibit the receptor function thus inducing the release of a PTH pulse [Cabal et al 2013]. Therefore, these molecules may represent new targets in the treatment of osteoporosis [Fraser et al 2004; Nemeth, 2004; John et al 2011].…”