Mixed-effects modeling of the pharmacodynamic response to the calcimimetic agent R-568

The parathyroid cell calcium receptor is a novel drug target for affecting parathyroid hormone (PTH) secretion and for treating hyperparathyroidism. R-568 is a calcium receptor agonist that inhibits PTH secretion and increases calcitonin release in preclinical studies. The objective of this study was to evaluate the effect of R-568 on PTH plasma concentrations in humans.

Eighteen healthy postmenopausal women were included in the study. Single ascending oral doses of 10 to 400 mg were administered in a randomized, placebo-controlled double-blind trial. PTH plasma concentrations were measured for up to 120 hours after each dose.

R-568 caused a dose-dependent decrease in plasma PTH, with peak effect observed within 1/2 to 2 hours after dosing. The maximum effect did not increase beyond doses from 80 to 160 mg, but duration of response increased at higher doses. An indirect-response model was developed to estimate the rates of input and output of the active moiety(ies), the inhibitory effect on PTH secretion, and the circadian variability in PTH. Population parameter estimates were 3.02 hour-1 and 0.49 hour-1 for rates of input and output of the active moiety(ies), respectively, IA50 (the unscaled amount of R-568 associated with 50% of Emax) was 16.3 mg, Emax (the maximum effect caused by R-568 expressed as a fraction of the rate of PTH secretion in the absence of any drug effect) was 89%, CPTH(baseline) (the baseline PTH plasma concentration in the absence of any drug effect) was 34.6 pg/mL, KePTH (the elimination rate constant for PTH) was 1.73 hour-1, amplitude of the circadian variability in PTH secretion was 5.8%, and the time of peak PTH secretion occurred at about 6 PM. Intersubject variability in parameter estimates ranged from 7% to 121%, and residual variability was 22%.

The model correctly described the onset, extent, and duration of effect on PTH after a wide range of doses of R-568.