Dataset Information

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

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 (2-600?mg) 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 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 (AUC(0-24?h)), concentration at 24 hours (C(24?h)) and maximum concentration (C(max,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 AUC(0-24?h), C(max,day1), C(max,overall) and C(24?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 ?5?mg and at 168?h postdose for ?10?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.

Conclusions

Odanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing.

SUBMITTER: Stoch SA

PROVIDER: S-EPMC3635595 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Publications

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

Stoch S Aubrey SA Zajic Stefan S Stone Julie A JA Miller Deborah L DL van Bortel Lucas L Lasseter Kenneth C KC Pramanik Barnali B Cilissen Caroline C Liu Qi Q Liu Lida L Scott Boyd B BB Panebianco Deborah D Ding Yu Y Gottesdiener Keith K Wagner John A JA

British journal of clinical pharmacology 20130501 5

<h4>Aims</h4>To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans.<h4>Methods</h4>Two 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).<h4>Results</h4>Adverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Head ...[more]

PMID: 23013236

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Project description:BACKGROUND:Denosumab is a fully human monoclonal antibody against receptor activator of nuclear factor kappa-B ligand, a cytokine essential for the formation, function and survival of osteoclasts. This study assessed the pharmacokinetics, pharmacodynamics, safety and tolerability of single-dose denosumab (60 and 120 mg) in healthy Chinese volunteers. METHODS:This randomized (3:3:2), single-blind, placebo-controlled study enrolled healthy Chinese volunteers to receive single subcutaneous injection of denosumab 60 mg, 120 mg, or placebo. Study consisted of screening period (up to 21 days), treatment and assessment period (19 weeks), and an end-of-study visit (at week 26). Denosumab pharmacokinetics and pharmacodynamics parameters were estimated using non-compartmental analysis. Safety and tolerability were assessed throughout the study. RESULTS:A total of 63 volunteers received the study treatment and 62 (98.4%) completed the study. Denosumab serum concentrations peaked at around Day 10 with dose-proportional increase from 60 mg to 120 mg. The mean terminal half-life of denosumab 60 mg and 120 mg was 15 days and 26 days, respectively. The serum C-terminal cross-linking telopeptide of type I collagen concentration-time profiles were similar (>80% decrease within 5 days) between denosumab 60 mg and 120 mg groups. The most commonly reported adverse event (AE) was decreased blood calcium levels (denosumab 60 mg, n = 13; denosumab 120 mg, n = 13; placebo, n = 1); however only one volunteer had calcium level below the abnormality value of potential clinical importance and none of the volunteers developed symptoms of hypocalcemia. The majority of AEs were of mild to moderate intensity. There were no deaths, serious AEs, or withdrawal from study due to AEs. No clinically significant findings in vital signs or electrocardiogram were observed. CONCLUSIONS:Both denosumab 60 mg and 120 mg were well tolerated with no new safety concerns identified in healthy Chinese volunteers with similar pharmacokinetics and pharmacodynamics profiles to that of Caucasians. TRIAL REGISTRATION:ClinicalTrial.gov NCT02135640.

Dataset Information

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

Aims

Methods

Results

Conclusions

Publications

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

Similar Datasets

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