Absence of Drug–Drug Interactions Between Luseogliflozin, a Sodium–Glucose Co-transporter-2 Inhibitor, and Various Oral Antidiabetic Drugs in Healthy Japanese Males

Sasaki, Takashi; Seino, Yutaka; Fukatsu, Atsushi; Ubukata, Michito; Sakai, Soichi; Samukawa, Yoshishige

doi:10.1007/s12325-015-0209-1

Cited by 10 publications

(13 citation statements)

References 18 publications

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“…A dedicated study investigated potential DDI between 5 mg luseogliflozin and 50 mg sitagliptin (dose used in Japan) in 12 healthy Japanese males [74] . When administered in combination with sitagliptin, the GMRs and 90%…”

Section: Luseogliflozin (Lusefi(®) Is An Orally Sglt2i Developed By Tmentioning

confidence: 99%

Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes

Scheen

2016

Clin Pharmacokinet

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SUMMARYType 2 diabetes (T2D) generally requires a combination of several pharmacological approaches to control hyperglycaemia. Combining a sodium-glucose cotransporter type 2 inhibitor (SGLT2i, known as gliflozin) and a dipeptidyl peptidase-4 inhibitor known as gliptin) appears to be an attractive strategy because of complementary modes of action.This narrative review analyzes the pharmacokinetics and clinical efficacy of different combined therapies with a SGLT2i (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, tofogliflozin) and a DPP-4i (linagliptin, saxagliptin, sitagliptin, teneligliptin). Drug-drug pharmacokinetic interaction studies do not show any significant changes in peak concentrations (C max ) and total exposure (area under the curve of plasma concentrations or AUC) of either drug when they were given orally together compared to corresponding values when each of them was absorbed alone. Some fixed-dose combinations (FDC) are already available (dapagliflozin-saxagliptin, empagliflozin-linagliptin) or in development (ertugliflozin-sitagliptin), and preliminary results showed bioequivalence of the two medications given as FDC tablets when compared with co-administration of the individual tablets. Dual therapy is more potent than either monotherapy in patients treated with diet and exercise or already treated with metformin. SGLT2i and DPP-4i could be used as initial combination or in a stepwise approach. The additional glucose-lowering effect appears to be more marked when a gliflozin is added to a gliptin than when a gliptin is added to a gliflozin. Combining the two pharmacological options is safe and does not induce hypoglycaemia. Key-words : Combined therapy -DPP-4 inhibitor -Fixed-dose combination -SGLT2 inhibitor -Type 2 diabetesKey points -The combination of a sodium-glucose cotransporter type 2 inhibitor (SGLT2i), which promotes glycosuria and improves glucose tolerance independently of insulin, and a dipeptidyl peptidase-4 inhibitor (DPP-4i), an incretin-based therapy that corrects islet dysfunction, is an attractive approach for the management of type 2 diabetes.-Both dapagliflozin plus saxagliptin and empagliflozin plus linagliptin combined therapies have been tested as separate tablets (no clinically relevant pharmacokinetic drug-drug interactions) and as fixed-dose combination (FDC: bioequivalence studies); such combined therapies are more efficacious than either monotherapy to control blood glucose, without worsening of the safety profile.-Other combinations of a SGLT2i and a DPP-4i have been evaluated in studies that also showed the absence of drug-drug pharmacokinetic interactions and better glucose control compared to either therapy alone. An ertugliflozin-sitagliptin FDC is in current development.-Initial SGLT2i -DPP-4i combination may be considered or one medication may be added to the other, with apparently better results when the SGLT2i was added to the DPP-4i compared with the reverse sequence. However, which glucose-lowering agent sh...

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Section: Luseogliflozin (Lusefi(®) Is An Orally Sglt2i Developed By Tmentioning

confidence: 99%

Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes

Scheen

2016

Clin Pharmacokinet

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“…In a clinical study, the ratio of 6b-hydroxycortisol to cortisol in the urine was measured to evaluate whether the activity of CYP3A4 increased after the repeated administration of luseogliflozin at 1-25 mg once a day for 7 days in patients with T2DM. As a result, the ratio of urinary 6b-hydroxycortisol to cortisol did not increase at any of the doses, suggesting that luseogliflozin does not affect CYP3A4 activity when used clinically (Sasaki et al, 2015).…”

Section: Discussionmentioning

confidence: 89%

“…Based on the simulated intestinal concentration and the rapid absorption of luseogliflozin, the potential DDI was estimated to be low (Mizuno-Yasuhira et al, 2011). Actually, luseogliflozin reportedly has no clinically relevant effect on the pharmacokinetics of miglitol (Sasaki et al, 2015). To obtain more detailed information on the potential DDI caused by drug transporters, other important membrane transporters should also be evaluated.…”

Section: Introductionmentioning

confidence: 99%

In vitro evaluation of potential drug interactions mediated by cytochrome P450 and transporters for luseogliflozin, an SGLT2 inhibitor

et al. 2016

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1. We evaluated potential in vitro drug interactions of luseogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, mediated by CYP inhibition, CYP induction and drug transporters using human liver microsomes, primary hepatocytes and recombinant cells-expressing efflux or uptake transporters, respectively. 2. Human CYP inhibition studies indicated that luseogliflozin was a weak inhibitor for CYP2C19 with an IC value of 58.3 μM, whereas it was not an inhibitor of the other eight major isoforms that were tested. The exposure of primary hepatocytes to luseogliflozin for 72 hrs weakly induced CYP3A4 at a concentration of 10 μM, whereas it did not induce CYP1A2 or CYP2B6 at concentrations of 0.1-10 μM. 3. An in vitro transport study suggested that luseogliflozin is a substrate for human P-glycoprotein (P-gp), but not for breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1 and OATP1B3, organic anion transporter (OAT) 1 and OAT3, or organic cation transporter (OCT) 2. Luseogliflozin weakly inhibited OATP1B3 with an IC value of 93.1 μM, but those for other transporters are greater than 100 μM. 4. Based on the therapeutic plasma concentration of the drug, clinically relevant drug interactions are unlikely to occur between luseogliflozin and coadministered drugs mediated by CYPs and/or transporters.

