The Experts below are selected from a list of 1755 Experts worldwide ranked by ideXlab platform
C. H. Lee - One of the best experts on this subject based on the ideXlab platform.
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an orally active Cathepsin K Inhibitor furan 2 carboxylic acid 1 1 4 fluoro 2 2 oxo pyrrolidin 1 yl phenyl 3 oxo piperidin 4 ylcarbamoyl cyclohexyl amide ost 4077 inhibits osteoclast activity in vitro and bone loss in ovariectomized rats
Journal of Pharmacology and Experimental Therapeutics, 2006Co-Authors: M. K. Kim, H. D. Kim, J. H. Park, J. I. Lim, J. S. Yang, W. Y. Kwak, S. Y. Sung, Hyun Jung Kim, Sang Hoon Kim, C. H. LeeAbstract:Human Cathepsin K, a cysteine proteinase of the papain family, has been recognized as a potential drug target for the treatment of osteoporosis. The predominant expression of Cathepsin K in osteoclasts has rendered the enzyme into a major target for the development of novel antiresorptive drugs. Now, we report the pharmacological properties of OST-4077 [furan-2-carboxylic acid (1-{1-[4-fluoro-2-(2-oxo-pyrrolidin-1-yl)-phenyl]-3-oxo-piperidin-4-ylcarbamoyl}-cyclohexyl)-amide] as a novel selective Cathepsin K Inhibitor. Human and rat Cathepsin K were inhibited in vitro by OST-4077 with the IC50 values of 11 and 427 nM, respectively. OST-4077 suppressed bone resorption induced by rabbit osteoclasts (IC50, 37 nM) but did not affect bone mineralization or cellular alKaline phosphatase activity in MC3T3-E1 cells. Parathyroid hormone-induced bone resorption was inhibited in a dose-dependent manner in thyroparathyroidectomized rats gavaged with a single dose of OST-4077 (ED50, 69 mg/Kg). When given orally twice daily for 4 weeKs to 3-month-old ovariectomized (OVX) rats, OST-4077 dose-dependently prevented bone loss, as monitored by bone densitometry, ash content, and urinary excretion of deoxypyridinoline. No change in serum osteocalcin in the OVX rats by OST-4077 suggested that bone formation might not be affected by the agent. In summary, OST-4077 selectively inhibited bone resorbing activities of osteoclasts and prevented bone loss induced by estrogen deficiency but did not affect bone formation. OST-4077, an orally active selective human Cathepsin K Inhibitor, may have the therapeutic potential for the treatment of diseases characterized by excessive bone loss including osteoporosis.
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An Orally Active Cathepsin K Inhibitor, Furan-2-Carboxylic Acid, 1-{1-[4-Fluoro-2-(2-oxo-pyrrolidin-1-yl)-phenyl]-3-oxo-piperidin-4-ylcarbamoyl}-cyclohexyl)-amide (OST-4077), Inhibits Osteoclast Activity in Vitro and Bone Loss in Ovariectomized Rats
The Journal of pharmacology and experimental therapeutics, 2006Co-Authors: M. K. Kim, H. D. Kim, J. H. Park, J. I. Lim, J. S. Yang, W. Y. Kwak, S. Y. Sung, Hyun Jung Kim, Sang Hoon Kim, C. H. LeeAbstract:Human Cathepsin K, a cysteine proteinase of the papain family, has been recognized as a potential drug target for the treatment of osteoporosis. The predominant expression of Cathepsin K in osteoclasts has rendered the enzyme into a major target for the development of novel antiresorptive drugs. Now, we report the pharmacological properties of OST-4077 [furan-2-carboxylic acid (1-{1-[4-fluoro-2-(2-oxo-pyrrolidin-1-yl)-phenyl]-3-oxo-piperidin-4-ylcarbamoyl}-cyclohexyl)-amide] as a novel selective Cathepsin K Inhibitor. Human and rat Cathepsin K were inhibited in vitro by OST-4077 with the IC50 values of 11 and 427 nM, respectively. OST-4077 suppressed bone resorption induced by rabbit osteoclasts (IC50, 37 nM) but did not affect bone mineralization or cellular alKaline phosphatase activity in MC3T3-E1 cells. Parathyroid hormone-induced bone resorption was inhibited in a dose-dependent manner in thyroparathyroidectomized rats gavaged with a single dose of OST-4077 (ED50, 69 mg/Kg). When given orally twice daily for 4 weeKs to 3-month-old ovariectomized (OVX) rats, OST-4077 dose-dependently prevented bone loss, as monitored by bone densitometry, ash content, and urinary excretion of deoxypyridinoline. No change in serum osteocalcin in the OVX rats by OST-4077 suggested that bone formation might not be affected by the agent. In summary, OST-4077 selectively inhibited bone resorbing activities of osteoclasts and prevented bone loss induced by estrogen deficiency but did not affect bone formation. OST-4077, an orally active selective human Cathepsin K Inhibitor, may have the therapeutic potential for the treatment of diseases characterized by excessive bone loss including osteoporosis.
