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HRL l6md000Q:`0?c胑-0 :1C;gaZA,O{zP &$ vdu^dNC_ xrO'R: &Ą^ /ȋ* X'k6R$21D{ endstream endobj 325 0 obj <> endobj 326 0 obj <> endobj 327 0 obj <> endobj 328 0 obj <> endobj 329 0 obj <>stream application/pdf Preclinical Development of KBP-5074, a Novel Non-SteroidalMineralocorticoid Receptor Antagonist for the Treatment ofCardiorenal Diseases Objective: Mineralocorticoid receptor antagonists have been demonstrated to reduce the mortality in patients with heart failure and to decrease proteinuria in patients with cardiorenal diseases. The primary objective of this study was to evaluate the preclinical safety profile of KBP-5074 to support the initiation of clinical trials in human. Results: Genotoxicity studies of KBP-5074 included in vitro mutagenicity and chromosomal aberration studies as well as in vivo micronucleus test in CD-1 mice. KBP-5074 demonstrated neither mutagenic nor clastogenic potential. Acute oral administration of KBP-5074 to SD rats and Beagle dogs showed the maximum tolerated dose was > 600 mg/kg in both species. A 4-week oral rat toxicity study was performed using 0, 2, 6 and 20 mg/kg/day. No significant clinical or behavioral signs of toxicity were observed after oral administration of KBP-5074 in any rats during the study. Treatment-related changes in clinical chemistry on Day 29 included increased hepatic enzymes, blood urea nitrogen, alkaline phosphatase and plasma potassium concentrations in the female rats. No changes in any clinical chemistry parameters on Day 29 were observed in male rats. Plasma concentrations in female rats were about 2-3 times higher than male rats. A 4-week oral dog toxicity study was performed using 0, 2, 6 and 20 mg/ kg/day. No overt clinical or behavioral signs of toxicity were observed after oral administration of KBP-5074 to male and female dogs at doses up to 20 mg/kg/day for 4 weeks. Safety pharmacology studies, including in vitro hERG assay (IC50: 17 μM) and the in vivo core battery of CNS safety pharmacology study in rats and cardiovascular safety pharmacology study in dogs conclusively demonstrated that KBP-5074 was well-tolerated at doses up to 10 and 15 mg/kg, respectively. Conclusion: Based on the results of the above studies, the preclinical safety profile of KBP-5074 would support the First-in-Human study. © 2018 Chow CP, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. C Paul Chow1 * JR Liu2 XJ Tan2 Fred Yang1 and ZH Huang2 Mineralocorticoid receptor antagonists Cardiorenal diseases Chronic kidney disease Systolic Blood Pressure Hyperkalemia 2018-06-29T17:12:19+05:30 2018-06-29T17:12:22+05:30 2018-06-29T17:12:22+05:30 4 Adobe InDesign CS6 (Windows) uuid:bb893a1f-09e2-42cf-a33b-4745b99fde9f xmp.did:FE00469DB0C7E411AEB789ACBE3823B3 xmp.id:4FEA6977917BE811BD56A771FAEBA98D proof:pdf xmp.iid:4EEA6977917BE811BD56A771FAEBA98D xmp.did:25700E8721B3E7119FB78DFA0FAB8027 xmp.did:FE00469DB0C7E411AEB789ACBE3823B3 default converted from application/x-indesign to application/pdf Adobe InDesign CS6 (Windows) / 2018-06-29T17:12:19+05:30 Chow CP, Liu JR, Tan XJ, Yang F, Huang ZH (2018) Preclinical Development of KBP-5074, a Novel Non-Steroidal MineralocorticoidReceptor Antagonist for the Treatment of Cardiorenal Diseases. J Drug Res Dev 4(2): dx.doi.org/10.16966/2470-1009.143 Paul Chow, PhD, DABT, KBP BioSciences USA Inc., 116 Village Boulevard, Suite 210, Princeton, New Jersey 08540, USA,E-mail: cpaul.chow@kbpbiosciences.com http://dx.doi.org/10.16966/2470-1009.143 Adobe PDF Library 10.0.1 False endstream endobj 330 0 obj < 600 mg/kg in both species. A 4-week oral rat toxicity study was performed using 0, 2,\ 6 and 20\nmg/kg/day. No significant clinical or behavioral signs of toxicity were observed after oral administration of KBP-507\ 4 in any rats during the study.