Abstract
In this study, a pharmacodynamic model is developed, based on calcium–parathyroid hormone (PTH) homeostasis, which describes the concentration–effect relationship of a negative allosteric modulator of the calcium-sensing receptor (CaR) in rats. Plasma concentrations of drug and PTH were determined from plasma samples obtained via serial jugular vein sampling following single subcutaneous doses of 1, 5, 45, and 150 mg/kg to male Sprague–Dawley rats (n = 5/dose). Drug pharmacokinetics was described by a one-compartment model with first-order absorption and linear elimination. Concentration-time profiles of PTH were characterized using a model in which the compound allosterically modulates Ca+2 binding to the CaR that, in turn, modulates PTH through a precursor-pool indirect response model. Additionally, negative feedback was incorporated to account for tolerance observed at higher dose levels. Model fitting and parameter estimation were conducted using the maximum likelihood algorithm. The proposed model well characterized the data and provided compound specific estimates of the K i and cooperativity constant (α) of 1.47 ng/mL and 0.406, respectively. In addition, the estimated model parameters for PTH turnover were comparable to that previously reported. The final generalized model is capable of characterizing both PTH–Ca+2 homeostasis and the pharmacokinetics and pharmacodynamics associated with the negative allosteric CaR modulator. As such, the model provides a simple platform for analysis of drugs targeting the PTH–Ca+2 system.
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Tarantino U, Cannata G, Lecce D, Celi M, Cerocchi I, Iundusi R. Incidence of fragility fractures. Aging Clin Exp Res. 2007;19(4 Suppl):7–11.
Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet. 2002;359(9319):1761–7.
Department of Health and Human Services US. Bone health and osteoporosis: a report of the surgeon general: Rockville, MD: U.S. Department of Health and Human Services, Office of the Surgeon General. 2004.
Friedman PA. Agents affecting mineral ion homeostasis and bone turnover. In: Brunton LL, Lazo JS, Parker KL, editors. Goodman & Gilman’s the pharmacological basis of therapeutics. 11th edn. New York McGraw-Hill Medical Publishing Division; 2006.
Lindsay R, Nieves J, Formica C, Henneman E, Woelfert L, Shen V, et al. Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet. 1997;350(9077):550–5.
Reeve J, Meunier PJ, Parsons JA, Bernat M, Bijvoet OL, Courpron P, et al. Anabolic effect of human parathyroid hormone fragment on trabecular bone in involutional osteoporosis: a multicentre trial. Br Med J. 1980;280(6228):1340–4.
Reeve J, Tregear GW, Parsons JA. Preliminary trial of low doses of human parathyroid hormone 1–34 peptide in treatment of osteoporosis. Calcif Tissue Res. 1976;21(Suppl):469–77.
Black DM, Bouxsein ML, Palermo L, McGowan JA, Newitt DC, Rosen E, et al. Randomized trial of once-weekly parathyroid hormone (1–84) on bone mineral density and remodeling. J Clin Endocrinol Metab. 2008;93(6):2166–72.
Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344(19):1434–41.
Juppner HW, Gardella TJ, Brown EM, Kronenberg HM, Potts Jr JT. Parathyroid hormone and parathyroid hormone-related peptide in the regulation of calcium homeostasis and bone development. In: DeGroot LJ, Jameson JL, editors. Endocrinology. Philadelphia: Saunders; 2001. p. 969–98.
Friedman PA, Goodman WG. PTH(1–84)/PTH(7–84): a balance of power. Am J Physiol Ren Physiol. 2006;290(5):F975–84.
Chen RA, Goodman WG. Role of the calcium-sensing receptor in parathyroid gland physiology. Am J Physiol Ren Physiol. 2004;286(6):F1005–11.
Gowen M, Stroup GB, Dodds RA, James IE, Votta BJ, Smith BR, et al. Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats. J Clin Invest. 2000;105(11):1595–604.
Nemeth EF, Delmar EG, Heaton WL, Miller MA, Lambert LD, Conklin RL, et al. Calcilytic compounds: potent and selective Ca2+ receptor antagonists that stimulate secretion of parathyroid hormone. J Pharmacol Exp Ther. 2001;299(1):323–31.
Marquis RW, Lago AM, Callahan JF, Rahman A, Dong X, Stroup GB, et al. Antagonists of the calcium receptor. 2. Amino alcohol-based parathyroid hormone secretagogues. J Med Chem. 2009;52(21):6599–605.
Marquis RW, Lago AM, Callahan JF, Trout RE, Gowen M, DelMar EG, et al. Antagonists of the calcium receptor I. Amino alcohol-based parathyroid hormone secretagogues. J Med Chem. 2009;52(13):3982–93.
Arey BJ, Seethala R, Ma Z, Fura A, Morin J, Swartz J, et al. A novel calcium-sensing receptor antagonist transiently stimulates parathyroid hormone secretion in vivo. Endocrinology. 2005;146(4):2015–22.