Lida Liu - One of the best experts on this subject based on the ideXlab platform.
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Odanacatib, a selective Cathepsin K Inhibitor to treat osteoporosis: safety, tolerability, pharmacoKinetics and pharmacodynamics--results from single oral dose studies in healthy volunteers.
British journal of clinical pharmacology, 2013Co-Authors: S. Aubrey Stoch, Stefan Zajic, Deborah L. Miller, Julie A. Stone, Lucas Van Bortel, Kenneth C. Lasseter, Barnali Pramanik, Caroline Cilissen, Q Liu, Lida LiuAbstract: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 (2600mg) 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 46h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of approximate to 4080h. The area under the curve0-24 hours (AUC024h), concentration at 24 hours (C24h) and maximum concentration (Cmax,overal) increased in a less than dose-proportional manner from 2 to 600mg. Administration of ODN with a high-fat meal led to approximate to 100% increases in AUC024h, Cmax,day1, Cmax,overall and C24h relative to the fasted state, while administration with a low-fat meal led to a approximate to 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 24h for doses 5mg and at 168h postdose for 10mg. In postmenopausal women administered 50mg ODN, reductions in serum CTx of 66% and urine NTx/creatinine (uNTx/Cr) of 51% relative to placebo were observed at 24h. At 168h, 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 43.8nM and approximate to 80% maximal reduction. Conclusions: Odanacatib was well tolerated and has a pharmacoKinetic and pharmacodynamic profile suitable for once weeKly dosing.
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Odanacatib, a selective Cathepsin K Inhibitor to treat osteoporosis: safety, tolerability, pharmacoKinetics and pharmacodynamics--results from single oral dose studies in healthy volunteers.
British journal of clinical pharmacology, 2013Co-Authors: S. Aubrey Stoch, Stefan Zajic, Deborah L. Miller, Julie A. Stone, Lucas Van Bortel, Kenneth C. Lasseter, Barnali Pramanik, Caroline Cilissen, Q Liu, Lida LiuAbstract:To evaluate the safety, tolerability, pharmacoKinetics and pharmacodynamics of odanacatib (ODN), a Cathepsin K Inhibitor, in humans. 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). 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. 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.
S. Aubrey Stoch - One of the best experts on this subject based on the ideXlab platform.
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A phase 1 pooled PK/PD analysis of bone resorption biomarKers for odanacatib, a Cathepsin K Inhibitor.
Journal of pharmacokinetics and pharmacodynamics, 2020Co-Authors: Stefan Zajic, Rose Witter, S. Aubrey Stoch, Jacqueline B. Mccrea, Ghassan N. Fayad, Monika Martinho, Julie A. StoneAbstract:To develop a frameworK for evaluating the resorption effects of Cathepsin K (CatK) Inhibitors and to inform dose regimen selection, a pharmacoKinetic/pharmacodynamic (PK/PD) model for odanacatib (ODN) was developed based upon data from Phase 1 studies. Pooled PK/PD data from 11 studies (N = 249) were fit reasonably to a population Inhibitory sigmoid Emax model. Body weight on E0 (baseline uNTx/Cr, urinary N-terminal telopeptide normalized by creatinine) and age on Emax (fractional inhibition of the biomarKer response) were significant covariates for biomarKer response. Simulations of typical osteoporosis patients (by age, sex and weight) indicated minimal differences between sexes in concentration-uNTx/Cr relationship. There was no evidence that regimen (daily vs. weeKly dosing) influenced the PK/PD relationship of resorption inhibition for odanacatib. PK/PD models based on data from odanacatib (ODN) Phase 1 studies demonstrated that uNTx/Cr was an appropriate bone resorption biomarKer for assessment of the effects of a CatK Inhibitor. The models also identified the determinants of response in the PK/PD relationship for ODN (body weight on E0 and age on Emax).