\nTreatment-related changes in clinical chemistry on Day 29 included increased hepatic enzymes, b\ lood urea nitrogen, alkaline phosphatase and\nplasma potassium concentrations in the female rats. No changes in any clinical che\ mistry parameters on Day 29 were observed in male rats. Plasma\nconcentrations in female rats were about 2-3 times higher than m\ ale rats. A 4-week oral dog toxicity study was performed using 0, 2, 6 and 20 mg/\nkg/day. No overt clinical or behavioral signs\ of toxicity were observed after oral administration of KBP-5074 to male and female dogs at doses up\nto 20 mg/kg/day for 4 week\ s. Safety pharmacology studies, including in vitro hERG assay \(IC50: 17 M\) and the in vivo core battery of CNS safety\npharmac\ ology study in rats and cardiovascular safety pharmacology study in dogs conclusively demonstrated that KBP-5074 was well-tolera\ ted at\ndoses up to 10 and 15 mg/kg, respectively.\nConclusion: Based on the results of the above studies, the preclinical safet\ y profile of KBP-5074 would support the First-in-Human study.)/Title(Preclinical Development of KBP-5074, a Novel Non-SteroidalMineralocorticoid Receptor Antagonist for the Treatment ofCardiorenal Diseases)/Trapped/False>> endobj xref 0 3002 0000000000 65535 f 0000290032 00000 n 0000290499 00000 n 0000299234 00000 n 0000299293 00000 n 0000299760 00000 n 0000308819 00000 n 0000308878 00000 n 0000309383 00000 n 0000317751 00000 n 0000317810 00000 n 0000318475 00000 n 0000332490 00000 n 0000369270 00000 n 0000369307 00000 n 0000406087 00000 n 0000406124 00000 n 0000442904 00000 n 0000442941 00000 n 0000479721 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Antagonist for the Treatment ofCardiorenal Diseases Objective: Mineralocorticoid receptor antagonists have been demonstrated to reduce the mortality in patients with heart failure and to decrease proteinuria in patients with cardiorenal diseases. The primary objective of this study was to evaluate the preclinical safety profile of KBP-5074 to support the initiation of clinical trials in human. Results: Genotoxicity studies of KBP-5074 included in vitro mutagenicity and chromosomal aberration studies as well as in vivo micronucleus test in CD-1 mice. KBP-5074 demonstrated neither mutagenic nor clastogenic potential. Acute oral administration of KBP-5074 to SD rats and Beagle dogs showed the maximum tolerated dose was > 600 mg/kg in both species. A 4-week oral rat toxicity study was performed using 0, 2, 6 and 20 mg/kg/day. No significant clinical or behavioral signs of toxicity were observed after oral administration of KBP-5074 in any rats during the study. Treatment-related changes in clinical chemistry on Day 29 included increased hepatic enzymes, blood urea nitrogen, alkaline phosphatase and plasma potassium concentrations in the female rats. No changes in any clinical chemistry parameters on Day 29 were observed in male rats. Plasma concentrations in female rats were about 2-3 times higher than male rats. A 4-week oral dog toxicity study was performed using 0, 2, 6 and 20 mg/ kg/day. No overt clinical or behavioral signs of toxicity were observed after oral administration of KBP-5074 to male and female dogs at doses