Balan G, Bauman J, Bhattacharya S, Castrodad M, Healy DR, Herr M, et al. The discovery of novel calcium sensing receptor negative allosteric modulators. Bioorg Med Chem Lett. 2009;19(12):3328–32.
Kumar S, Matheny CJ, Hoffman SJ, Marquis RW, Schultz M, Liang X, et al. An orally active calcium-sensing receptor antagonist that transiently increases plasma concentrations of PTH and stimulates bone formation. Bone. 2010;46(2):534–42.
Lotinun S, Sibonga JD, Turner RT. Differential effects of intermittent and continuous administration of parathyroid hormone on bone histomorphometry and gene expression. Endocrine. 2002;17(1):29–36.
Dobnig H, Turner RT. The effects of programmed administration of human parathyroid hormone fragment (1–34) on bone histomorphometry and serum chemistry in rats. Endocrinology. 1997;138(11):4607–12.
Frolik CA, Black EC, Cain RL, Satterwhite JH, Brown-Augsburger PL, Sato M, et al. Anabolic and catabolic bone effects of human parathyroid hormone (1–34) are predicted by duration of hormone exposure. Bone. 2003;33(3):372–9.
Brown EM. Four-parameter model of the sigmoidal relationship between parathyroid hormone release and extracellular calcium concentration in normal and abnormal parathyroid tissue. J Clin Endocrinol Metab. 1983;56(3):572–81.
Momsen G, Schwarz P. A mathematical/physiological model of parathyroid hormone secretion in response to blood-ionized calcium lowering in vivo. Scand J Clin Lab Investig. 1997;57(5):381–94.
Raposo JF, Sobrinho LG, Ferreira HG. A minimal mathematical model of calcium homeostasis. J Clin Endocrinol Metab. 2002;87(9):4330–40.
Abraham AK, Mager DE, Gao X, Li M, Healy DR, Maurer TS. Mechanism-based pharmacokinetic/pharmacodynamic model of parathyroid hormone-calcium homeostasis in rats and humans. J Pharmacol Exp Ther. 2009;330(1):169–78.
Van Wagenen BC, Del Mar EG, Sheehan D, Barmore RM, Keenan RM, Kotecha NR, et al., inventors; Calcilytic Compounds patent WO 97/37967 A1. 1997.
Sharma A, Ebling WF, Jusko WJ. Precursor-dependent indirect pharmacodynamic response model for tolerance and rebound phenomena. J Pharm Sci. 1998;87(12):1577–84.
Martin KJ, Hruska KA, Lewis J, Anderson C, Slatopolsky E. The renal handling of parathyroid hormone. Role of peritubular uptake and glomerular filtration. J Clin Invest. 1977;60(4):808–14.
Daugaard H, Egfjord M, Olgaard K. Metabolism of parathyroid hormone in isolated perfused rat kidney and liver combined. Kidney Int. 1990;38(1):55–62.
Nemeth EF. Pharmacological regulation of parathyroid hormone secretion. Curr Pharm Des. 2002;8(23):2077–87.
Chattopadhyay N. Biochemistry, physiology and pathophysiology of the extracellular calcium-sensing receptor. Int J Biochem Cell Biol. 2000;32(8):789–804.
Kenakin T. Allosteric modulators: the new generation of receptor antagonist. Mol Interv. 2004;4(4):222–9.
Kenakin T. Allosteric drug antagonism. A pharmacology primer: theory, application, and method 2nd edn: Academic Press; 2006. p. 127–46.
Ehlert FJ. Estimation of the affinities of allosteric ligands using radioligand binding and pharmacological null methods. Mol Pharmacol. 1988;33(2):187–94.
D’Argenio D, Schumitzky A. ADAPT II user’s guide. Los Angeles: Biomedical Simulations Resource; 1997.
Hu J, Reyes-Cruz G, Goldsmith PK, Spiegel AM. The Venus’s-flytrap and cysteine-rich domains of the human Ca2+ receptor are not linked by disulfide bonds. J Biol Chem. 2001;276(10):6901–4.
Brown EM. Calcium receptor and regulation of parathyroid hormone secretion. Rev Endocr Metab Disord. 2000;1(4):307–15.
Ostrowska Z, Kos-Kudla B, Marek B, Kajdaniuk D, Ciesielska-Kopacz N. The relationship between the daily profile of chosen biochemical markers of bone metabolism and melatonin and other hormone secretion in rats under physiological conditions. Neuro Endocrinol Lett. 2002;23(5–6):417–25.
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This study was funded, in part, by the University at Buffalo–Pfizer Strategic Alliance.
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Guest Editors: Cheryl Li, Pratap Singh, and Anjaneya Chimalakonda
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Abraham, A.K., Maurer, T.S., Kalgutkar, A.S. et al. Pharmacodynamic Model of Parathyroid Hormone Modulation by a Negative Allosteric Modulator of the Calcium-Sensing Receptor. AAPS J 13, 265–273 (2011). https://doi.org/10.1208/s12248-011-9266-9
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DOI: https://doi.org/10.1208/s12248-011-9266-9