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Clinical and translational pharmacology of the Cathepsin K Inhibitor odanacatib studied for osteoporosis.
British journal of clinical pharmacology, 2019Co-Authors: Julie A. Stone, Rose Witter, Stefan Zajic, Jacqueline B. Mccrea, S. Aubrey StochAbstract: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 formation-sparing 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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Disposition and Metabolism of the Cathepsin K Inhibitor Odanacatib in Humans
Drug metabolism and disposition: the biological fate of chemicals, 2014Co-Authors: Kelem Kassahun, Stefan Zajic, Ian Mcintosh, Kenneth A. Koeplinger, Li Sun, Jennifer Talaty, Deborah L. Miller, Russell Dixon, S. Aubrey StochAbstract:Odanacatib is a selective Inhibitor of the Cathepsin K enzyme that is expressed in osteoclasts involved in the degradation of bone organic matrix, and is being developed as a novel treatment of osteoporosis. Odanacatib has demonstrated increases in bone mineral density in postmenopausal women and is undergoing a pivotal phase III trial. The absorption, metabolism, and excretion of [14C]odanacatib were studied in healthy male volunteers (n = 6) after a single oral dose of 25 mg (100 µCi). Plasma, urine, and fecal samples were collected at intervals up to 34 days postdose. The pharmacoKinetics of odanacatib were characterized by slow absorption (mean time to achieve maximum plasma concentration of 14.2 hours) and long apparent elimination half-life (mean t1/2 96.7 hours); 74.5% of the dose was recovered in feces and 16.9% in urine, resulting in a total recovery of 91.4%. Seven metabolites were identified in urine; the major pathway (methyl hydroxylation producing M8 and its derivatives) was largely dependent on CYP3A. Metabolites and odanacatib accounted for 77% and 23% of urinary radioactivity, respectively. In fecal extracts, the only radioactive components identified were odanacatib (60.9%) and M8 (9.5%). The fraction of odanacatib in feces derived from absorbed drug was estimated using a bioavailability value obtained from the results of a separate intravenous study. Collectively, the data indicate that odanacatib has a long t1/2 on account of its low metabolic intrinsic clearance, and that metabolism (principally mediated by CYP3A) and excretion of intact parent compound account for ∼70% and ∼30% of the clearance of odanacatib in humans.
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Odanacatib, a selective Cathepsin K Inhibitor to treat osteoporosis: safety, tolerability, pharmacoKinetics and pharmacodynamics--results from single oral dose studies in healthy volunteers.
British journal of clinical pharmacology, 2013Co-Authors: S. Aubrey Stoch, Stefan Zajic, Deborah L. Miller, Julie A. Stone, Lucas Van Bortel, Kenneth C. Lasseter, Barnali Pramanik, Caroline Cilissen, Q Liu, Lida LiuAbstract: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 (2600mg) 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 46h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of approximate to 4080h. The area under the curve0-24 hours (AUC024h), concentration at 24 hours (C24h) and maximum concentration (Cmax,overal) increased in a less than dose-proportional manner from 2 to 600mg. Administration of ODN with a high-fat meal led to approximate to 100% increases in AUC024h, Cmax,day1, Cmax,overall and C24h relative to the fasted state, while administration with a low-fat meal led to a approximate to 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 24h for doses 5mg and at 168h postdose for 10mg. In postmenopausal women administered 50mg ODN, reductions in serum CTx of 66% and urine NTx/creatinine (uNTx/Cr) of 51% relative to placebo were observed at 24h. At 168h, 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 43.8nM and approximate to 80% maximal reduction. Conclusions: Odanacatib was well tolerated and has a pharmacoKinetic and pharmacodynamic profile suitable for once weeKly dosing.
