Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Canagliflozin in Healthy Chinese Subjects

Chen, Xia; Hu, Pei; Vaccaro, Nicole; Polidori, David; Curtin, Christopher R.; Stieltjes, Hans; Sha, Sue; Weiner, Sveta; Devineni, Damayanthi

doi:10.1016/j.clinthera.2015.04.015

Cited by 25 publications

(18 citation statements)

References 26 publications

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“…A1c and eGFR MDRD were positively correlated with tubular SGLT2 log 2 mRNA expression. In diabetes, hyperglycemia promotes SGLT2 bioactivity and changes in the renal transport maximum for glucose (3). This relationship was consistent with our nondiabetic GN cohort, with the important caveat that the majority of NEPTUNE participants had an A1c less than the prediabetes threshold of 6% (mean A1c of 5.6 Ϯ 0.4%).…”

Section: F1225supporting

confidence: 86%

Renal SGLT mRNA expression in human health and disease: a study in two cohorts

Sridhar

Ambinathan

Kretzler

et al. 2019

American Journal of Physiology-Renal Physiology

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Pharmacological Na+-glucose linked cotransporter (SGLT)2 inhibition is being examined as a renal protection strategy in nondiabetic chronic kidney disease. We quantified renal SGLT mRNA expression in healthy controls (HC), glomerulonephritis (GN), and diabetic kidney disease (DKD) to identify differences in expression across a spectrum of renal diseases. mRNA expression of SGLT1 and SGLT2 in renal tubules and glomeruli, obtained using microdissection and microarray techniques, was evaluated in two large cohorts. The European Renal cDNA bank included HC, GN, and DKD (98 glomeruli and 93 tubulointerstitium). The Nephrotic Syndrome Study Network cohort included 124 adults with membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, and IgA nephropathy. Within the European Renal cDNA bank, SGLT2 tubular and glomerular log2 mRNA expression significantly differed across HC, GN, and DKD ( P = 0.0009 and P = 0.0004), with the highest expression in HC. Within the Nephrotic Syndrome Study Network, there were no differences in SGLT log2 mRNA expression across GN subtypes. Tubular SGLT2 log2 mRNA expression positively correlated with estimated glomerular filtration rate (by the Modification of Diet in Renal Disease Study equation) and glycated hemoglobin ( r = 0.33 and 0.34, P < 0.05) and inversely correlated with interstitial fibrosis ( r = −0.21, P < 0.05). In conclusion, SGLT2 mRNA expression was lower in DKD compared with HC or GN and inversely related to interstitial fibrosis. The relationships between SGLT mRNA, protein expression, and transporter activity require further elucidation.

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Section: F1225supporting

confidence: 86%

Renal SGLT mRNA expression in human health and disease: a study in two cohorts

Sridhar

Ambinathan

Kretzler

et al. 2019

American Journal of Physiology-Renal Physiology

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“…Results from a population PK analysis of ertugliflozin indicate that sex does not have a clinically relevant effect on the PK of ertugliflozin . Similar to ertugliflozin, lower body weight is associated with higher exposures of both empagliflozin and canagliflozin in Chinese subjects compared with Western counterparts. Nevertheless, the observed exposure differences in ertugliflozin AUC and C max are ≤50% between Chinese and non‐Asian populations and are not considered clinically meaningful.…”

Section: Discussionmentioning

confidence: 98%

Pharmacokinetic Properties of Single and Multiple Doses of Ertugliflozin, a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects

Shi

et al. 2019

Clinical Pharm in Drug Dev

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Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus, prevents renal glucose reabsorption resulting in urinary glucose excretion. This open-label, parallel cohort, randomized study conducted in healthy Chinese adults residing in China assessed the pharmacokinetics, tolerability, and safety of 5 mg and 15 mg of ertugliflozin following single (fasted condition) and multiple-dose (fed condition) administration. Sixteen subjects were randomized and completed the study. Ertugliflozin absorption was rapid, with maximum plasma concentrations observed 1 hour after dosing under fasted conditions and 2 to 4 hours after dosing under fed conditions. Following single-and multiple-dose administration, ertugliflozin exhibited dose-proportional exposures with an apparent mean terminal halflife of approximately 9.5 to 11.9 hours. Steady state was reached after 4 once-daily doses. The accumulation ratio based on the area under the plasma concentration-time curve after multiple-dose administration was approximately 1.3 and 1.2 for ertugliflozin 5 mg and 15 mg, respectively. Ertugliflozin was generally well tolerated following administration of single and multiple oral doses of 5 mg and 15 mg in healthy Chinese subjects. Pharmacokinetic comparison with non-Asian subjects indicated that there are no clinically meaningful racial differences and no dose modification of ertugliflozin is required based on race or body weight.

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“…There are no related reports of canagliflozin and telmisartan binding as new compounds in vivo. Glucuronic acid binding is the mainly metabolic form of telmisartan (27); M5 and M7 were the O-glucuronide metabolite of canagliflozin, which were two main inactive metabolites (21,28).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of influence of telmisartan on the pharmacokinetics and tissue distribution of canagliflozin in rats and mice

Wang¹,

Liu²,

Meng³

et al. 2021

Ann Palliat Med

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Background: Canagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, is widely used for the treatment of type 2 diabetes mellitus. However, drug interactions with canagliflozin can affect its glucoselowering therapeutic effects or exacerbate its adverse effects. Telmisartan, an angiotensin receptor blocker (ARB), has been approved for the treatment of diabetic kidney disease. This study aimed to investigate the effects of telmisartan on the pharmacokinetics and tissue distribution of canagliflozin. Methods: An ultra-performance liquid chromatography-tandem mass spectrometry method was successfully validated to determine the levels of canagliflozin in the plasma and tissues. The main pharmacokinetic parameters were calculated using the non-compartmental model. Results: Compared with animals administered canagliflozin alone, the area under the receiver operating characteristic curve of animals co-administered telmisartan and canagliflozin was significantly increased after a single-day administration, but significantly decreased after a seven-day treatment regimen (both P<0.05). The highest concentrations of canagliflozin were detected in the kidneys, followed by the intestine, liver, heart, lung, spleen, and brain tissues. Furthermore, the concentration of canagliflozin in the heart, liver, lung, and kidney tissues at 2 hours post-administration was significantly higher in the telmisartan and canagliflozin group compared to the group treated with canagliflozin alone (P<0.05). Conclusions: A pharmacokinetic drug-drug interaction between telmisartan and canagliflozin might occur during drug co-administration.

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Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Canagliflozin in Healthy Chinese Subjects

Cited by 25 publications

References 26 publications

Renal SGLT mRNA expression in human health and disease: a study in two cohorts

Renal SGLT mRNA expression in human health and disease: a study in two cohorts

Pharmacokinetic Properties of Single and Multiple Doses of Ertugliflozin, a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects

Evaluation of influence of telmisartan on the pharmacokinetics and tissue distribution of canagliflozin in rats and mice

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