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

Abstract

AIMSTo evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans. METHODSTwo double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2-600 mg) in 44 healthy volunteers (36 men and eight postmenopausal women). RESULTSAdverse 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 4-6 h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of 40-80 h. The area under the curve0-24 hours (AUC0-24 h), concentration at 24 hours (C24 h) and maximum concentration (Cmax,overal) increased in a less than dose-proportional manner from 2 to 600 mg. Administration of ODN with a high-fat meal led to~100% increases in AUC0-24 h, Cmax,day1, Cmax,overall and C24 h relative to the fasted state, while administration with a low-fat meal led to a~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 24 h for doses Ն5 mg and at 168 h postdose for Ն10 mg. In postmenopausal women administered 50 mg ODN, reductions in serum CTx of -66% and urine NTx/creatinine (uNTx/Cr) of -51% relative to placebo were observed at 24 h. At 168 h, 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 43.8 nM and~80% maximal reduction. CONCLUSIONSOdanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing.

The Absolute Bioavailability and Effect of Food on the Pharmacokinetics of Odanacatib: A Stable-Label i.v./Oral Study in Healthy Postmenopausal Women

“…In several phase 1 studies (Stoch et al, 2013), including this one, multiple peaks were observed in individual concentration-time profiles, typically an initial peak at around 4-10 hours and a peak at 24 hours or later, which was occasionally higher than the first peak. Thus, T max values of 24 hours or as late as 72 hours have been observed.…”

“…The pharmacokinetics (PK) of odanacatib have been investigated in phase 1 single-dose (Stoch et al, 2013) and multiple-dose (Stoch et al, 2009;Anderson et al, 2014) studies. In addition, an absorption, distribution, metabolism, and excretion study was conducted in humans (Kassahun et al, 2014), after detailed characterization of metabolism in rats, dogs, and monkeys (Kassahun et al, 2011).…”

Modulation of osteoclast differentiation and bone resorption by Rho GTPases

“…They indeed show encouraging results with decreased bone resorption and preserved bone formation. [111][112][113][114][115] An alternative approach Polarized osteoclasts have the unique ability to resorb bone (1). Then, the sealing zone (SZ) is disassembled and osteoclasts can spread under a Rac/ Rho effect (2).…”

Screening of Protease Inhibitory Activity in Aqueous Extracts of Marine Invertebrates from Cuban Coast

“…Advances in genomics and proteomics have allowed the detection of many proteases, which according to the role they play, constitute therapeutic targets for different systemic and infectious diseases. Consequently, besides the importance of inhibitors as biotechnological and biochemical tools, a new therapeutic strategy based on PI is successfully emerging validated by the efficacy of several inhibitors already applied as drugs and the high number of many others in different stages of development at lab or at preclinical and clinical trials [12] [40]- [42]. The screening of natural sources is a traditional methodology to identify functional biomolecules including new protease inhibitors with potential applications in Biomedicine and Biotechnology.…”