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

Zajic, Stefan; Rossenu, Stefaan; Hreniuk, David; Kesisoglou, Filippos; McCrea, Jacqueline B.; Liu, Fang; Sun, Li; Witter, Rose; Gauthier, Donald R.; Helmy, Roy; Joss, D.V.; Ni, Tong; Stoltz, Randall; Stone, Julie A.; Stoch, S. Aubrey

doi:10.1124/dmd.116.069906

Cited by 8 publications

(20 citation statements)

References 18 publications

(23 reference statements)

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“…Based on data from a phase 2b dose-ranging study, dosedependent increases in bone mineral density (BMD) at the lumbar spine and hip sites have been observed with once-weekly administration of ODN at doses ranging from 10 to 50 mg. 1-3 ODN has been evaluated in different populations, including Japanese subjects in a separate dose-ranging phase 2b study, 4 which also demonstrated dose-dependent increases in BMD and further supported the selection of the 50-mg dose for the global phase 3 Long-term Odanacatib Fracture Trial (LOFT; NCT00529373). 6 The pharmacokinetics (PK) and pharmacodynamics of ODN have been characterized in phase 1 single-dose 7 and multiple-dose 8,9 studies conducted in healthy men and postmenopausal women. 5 ODN is a Biopharmaceutics Classification System class II drug with high permeability (consistent with absorption via passive diffusion) and low solubility (below 0.001 mg/mL in water).…”

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confidence: 99%

“…5 ODN is a Biopharmaceutics Classification System class II drug with high permeability (consistent with absorption via passive diffusion) and low solubility (below 0.001 mg/mL in water). 6 The pharmacokinetics (PK) and pharmacodynamics of ODN have been characterized in phase 1 single-dose 7 and multiple-dose 8,9 studies conducted in healthy men and postmenopausal women. The absorption, distribution, metabolism, and excretion of ODN were investigated in both animals 10 and humans.…”

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confidence: 99%

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Odanacatib Pharmacokinetics Comparison Between Chinese and Non‐Chinese Postmenopausal Women

Chen

Jiang

et al. 2018

Clinical Pharm in Drug Dev

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Odanacatib (ODN), an oral selective inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. In this phase 1 open-label study, 12 healthy Chinese postmenopausal women received single-dose ODN 50 mg on day 1 and multiple-dose ODN 50 mg once weekly on days 15, 22, 29, and 36 under fasted conditions. Pharmacokinetic (PK) parameters were evaluated on days 1 and 36. Multiple-dose area under the concentration-time profile (AUC ) and maximum plasma concentration (C ) were compared with historical data from 9 non-Chinese postmenopausal women who also received ODN 50 mg once weekly for 4 weeks. Median time to C (t ) was 3 and 4 hours following single- and multiple-dose administration, respectively. The arithmetic mean ± SD terminal half-life was 81.0 ± 14.0 and 106.7 ± 14.4 hours following single- and multiple-dose administration, respectively. Comparison of multiple-dose PK parameters showed that the geometric mean ratios (Chinese/non-Chinese) and 95%CIs for AUC and C were 0.81 (0.55-1.19) and 0.87 (0.69-1.11), respectively. All adverse events were mild, none were serious, and none led to discontinuation. Single- and multiple-dose PKs of ODN 50 mg in Chinese postmenopausal women were generally similar to those previously reported in non-Chinese postmenopausal women.

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Odanacatib Pharmacokinetics Comparison Between Chinese and Non‐Chinese Postmenopausal Women

Chen

Jiang

et al. 2018

Clinical Pharm in Drug Dev

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“…The odanacatib pharmacokinetic (PK) profile was qualitatively similar throughout Phase 1 development including in PMW and older men who are more representative of populations in which osteoporosis is prevalent . Following 3 weeks of 50 mg once weekly dosing in healthy subjects, the geometric mean steady state area under the curve from 0 to 168 hours (AUC 0‐168 ) was 41.1 μM h, maximum plasma concentration was 393 nM, concentration at 168 hours was 126 nM and the harmonic mean apparent terminal half‐life was 84.8 hours .…”