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Odanacatib, a selective Cathepsin K Inhibitor to treat osteoporosis: safety, tolerability, pharmacoKinetics and pharmacodynamics--results from single oral dose studies in healthy volunteers.
British journal of clinical pharmacology, 2013Co-Authors: S. Aubrey Stoch, Stefan Zajic, Deborah L. Miller, Julie A. Stone, Lucas Van Bortel, Kenneth C. Lasseter, Barnali Pramanik, Caroline Cilissen, Q Liu, Lida LiuAbstract:To evaluate the safety, tolerability, pharmacoKinetics and pharmacodynamics of odanacatib (ODN), a Cathepsin K Inhibitor, in humans. 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). 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. 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.
Philippe Clézardin - One of the best experts on this subject based on the ideXlab platform.
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A Cathepsin K Inhibitor Reduces Breast Cancer–Induced Osteolysis and SKeletal Tumor Burden
Cancer research, 2007Co-Authors: Céline Le Gall, Akeila Bellahcene, Edith Bonnelye, Jürg A. Gasser, Vincent Castronovo, Jonathan Green, Johann Zimmermann, Philippe ClézardinAbstract:Osteoclasts mediate bone destruction in breast cancer sKeletal metastases. Cathepsin K is a proteinase that is secreted by osteoclasts and degrades bone. Here, immunohistochemistry revealed that Cathepsin K was expressed not only by osteoclasts but also by breast cancer cells that metastasize to bone. Following intratibial injection with Cathepsin K-expressing human BT474 breast cancer cells, tumor-bearing mice treated with a clinical dosing regimen of Cathepsin K Inhibitor (CKI; 50 mg/Kg, twice daily) had osteolytic lesions that were 79% smaller than those of tumor-bearing mice treated with the vehicle. The effect of CKI was also studied in a mouse model in which the i.v. inoculation of human B02 breast cancer cells expressing Cathepsin K leads to bone metastasis formation. Drug administration was started before (preventive protocol) or after (treatment protocol) the occurrence of osteolytic lesions. In treatment protocols, CKI (50 mg/Kg, twice daily) or a single clinical dose of 100 microg/Kg zoledronic acid (osteoclast Inhibitor) reduced the progression of osteolytic lesions by 59% to 66%. CKI therapy also reduced sKeletal tumor burden by 62% compared with vehicle, whereas zoledronic acid did not decrease the tumor burden. The efficacy of CKI at inhibiting sKeletal tumor burden was similar in the treatment and preventive protocols. By contrast, CKI did not blocK the growth of s.c. B02 tumor xenografts in animals. Thus, CKI may render the bone a less favorable microenvironment for tumor growth by inhibiting bone resorption. These findings raise the possibility that Cathepsin K could be a therapeutic target for the treatment of bone metastases.
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a Cathepsin K Inhibitor reduces breast cancer induced osteolysis and sKeletal tumor burden
Cancer Research, 2007Co-Authors: Celine Le Gall, Akeila Bellahcene, Edith Bonnelye, Jürg A. Gasser, Vincent Castronovo, Jonathan Green, Johann Zimmermann, Philippe ClézardinAbstract:Osteoclasts mediate bone destruction in breast cancer sKeletal metastases. Cathepsin K is a proteinase that is secreted by osteoclasts and degrades bone. Here, immunohistochemistry revealed that Cathepsin K was expressed not only by osteoclasts but also by breast cancer cells that metastasize to bone. Following intratibial injection with Cathepsin K–expressing human BT474 breast cancer cells, tumor-bearing mice treated with a clinical dosing regimen of Cathepsin K Inhibitor (CKI; 50 mg/Kg, twice daily) had osteolytic lesions that were 79% smaller than those of tumor-bearing mice treated with the vehicle. The effect of CKI was also studied in a mouse model in which the i.v. inoculation of human B02 breast cancer cells expressing Cathepsin K leads to bone metastasis formation. Drug administration was started before (preventive protocol) or after (treatment protocol) the occurrence of osteolytic lesions. In treatment protocols, CKI (50 mg/Kg, twice daily) or a single clinical dose of 100 μg/Kg zoledronic acid (osteoclast Inhibitor) reduced the progression of osteolytic lesions by 59% to 66%. CKI therapy also reduced sKeletal tumor burden by 62% compared with vehicle, whereas zoledronic acid did not decrease the tumor burden. The efficacy of CKI at inhibiting sKeletal tumor burden was similar in the treatment and preventive protocols. By contrast, CKI did not blocK the growth of s.c. B02 tumor xenografts in animals. Thus, CKI may render the bone a less favorable microenvironment for tumor growth by inhibiting bone resorption. These findings raise the possibility that Cathepsin K could be a therapeutic target for the treatment of bone metastases. [Cancer Res 2007;67(20):9894–902]
Stefan Zajic - One of the best experts on this subject based on the ideXlab platform.
