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.

© 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Figures

Figure 1

Study design. Abbreviation: Pbo, placebo

Figure 2

Arithmetic mean odanacatib plasma concentrations vs. time postdose following single dose administration of 2–600 mg in the fasted state to young healthy male healthy subjects (inset: semi logarithmic scale). One data point from the 5 mg treatment group (time 0, value <0.1 nmol l−1) is not included in the inset plot for scaling purposes. , 2 mg; , 5 mg; , 10 mg; , 25 mg; , 50 mg; , 100 mg; , 200 mg; , 400 mg; , 600 mg

Figure 3

Arithmetic mean odanacatib plasma concentrations vs. time postdose following single dose administration of 25 mg (A), 100 mg (B) and 200 mg (C) in the fasted and fed (high-fat meal) states to young healthy male subjects (inset, semi-logarithmic scale) and in healthy young males following a single oral dose of 100 mg odanacatib (D) taken with and without a light breakfast. (A) , 25 mg Fasted; , 25 mg Fed; (B) , 100 mg Fasted; , 100 mg Fed; (C) , 200 mg Fasted; , 200 mg Fed; (D) ○, Fasted; ▿, Low-fat Breakfast

Figure 4

Percentage change (observed geometric mean ± SEM) from baseline of serum CTx during the 168 h postdose period in panels A and B following administration of single oral doses of odanacatib (ODN) to healthy male subjects (A) and in panel C following administration of single oral doses of ODN to healthy postmenopausal female subjects (B). Percentage change (observed geometric mean ± SEM) from baseline of urinary NTx/Cr during the 168 h postdose period in panels A and B following administration of single oral doses of ODN to healthy male subjects (C) and in panel C following administration of single oral doses of ODN to healthy postmenopausal female subjects (D). (A), □, Panel A: Placebo (n = 2 to 8); , Panel B: Placebo (n = 2 to 8); , Panel A: Odanacatib 10 mg (n = 6); , Panel B: Odanacatib 5 mg (n = 6); ▵, Panel A: Odanacatib 50 mg (n = 6); ▴, Panel B: Odanacatib 25 mg (n = 6); , Panel A: Odanacatib 200 mg (n = 6); ⋆, Panel B: Odanacatib 100 mg (n = 6); ○, Panel A: Odanacatib 400 mg (n = 6); •, Panel B: Odanacatib 600 mg (n = 6); (B), □, Panel C: Placebo (n = 2 to 4); ▴, Panel C: Odanacatib 50 mg (n = 6); ⋆, Panel C: Odanacatib 100 mg (n = 6); (C), □, Panel A: Placebo (n = 6 to 10); , Panel B: Placebo (n = 6 to 8); , Panel A: Odanacatib 2 mg (n = 6); , Panel B: Odanacatib 5 mg (n = 6); ▵, Panel A: Odanacatib 10 mg (n = 6); ▴, Panel B: Odanacatib 25 mg (n = 6); , Panel A: Odanacatib 50 mg (n = 6); ⋆, Panel B: Odanacatib 100 mg (n = 6); ○, Panel A: Odanacatib 200 mg (n = 6); •, Panel B: Odanacatib 600 mg (n = 6); ◃, Panel A: Odanacatib 400 mg (n = 6); ◂, Panel B: Odanacatib 25 mg (n = 6); (D), □, Panel C: Placebo (n = 2 to 3); ▴, Panel C: Odanacatib 50 mg (n = 5 to 6); ⋆, Panel C: Odanacatib 100 mg (n = 6). Cr, creatinine; CTx, C-terminal telopeptide of type I collagen; NTx, N-terminal telopeptide of type I collagen

Figure 5

Pharmacokinetic/pharmacodynamic data and population mean model fit for NTx/Cr following single doses of odanacatib. Abbreviations: Cr, creatinine; CV, coefficient of variation; E0, baseline; EC50, half-maximal effective concentration; Emax, fractional maximal drug effect; NTx, N-terminal telopeptide of type I collagen; s, sigmoidicity factor. □, Observed; , Model Fit