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confidence: 94%

Clinical and translational pharmacology of the cathepsin K inhibitor odanacatib studied for osteoporosis

Stone

McCrea

Witter

et al. 2019

Brit J Clinical Pharma

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Cathepsin K (CatK) is a cysteine protease abundantly expressed by osteoclasts and localized in the lysosomes and resorption lacunae of these cells. CatK is the principal enzyme responsible for the degradation of bone collagen. Odanacatib is a selective, reversible inhibitor of CatK at subnanomolar potency. The pharmacokinetics of odanacatib have been extensively studied and are similar in young healthy men, postmenopausal women and elderly men, and were qualitatively similar throughout Phase 1 development and in-patient studies. Following 3 weeks of 50 mg once weekly dosing the geometric mean area under the curve from 0 to 168 hours was 41.1 μM h, the concentration at 168 hours was 126 nM and the harmonic mean apparent terminal half-life was 84.8 hr. Odanacatib exposure increased in a less than dose proportional manner due to solubility limited absorption. It is estimated that approximately 70% of the absorbed dose of odanacatib is eliminated via metabolism, 20% is excreted as unchanged drug in the bile or faeces, and 10% is excreted as unchanged drug in the urine. The systemic clearance was low (approximately 13 mL/min). Odanacatib decreases the degradation of bone matrix proteins and reduces the efficiency of bone resorption with target engagement confirmed by a robust decrease in serum C-telopeptides of type 1 collagen (approximately 60%), urinary aminoterminal crosslinked telopeptides of type 1 collagen to creatinine ratio (approximately 50%) and total urine deoxypyridinoline/Cr (approximately 30%), with an increase in serum cross-linked carboxy-terminal telopeptide of type 1 collagen (approximately 55%). The 50-mg weekly dosing regimen evaluated in Phase 3 achieved near maximal reduction in bone resorption throughout the treatment period. The extensive clinical programme for odanacatib, together with more limited clinical experience with other CatK inhibitors (balicatib and ONO-5334), provides important insights into the clinical pharmacology of CatK inhibition and the potential role of CatK in bone turnover and mineral homeostasis. Key findings include the ability of this mechanism to: (i) provide sustained reductions in resorption markers, increases in bone mineral density, and demonstrated fracture risk reduction; (ii) be associated with relative formationsparing effects such that sustained resorption reduction is achieved without accompanying meaningful reductions in bone formation; and (iii) lead to increases in osteoclast number as well as other osteoclast activity (including build-up of CatK enzyme), which may yield transient increases in resorption following treatment discontinuation and the potential for nonmonotonic responses at subtherapeutic doses.

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“…Based on previous study data, the supratherapeutic dosing regimen selected was 300 mg of odanacatib on day 1 followed by 25 mg once daily on days 2 through 21, all administered with a high‐fat meal to augment exposure. This regimen was chosen in an attempt to provide odanacatib exposures in excess of those achieved in the clinical program to date . Following review of data in the supratherapeutic safety study, a similar regimen was chosen with a shorter duration for the thorough QTc study (300 mg of odanacatib on day 1 followed by 25 mg once daily for 3 days).…”

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confidence: 99%

“…This regimen was chosen in an attempt to provide odanacatib exposures in excess of those achieved in the clinical program to date. 11 Following review of data in the supratherapeutic safety study, a similar regimen was chosen with a shorter duration for the thorough QTc study (300 mg of odanacatib on day 1 followed by 25 mg once daily for 3 days).…”

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Thorough QTc Evaluation and the Safety of Supratherapeutic Doses of Odanacatib in Healthy Subjects

McCrea

Mostoller

Mahon

et al. 2019

Clinical Pharm in Drug Dev

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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.

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

Cited by 8 publications

References 18 publications

Odanacatib Pharmacokinetics Comparison Between Chinese and Non‐Chinese Postmenopausal Women

Odanacatib Pharmacokinetics Comparison Between Chinese and Non‐Chinese Postmenopausal Women

Clinical and translational pharmacology of the cathepsin K inhibitor odanacatib studied for osteoporosis

Thorough QTc Evaluation and the Safety of Supratherapeutic Doses of Odanacatib in Healthy Subjects

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