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A phase 1 pooled PK/PD analysis of bone resorption biomarKers for odanacatib, a Cathepsin K Inhibitor.
Journal of pharmacokinetics and pharmacodynamics, 2020Co-Authors: Stefan Zajic, Rose Witter, S. Aubrey Stoch, Jacqueline B. Mccrea, Ghassan N. Fayad, Monika Martinho, Julie A. StoneAbstract:To develop a frameworK for evaluating the resorption effects of Cathepsin K (CatK) Inhibitors and to inform dose regimen selection, a pharmacoKinetic/pharmacodynamic (PK/PD) model for odanacatib (ODN) was developed based upon data from Phase 1 studies. Pooled PK/PD data from 11 studies (N = 249) were fit reasonably to a population Inhibitory sigmoid Emax model. Body weight on E0 (baseline uNTx/Cr, urinary N-terminal telopeptide normalized by creatinine) and age on Emax (fractional inhibition of the biomarKer response) were significant covariates for biomarKer response. Simulations of typical osteoporosis patients (by age, sex and weight) indicated minimal differences between sexes in concentration-uNTx/Cr relationship. There was no evidence that regimen (daily vs. weeKly dosing) influenced the PK/PD relationship of resorption inhibition for odanacatib. PK/PD models based on data from odanacatib (ODN) Phase 1 studies demonstrated that uNTx/Cr was an appropriate bone resorption biomarKer for assessment of the effects of a CatK Inhibitor. The models also identified the determinants of response in the PK/PD relationship for ODN (body weight on E0 and age on Emax).
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Clinical and translational pharmacology of the Cathepsin K Inhibitor odanacatib studied for osteoporosis.
British journal of clinical pharmacology, 2019Co-Authors: Julie A. Stone, Rose Witter, Stefan Zajic, Jacqueline B. Mccrea, S. Aubrey StochAbstract: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 formation-sparing 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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Disposition and Metabolism of the Cathepsin K Inhibitor Odanacatib in Humans
Drug metabolism and disposition: the biological fate of chemicals, 2014Co-Authors: Kelem Kassahun, Stefan Zajic, Ian Mcintosh, Kenneth A. Koeplinger, Li Sun, Jennifer Talaty, Deborah L. Miller, Russell Dixon, S. Aubrey StochAbstract:Odanacatib is a selective Inhibitor of the Cathepsin K enzyme that is expressed in osteoclasts involved in the degradation of bone organic matrix, and is being developed as a novel treatment of osteoporosis. Odanacatib has demonstrated increases in bone mineral density in postmenopausal women and is undergoing a pivotal phase III trial. The absorption, metabolism, and excretion of [14C]odanacatib were studied in healthy male volunteers (n = 6) after a single oral dose of 25 mg (100 µCi). Plasma, urine, and fecal samples were collected at intervals up to 34 days postdose. The pharmacoKinetics of odanacatib were characterized by slow absorption (mean time to achieve maximum plasma concentration of 14.2 hours) and long apparent elimination half-life (mean t1/2 96.7 hours); 74.5% of the dose was recovered in feces and 16.9% in urine, resulting in a total recovery of 91.4%. Seven metabolites were identified in urine; the major pathway (methyl hydroxylation producing M8 and its derivatives) was largely dependent on CYP3A. Metabolites and odanacatib accounted for 77% and 23% of urinary radioactivity, respectively. In fecal extracts, the only radioactive components identified were odanacatib (60.9%) and M8 (9.5%). The fraction of odanacatib in feces derived from absorbed drug was estimated using a bioavailability value obtained from the results of a separate intravenous study. Collectively, the data indicate that odanacatib has a long t1/2 on account of its low metabolic intrinsic clearance, and that metabolism (principally mediated by CYP3A) and excretion of intact parent compound account for ∼70% and ∼30% of the clearance of odanacatib in humans.
