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Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics: results from single oral dose studies in healthy volunteers

S Aubrey Stoch, Stefan Zajic, Julie A Stone, Deborah L Miller, Lucas Van Bortel, Kenneth C Lasseter, Barnali Pramanik, Caroline Cilissen, Qi Liu, Lida Liu, et al. (2013) BRITISH JOURNAL OF CLINICAL PHARMACOLOGY. 75(5). p.1240-1254
abstract
Aims: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans. Methods: Two double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2600mg) in 44 healthy volunteers (36 men and eight postmenopausal women). Results: Adverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Headache was the most frequent AE. After absorption of ODN (initial peak concentrations 46h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of approximate to 4080h. The area under the curve0-24 hours (AUC024h), concentration at 24 hours (C24h) and maximum concentration (Cmax,overal) increased in a less than dose-proportional manner from 2 to 600mg. Administration of ODN with a high-fat meal led to approximate to 100% increases in AUC024h, Cmax,day1, Cmax,overall and C24h relative to the fasted state, while administration with a low-fat meal led to a approximate to 30% increase in those parameters. Reduction of biomarkers of bone resorption, the C- and N-telopeptides of cross-links of type I collagen, (CTx and NTx, respectively), was noted at 24h for doses 5mg and at 168h postdose for 10mg. In postmenopausal women administered 50mg ODN, reductions in serum CTx of 66% and urine NTx/creatinine (uNTx/Cr) of 51% relative to placebo were observed at 24h. At 168h, reductions in serum CTx (70%) and uNTx/Cr (78%) were observed relative to baseline. Pharmacokinetic/pharmacodynamic modeling characterized the ODN concentration/uNTx/Cr relation, with a modeled EC50 value of 43.8nM and approximate to 80% maximal reduction. Conclusions: Odanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
pharmacokinetics, BONE TURNOVER, pharmacodynamics, osteoporosis, odanacatib, cathepsin K inhibitor, BIOCHEMICAL MARKERS, ALENDRONATE TREATMENT, WOMEN, RESORPTION, MASS, PROTEINASES, BIOMARKERS, MANAGEMENT, DIAGNOSIS
journal title
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
Br. J. Clin. Pharmacol.
volume
75
issue
5
pages
1240 - 1254
Web of Science type
Article
Web of Science id
000317356600008
JCR category
PHARMACOLOGY & PHARMACY
JCR impact factor
3.688 (2013)
JCR rank
50/256 (2013)
JCR quartile
1 (2013)
ISSN
0306-5251
DOI
10.1111/j.1365-2125.2012.04471.x
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
4283613
handle
http://hdl.handle.net/1854/LU-4283613
date created
2014-02-08 12:06:52
date last changed
2016-12-19 15:39:39
@article{4283613,
  abstract     = {Aims: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans.
Methods: Two double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2600mg) in 44 healthy volunteers (36 men and eight postmenopausal women).
Results: Adverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Headache was the most frequent AE. After absorption of ODN (initial peak concentrations 46h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of approximate to 4080h. The area under the curve0-24 hours (AUC024h), concentration at 24 hours (C24h) and maximum concentration (Cmax,overal) increased in a less than dose-proportional manner from 2 to 600mg. Administration of ODN with a high-fat meal led to approximate to 100\% increases in AUC024h, Cmax,day1, Cmax,overall and C24h relative to the fasted state, while administration with a low-fat meal led to a approximate to 30\% increase in those parameters. Reduction of biomarkers of bone resorption, the C- and N-telopeptides of cross-links of type I collagen, (CTx and NTx, respectively), was noted at 24h for doses 5mg and at 168h postdose for 10mg. In postmenopausal women administered 50mg ODN, reductions in serum CTx of 66\% and urine NTx/creatinine (uNTx/Cr) of 51\% relative to placebo were observed at 24h. At 168h, reductions in serum CTx (70\%) and uNTx/Cr (78\%) were observed relative to baseline. Pharmacokinetic/pharmacodynamic modeling characterized the ODN concentration/uNTx/Cr relation, with a modeled EC50 value of 43.8nM and approximate to 80\% maximal reduction.
Conclusions: Odanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing.},
  author       = {Stoch, S Aubrey and Zajic, Stefan and Stone, Julie A and Miller, Deborah L and Van Bortel, Lucas and Lasseter, Kenneth C and Pramanik, Barnali and Cilissen, Caroline and Liu, Qi and Liu, Lida and Scott, Boyd B and Panebianco, Deborah and Ding, Yu and Gottesdiener, Keith and Wagner, John A},
  issn         = {0306-5251},
  journal      = {BRITISH JOURNAL OF CLINICAL PHARMACOLOGY},
  keyword      = {pharmacokinetics,BONE TURNOVER,pharmacodynamics,osteoporosis,odanacatib,cathepsin K inhibitor,BIOCHEMICAL MARKERS,ALENDRONATE TREATMENT,WOMEN,RESORPTION,MASS,PROTEINASES,BIOMARKERS,MANAGEMENT,DIAGNOSIS},
  language     = {eng},
  number       = {5},
  pages        = {1240--1254},
  title        = {Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics: results from single oral dose studies in healthy volunteers},
  url          = {http://dx.doi.org/10.1111/j.1365-2125.2012.04471.x},
  volume       = {75},
  year         = {2013},
}

Chicago
Stoch, S Aubrey, Stefan Zajic, Julie A Stone, Deborah L Miller, Lucas Van Bortel, Kenneth C Lasseter, Barnali Pramanik, et al. 2013. “Odanacatib, a Selective Cathepsin K Inhibitor to Treat Osteoporosis: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics: Results from Single Oral Dose Studies in Healthy Volunteers.” British Journal of Clinical Pharmacology 75 (5): 1240–1254.
APA
Stoch, S. A., Zajic, S., Stone, J. A., Miller, D. L., Van Bortel, L., Lasseter, K. C., Pramanik, B., et al. (2013). Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics: results from single oral dose studies in healthy volunteers. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 75(5), 1240–1254.
Vancouver
1.
Stoch SA, Zajic S, Stone JA, Miller DL, Van Bortel L, Lasseter KC, et al. Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics: results from single oral dose studies in healthy volunteers. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY. 2013;75(5):1240–54.
MLA
Stoch, S Aubrey, Stefan Zajic, Julie A Stone, et al. “Odanacatib, a Selective Cathepsin K Inhibitor to Treat Osteoporosis: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics: Results from Single Oral Dose Studies in Healthy Volunteers.” BRITISH JOURNAL OF CLINICAL PHARMACOLOGY 75.5 (2013): 1240–1254. Print.