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Pharmacokinetic and Pharmacodynamic Profiles of Canagliflozin in Japanese Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment

BACKGROUND AND OBJECTIVES: This study examined the effects of moderate renal impairment on the pharmacokinetics and pharmacodynamics of canagliflozin in Japanese patients with type 2 diabetes mellitus. METHODS: Japanese patients with stable type 2 diabetes (12 with moderate renal impairment and 12 w...

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Autores principales: Inagaki, Nobuya, Kondo, Kazuoki, Yoshinari, Toru, Ishii, Manabu, Sakai, Masaki, Kuki, Hideki, Furihata, Kenichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4168221/
https://www.ncbi.nlm.nih.gov/pubmed/25200141
http://dx.doi.org/10.1007/s40261-014-0226-x
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author Inagaki, Nobuya
Kondo, Kazuoki
Yoshinari, Toru
Ishii, Manabu
Sakai, Masaki
Kuki, Hideki
Furihata, Kenichi
author_facet Inagaki, Nobuya
Kondo, Kazuoki
Yoshinari, Toru
Ishii, Manabu
Sakai, Masaki
Kuki, Hideki
Furihata, Kenichi
author_sort Inagaki, Nobuya
collection PubMed
description BACKGROUND AND OBJECTIVES: This study examined the effects of moderate renal impairment on the pharmacokinetics and pharmacodynamics of canagliflozin in Japanese patients with type 2 diabetes mellitus. METHODS: Japanese patients with stable type 2 diabetes (12 with moderate renal impairment and 12 with normal renal function or mild renal impairment) were eligible. This was an open-label, randomized, two-way crossover, two-sequence, single-dose study performed at a single center in Japan. The subjects were hospitalized for the pharmacodynamic/pharmacokinetic evaluations. Twenty-four patients received a single dose each of canagliflozin 100 and 200 mg before breakfast in a crossover manner with a 14-day washout between doses. The main outcome measures were pharmacokinetics of canagliflozin and its main metabolites (M5 and M7) in plasma and urine, and change from baseline in 24-h urinary glucose excretion (ΔUGE24 h). RESULTS: There was no significant effect of moderate renal impairment on the maximum canagliflozin concentration. The ratios of least square means (90 % confidence intervals [CIs]) of moderate renal impairment relative to normal renal function or mild renal impairment were 0.982 (0.821–1.173) and 0.989 (0.827–1.182) for the 100 and 200 mg doses, respectively. The canagliflozin area under the plasma concentration–time curve was greater in those with moderate renal impairment than in those without, after both canagliflozin doses (ratio of least square means [90 % CI] 1.258 [1.061–1.490] and 1.216 [1.026–1.441]). ΔUGE24 h increased after administration of both doses, but in patients with moderate renal impairment, the increase was approximately 70 % of that in patients with normal renal function or mild renal impairment. The incidence of adverse events was low and no patient developed hypoglycemia. CONCLUSION: The pharmacokinetics of canagliflozin are affected by renal function, with slight decreases in renal clearance observed. No effect of renal impairment on the maximum concentration was observed. Renal impairment reduced the ability of canagliflozin to promote urinary glucose excretion. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40261-014-0226-x) contains supplementary material, which is available to authorized users.
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spelling pubmed-41682212014-09-24 Pharmacokinetic and Pharmacodynamic Profiles of Canagliflozin in Japanese Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment Inagaki, Nobuya Kondo, Kazuoki Yoshinari, Toru Ishii, Manabu Sakai, Masaki Kuki, Hideki Furihata, Kenichi Clin Drug Investig Original Research Article BACKGROUND AND OBJECTIVES: This study examined the effects of moderate renal impairment on the pharmacokinetics and pharmacodynamics of canagliflozin in Japanese patients with type 2 diabetes mellitus. METHODS: Japanese patients with stable type 2 diabetes (12 with moderate renal impairment and 12 with normal renal function or mild renal impairment) were eligible. This was an open-label, randomized, two-way crossover, two-sequence, single-dose study performed at a single center in Japan. The subjects were hospitalized for the pharmacodynamic/pharmacokinetic evaluations. Twenty-four patients received a single dose each of canagliflozin 100 and 200 mg before breakfast in a crossover manner with a 14-day washout between doses. The main outcome measures were pharmacokinetics of canagliflozin and its main metabolites (M5 and M7) in plasma and urine, and change from baseline in 24-h urinary glucose excretion (ΔUGE24 h). RESULTS: There was no significant effect of moderate renal impairment on the maximum canagliflozin concentration. The ratios of least square means (90 % confidence intervals [CIs]) of moderate renal impairment relative to normal renal function or mild renal impairment were 0.982 (0.821–1.173) and 0.989 (0.827–1.182) for the 100 and 200 mg doses, respectively. The canagliflozin area under the plasma concentration–time curve was greater in those with moderate renal impairment than in those without, after both canagliflozin doses (ratio of least square means [90 % CI] 1.258 [1.061–1.490] and 1.216 [1.026–1.441]). ΔUGE24 h increased after administration of both doses, but in patients with moderate renal impairment, the increase was approximately 70 % of that in patients with normal renal function or mild renal impairment. The incidence of adverse events was low and no patient developed hypoglycemia. CONCLUSION: The pharmacokinetics of canagliflozin are affected by renal function, with slight decreases in renal clearance observed. No effect of renal impairment on the maximum concentration was observed. Renal impairment reduced the ability of canagliflozin to promote urinary glucose excretion. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40261-014-0226-x) contains supplementary material, which is available to authorized users. Springer International Publishing 2014-09-09 2014 /pmc/articles/PMC4168221/ /pubmed/25200141 http://dx.doi.org/10.1007/s40261-014-0226-x Text en © The Author(s) 2014 https://creativecommons.org/licenses/by-nc/4.0/ Open AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
spellingShingle Original Research Article
Inagaki, Nobuya
Kondo, Kazuoki
Yoshinari, Toru
Ishii, Manabu
Sakai, Masaki
Kuki, Hideki
Furihata, Kenichi
Pharmacokinetic and Pharmacodynamic Profiles of Canagliflozin in Japanese Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment
title Pharmacokinetic and Pharmacodynamic Profiles of Canagliflozin in Japanese Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment
title_full Pharmacokinetic and Pharmacodynamic Profiles of Canagliflozin in Japanese Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment
title_fullStr Pharmacokinetic and Pharmacodynamic Profiles of Canagliflozin in Japanese Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment
title_full_unstemmed Pharmacokinetic and Pharmacodynamic Profiles of Canagliflozin in Japanese Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment
title_short Pharmacokinetic and Pharmacodynamic Profiles of Canagliflozin in Japanese Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment
title_sort pharmacokinetic and pharmacodynamic profiles of canagliflozin in japanese patients with type 2 diabetes mellitus and moderate renal impairment
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4168221/
https://www.ncbi.nlm.nih.gov/pubmed/25200141
http://dx.doi.org/10.1007/s40261-014-0226-x
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