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Odanacatib, a Selective Cathepsin K Inhibitor, Demonstrates Comparable Pharmacodynamics and PharmacoKinetics in Older Men and Postmenopausal Women
The Journal of clinical endocrinology and metabolism, 2013Co-Authors: Matt S. Anderson, Chengcheng Liu, Stefan Zajic, Anish Mehta, Chantal Mahon, Kate Mostoller, I.n. Gendrano, Steven Jeffers, Denise Morris, Jessie LeeAbstract:BacKground: Odanacatib is a Cathepsin K Inhibitor in development for the treatment of osteoporosis. Evaluation of therapies to ensure that treatment effects are relevant regardless of sex is clinically important. Methods: In this double-blind, randomized controlled trial, older men (aged 50–75 years) and postmenopausal women (aged 45–75 years) were given odanacatib 50 mg once weeKly or placebo for 4 weeKs. Pharmacodynamic (PD) evaluation measured weighted average inhibition (WAI) of urine amino-terminal cross-linKed telopeptide of type I collagen/creatinine (uNTx/Cr) after odanacatib administration. PharmacoKinetic (PK) parameter data were collected, and an analysis of sex as a factor in the PK/PD relationship was conducted. Adverse events were monitored. The hypotheses were that WAI of uNTx/Cr would be >40% (including >40% for the lower limit of the 90% confidence intervals [CIs]) for older men and postmenopausal women, that there would be no important differences in area under the curve from 0 to 168 ho...
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Odanacatib, a Selective Cathepsin K Inhibitor, Demonstrates Comparable Pharmacodynamics and PharmacoKinetics in Older Men and Postmenopausal Women
The Journal of clinical endocrinology and metabolism, 2013Co-Authors: Matt S. Anderson, Chengcheng Liu, Stefan Zajic, Anish Mehta, Chantal Mahon, Kate Mostoller, I.n. Gendrano, Steven Jeffers, Denise Morris, Jessie LeeAbstract:Odanacatib is a Cathepsin K Inhibitor in development for the treatment of osteoporosis. Evaluation of therapies to ensure that treatment effects are relevant regardless of sex is clinically important. In this double-blind, randomized controlled trial, older men (aged 50-75 years) and postmenopausal women (aged 45-75 years) were given odanacatib 50 mg once weeKly or placebo for 4 weeKs. Pharmacodynamic (PD) evaluation measured weighted average inhibition (WAI) of urine amino-terminal cross-linKed telopeptide of type I collagen/creatinine (uNTx/Cr) after odanacatib administration. PharmacoKinetic (PK) parameter data were collected, and an analysis of sex as a factor in the PK/PD relationship was conducted. Adverse events were monitored. The hypotheses were that WAI of uNTx/Cr would be >40% (including >40% for the lower limit of the 90% confidence intervals [CIs]) for older men and postmenopausal women, that there would be no important differences in area under the curve from 0 to 168 hours (AUC0-168 h) between men and women, and that odanacatib would be safe and well tolerated. A total of 44 subjects (32 men and 12 women) were randomized. The least squares mean WAI (uNTx/Cr) at weeK 4 was 42.8% (90% CI, 35.5%-49.3%) for men and 42.7% (90% CI, 30.3%-52.9%) for women; mean values were >40%, but lower bounds were <40% as prespecified in the primary hypothesis. The differences among men and women in PD parameters were not meaningful (0.1; 90% CI, -14.7 to 14.9). PK parameters for both groups were comparable (geometric mean ratio of AUC0-168 h, 0.90; 90% CI, 0.75-1.07). A PK/PD analysis found that the EC50 and maximum fractional inhibition were similar in male and female subjects. There were no notable or serious adverse events in this study. Although the primary hypothesis was not met, there were no clinically meaningful differences in PD, PK, or PK/PD parameters between older men and postmenopausal women, supporting further research on odanacatib (50 mg once weeKly) as a treatment for male osteoporosis. Odanacatib was generally well tolerated.