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“…Blood samples (5 mL) collected in tubes containing sodium heparin were centrifuged immediately after collection at the clinical facility (4°C, 3000 rpm, for 15 minutes) at predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3,4,6,8,12,24,48, and 72-hours postdose to record plasma concentrations of luseogliflozin and its metabolites (M1, M2, M3, and M17). The 24-hour urine sample was pooled at 4°C, and a 6-mL sample for pharmacokinetic assessment was aliquoted and stored at -70°C until analysis to determine urinary concentrations of unchanged luseogliflozin and its metabolites on days -1 (-24 to 0 hours before administration), 1, 2, and 3 (0-24, 24-48, and 48-72 hours after administration).…”

Section: Pharmacokinetic Assessmentsmentioning

confidence: 99%

“…In clinical studies conducted so far, the pharmacokinetics of luseogliflozin have been evaluated mainly in healthy adult or elderly subjects as well as patients with type 2 diabetes and renal impairment. [7][8][9][10][11][12][13][14] However, the pharmacokinetics of luseogliflozin in a special population, such as patients with hepatic impairment, has not been evaluated.…”

mentioning

confidence: 99%

Luseogliflozin, an SGLT2 Inhibitor, in Japanese Patients With Mild/Moderate Hepatic Impairment: A Pharmacokinetic Study

Samukawa

Sata

Furihata

et al. 2017

Clinical Pharm in Drug Dev

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This open-label, parallel-group study evaluated the effect of mild and moderate hepatic impairment on the pharmacokinetics of a single dose of luseogliflozin in Japanese subjects. Thirteen subjects with hepatic impairment (mild, n = 8; moderate, n = 5) and 6 healthy subjects received a single 5-mg dose of luseogliflozin. Serial blood sampling over 72 hours and 24-hour urine collection were done for pharmacokinetic analysis of luseogliflozin and its metabolites and to measure pharmacokinetic and pharmacodynamic parameters, respectively. Demographic characteristics were similar at baseline for both groups. Geometric mean ratios of maximum plasma concentration (C max ) and area under the plasma concentration-time curve from time zero to infinity (AUC inf [90%CI]) of unchanged luseogliflozin were 1.02 (0.790-1.32) and 0.774 (0.580-1.03),respectively,on comparing patients with hepatic impairment with healthy subjects,and 0.939 (0.752-1.17) and 1.00 (0.780-1.28), respectively, in subjects with mild and moderate hepatic impairment. Although mean plasma concentrations of metabolites were slightly higher in patients with hepatic impairment versus healthy subjects, their time-course plasma concentrations were very low compared with those of unchanged luseogliflozin. Single-dose luseogliflozin 5 mg was well tolerated by study participants, indicating luseogliflozin dose adjustment is not necessary in patients with mild and moderate hepatic impairment. Keywords luseogliflozin, SGLT2 inhibitor, hepatic impairment, pharmacokinetics, diabetesThe prevalence of type 2 diabetes is higher in patients who have liver diseases, such as nonalcoholic fatty liver disease, alcoholic liver disease, and cirrhosis. Most patients with cirrhosis have diabetes or impaired glucose tolerance. 1In addition, increased insulin resistance is frequently associated with chronic liver diseases such as hepatitis C virus (HCV)-associated cirrhosis.2 Furthermore, a possible association between the use of exogenous insulin or sulfonylureas and the incidence of hepatocellular carcinoma in hepatitis C-positive patients with diabetes mellitus, particularly in noncirrhotic patients, has been reported. 3 These findings indicate that caution should be exercised when selecting antidiabetic agents in patients with type 2 diabetes mellitus coexistent with chronic liver diseases. 4 Luseogliflozin is a highly selective sodium-glucose cotransporter 2 (SGLT2) inhibitor. 5 The half-maximal inhibitory concentrations (IC 50 ) of luseogliflozin against human SGLT1 and SGLT2 are 2900 and 2.26 nmol/L, respectively. Therefore, luseogliflozin specifically inhibits the activity of SGLT2, with a resultant hypoglycemic effect based on the promotion of urinary glucose excretion (UGE) by the inhibition 1 Taisho Pharmaceutical Co., Ltd., Tokyo, Japan 2 Kurume University School of Medicine, Fukuoka, Japan 3 Keikokai Medical Corp. P-One Clinic, Tokyo, Japan 4 Japan Community Healthcare Organization Osaka Hospital, Osaka, Japan 5 Medical Corporation Kyosoukai AMC Nishi Umeda Cl...

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Absence of Drug–Drug Interactions Between Luseogliflozin, a Sodium–Glucose Co-transporter-2 Inhibitor, and Various Oral Antidiabetic Drugs in Healthy Japanese Males

Cited by 10 publications

References 18 publications

Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes

Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes

In vitro evaluation of potential drug interactions mediated by cytochrome P450 and transporters for luseogliflozin, an SGLT2 inhibitor

Luseogliflozin, an SGLT2 Inhibitor, in Japanese Patients With Mild/Moderate Hepatic Impairment: A Pharmacokinetic Study

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