up to 20 mg/kg/day for 4 weeks. Safety pharmacology studies, including in vitro hERG assay (IC50: 17 μM) and the in vivo core battery of CNS safety pharmacology study in rats and cardiovascular safety pharmacology study in dogs conclusively demonstrated that KBP-5074 was well-tolerated at doses up to 10 and 15 mg/kg, respectively. Conclusion: Based on the results of the above studies, the preclinical safety profile of KBP-5074 would support the First-in-Human study. © 2018 Chow CP, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. C Paul Chow1 * JR Liu2 XJ Tan2 Fred Yang1 and ZH Huang2 Mineralocorticoid receptor antagonists Cardiorenal diseases Chronic kidney disease Systolic Blood Pressure Hyperkalemia 2018-06-29T17:12:19+05:30 2018-06-29T17:12:26+05:30 2018-06-29T17:12:26+05:30 4 Adobe InDesign CS6 (Windows) uuid:252da735-9304-4b68-9d32-a00f2cc08630 xmp.did:FE00469DB0C7E411AEB789ACBE3823B3 xmp.id:4FEA6977917BE811BD56A771FAEBA98D proof:pdf xmp.iid:4EEA6977917BE811BD56A771FAEBA98D xmp.did:25700E8721B3E7119FB78DFA0FAB8027 xmp.did:FE00469DB0C7E411AEB789ACBE3823B3 default converted from application/x-indesign to application/pdf Adobe InDesign CS6 (Windows) / 2018-06-29T17:12:19+05:30 Chow CP, Liu JR, Tan XJ, Yang F, Huang ZH (2018) Preclinical Development of KBP-5074, a Novel Non-Steroidal MineralocorticoidReceptor Antagonist for the Treatment of Cardiorenal Diseases. J Drug Res Dev 4(2): dx.doi.org/10.16966/2470-1009.143 Paul Chow, PhD, DABT, KBP BioSciences USA Inc., 116 Village Boulevard, Suite 210, Princeton, New Jersey 08540, USA,E-mail: cpaul.chow@kbpbiosciences.com http://dx.doi.org/10.16966/2470-1009.143 Adobe PDF Library 10.0.1 False endstream endobj 330 0 obj < 600 mg/kg in both species. A 4-week oral rat toxicity study was performed using 0, 2,\ 6 and 20\nmg/kg/day. No significant clinical or behavioral signs of toxicity were observed after oral administration of KBP-507\ 4 in any rats during the study.\nTreatment-related changes in clinical chemistry on Day 29 included increased hepatic enzymes, b\ lood urea nitrogen, alkaline phosphatase and\nplasma potassium concentrations in the female rats. No changes in any clinical che\ mistry parameters on Day 29 were observed in male rats. Plasma\nconcentrations in female rats were about 2-3 times higher than m\ ale rats. A 4-week oral dog toxicity study was performed using 0, 2, 6 and 20 mg/\nkg/day. No overt clinical or behavioral signs\ of toxicity were observed after oral administration of KBP-5074 to male and female dogs at doses up\nto 20 mg/kg/day for 4 week\ s. Safety pharmacology studies, including in vitro hERG assay \(IC50: 17 M\) and the in vivo core battery of CNS safety\npharmac\ ology study in rats and cardiovascular safety pharmacology study in dogs conclusively demonstrated that KBP-5074 was well-tolera\ ted at\ndoses up to 10 and 15 mg/kg, respectively.\nConclusion: Based on the results of the above studies, the preclinical safet\ y profile of KBP-5074 would support the First-in-Human study.)/Title(Preclinical Development of KBP-5074, a Novel Non-SteroidalMineralocorticoid Receptor Antagonist for the Treatment ofCardiorenal Diseases)/Trapped/False>> endobj 3003 0 obj <>/Metadata 329 0 R/Names 3004 0 R/Outlines 233 0 R/PageMode/UseOutlines/Pages 328 0 R/StructTreeRoot 331 0 R/Type/Catalog/ViewerPreferences<>>> endobj xref 0 1 0000000000 65535 f 329 2 0000835272 00000 n 0000844176 00000 n 3003 1 0000848509 00000 n trailer <<5E4BA48AD4748944BE687D8C8635F436>]/Prev 116>> startxref 848713 %%EOF