Search

Assessing risk for QTc interval prolongation in a thorough QTc study is a standard recommendation when evaluating new chemical entities. As part of the clinical development program for odanacatib, an oral selective inhibitor of cathepsin K previously in development for the treatment of osteoporosis, 2 clinical studies in healthy subjects assessed pharmacokinetics and overall safety (including potential for delayed ventricular repolarization) of a supratherapeutic dose. In study 1, subjects received a supratherapeutic dose regimen of odanacatib (300 mg on day 1, then daily multiple doses of 25 mg to day 21) or placebo. In study 2 (days 1–4), subjects received the odanacatib supratherapeutic dose regimen or moxifloxacin (positive control, single 400‐mg dose on day 4; matching placebo for odanacatib/moxifloxacin) or placebo. All doses were administered with a high‐fat meal. In study 1 (N = 12), the supratherapeutic dosing regimen achieved exposure ∼3.5‐fold of the proposed therapeutic dose (50 mg once weekly) and was sufficiently well tolerated to permit assessment in the thorough QTc study (study 2). In study 2 (N = 116), the primary objective was placebo‐corrected change from baseline in QTcF interval (Fridericia's correction), assessed by replicate electrocardiograms (12‐lead Holter recordings; days –1 through 7). Supratherapeutic odanacatib dosing was not associated with increased risk of prolonged QT interval, unlike moxifloxacin (confirming assay sensitivity). Pooled safety data across both studies suggested that the safety profile of odanacatib at high exposures was similar to placebo, with a small clustering of oral cavity adverse events. Odanacatib was not associated with increased risk of prolonged QT interval. [ABSTRACT FROM AUTHOR]

We evaluated the effect of prednisone on midazolam and odanacatib pharmacokinetics. In this open-label, 2-period crossover study in healthy male subjects, midazolam 2mg was administered (Day 1) followed by odanacatib 50 mg (Day 1) during Part 1. In Period 2, prednisone 10 mg once daily (qd) was administered on Days 1-28; odanacatib was co-administered on Day 14 and midazolam 2mg was co-administered on Days 1 and 28. Subjects were administered midazolam 2mg on Days 42 and 56. Safety and tolerability were assessed throughout the study. A physiologically-based pharmacokinetic (PBPK) model was also built. There were 15 subjects enrolled; mean age was 31 years. The odanacatib AUC0-∞ GMR (90% CI) [odanacatibþprednisone (Day 14, Period 2)/odanacatib alone (Day 1, Period 1] was 1.06 (0.96, 1.17). AUC0-∞ GMR (90%CI) [midazolamþ prednisone (Day 28, Period 2)/midazolam alone (Day 1, Period 1] was 1.08 (0.93,1.26). There were no serious AEs or AEs leading to discontinuation. PBPK modeling showed that prednisone does not cause significant effects on the exposure of sensitive CYP3A4 substrates in vivo at therapeutic doses. Co-administration of prednisone 10 mg qd had no effect on pharmacokinetics of either odanacatib 10 mg or midazolam 2 mg. [ABSTRACT FROM AUTHOR]