Evaluation of Drug-Drug Interaction Between Henagliflozin and Hydrochlorothiazide in Healthy Chinese Volunteers.

Purpose: Henagliflozin is an original, selective sodium-glucose cotransporter 2 (SGLT2) inhibitor. Hydrochlorothiazide (HCTZ) is a common anti-hypertensive drug. This study aimed to evaluate the potential interaction between henagliflozin and HCTZ. Methods: This was a single-arm, open-label, multi-dose, three-period study that was conducted in healthy Chinese volunteers. Twelve subjects were treated in three periods, period 1: 25 mg HCTZ for four days, period 2: 10 mg henagliflozin for four days and period 3: 25 mg HCTZ + 10 mg henagliflozin for four days. Blood samples and urine samples were collected before and up to 24 hours after drug administrations on day 4, day 10 and day 14. The plasma concentrations of henagliflozin and HCTZ were analyzed using LC-MS/MS. The urine samples were collected for pharmacodynamic glucose and electrolyte analyses. Tolerability was also evaluated. Results: The 90% CI of the ratio of geometric means (combination: monotherapy) for AUCτ,ss of henagliflozin and HCTZ was within the bioequivalence interval of 0.80-1.25. For henagliflozin, co-administration increased Css, max by 24.32% and the 90% CI of the GMR was (108.34%, 142.65%), and the 24-hour urine volume and glucose excretion decreased by 0.43% and 19.6%, respectively. For HCTZ, co-administration decreased Css, max by 19.41% and the 90% CI of the GMR was (71.60%, 90.72%), and the 24-hour urine volume and urinary calcium, potassium, phosphorus, chloride, and sodium excretion decreased by 11.7%, 20.8%, 11.8%, 11.9%, 22.0% and 15.5%, respectively. All subjects (12/12) reported adverse events (AEs), but the majority of theses AEs were mild and no serious AEs were reported. Conclusion: Although Css,max was affected by the combination of henagliflozin and HCTZ, there was no clinically meaningful safety interaction between them. Given these results, coadministration of HCTZ should not require any adaptation of henagliflozin dosing. Trial Registration: ClinicalTrials.gov NCT06083116.

The effect of renal function on the pharmacokinetics and pharmacodynamics of enavogliflozin, a potent and selective sodium-glucose cotransporter-2 inhibitor, in type 2 diabetes.

AIMS: To explore the effect of renal function on the pharmacokinetic (PK) and pharmacodynamic (PD) profile and safety of enavogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM). METHODS: An open-label, two-part clinical trial was conducted in T2DM patients, stratified by renal function: Group 1, normal renal function; Group 2, mild renal impairment (RI); Group 3, moderate RI; and Group 4, severe RI. In Part A, Groups 2 and 4 received enavogliflozin 0.5 mg once. In Part B, Groups 1 and 3 received enavogliflozin 0.5 mg once daily for 7 days. Serial blood and timed urine samples were collected to analyse the PK and PD characteristics of enavogliflozin. Pearson's correlation coefficients were calculated to assess the correlations between PK or PD parameters and creatinine clearance (CrCL). RESULTS: A total of 21 patients completed the study as planned. The area under the curve (AUC) for enavogliflozin was not significantly correlated with CrCL, although the maximum concentration slightly decreased as renal function decreased. By contrast, daily urinary glucose excretion (UGE) was positively correlated with CrCL after both single- (r = 0.7866, p < 0.0001) and multiple-dose administration (r = 0.6606, p = 0.0438). CONCLUSIONS: Systemic exposure to oral enavogliflozin 0.5 mg was similar among the patients with T2DM regardless of their renal function levels. However, the glucosuric effect of enavogliflozin decreased with RI. Considering the UGE observed and approved therapeutic use of other SGLT2 inhibitors, the efficacy of enavogliflozin with regard to glycaemic control could be explored in patients with mild and moderate RI (estimated glomerular filtration rate ≥30 or ≥45 mL/min/1.73 m2) in a subsequent larger study.

Mechanistic Modeling of Empagliflozin: Predicting Pharmacokinetics, Urinary Glucose Excretion, and Investigating Compensatory Role of SGLT1 in Renal Glucose Reabsorption.

The aim of this study was to use a combination of physiologically based pharmacokinetic (PBPK) modeling and urinary glucose excretion (UGE) modeling to predict the time profiles of pharmacokinetics (PK) and UGE for the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMP). Additionally, the study aims to explore the compensatory effect of SGLT1 in renal glucose reabsorption (RGR) when SGLT2 is inhibited. The PBPK-UGE model was developed using physicochemical and biochemical properties, renal physiological parameters, binding kinetics, glucose, and Na+ reabsorption kinetics by SGLT1/2. For area under the plasma concentration-time curve, maximum plasma concentration, and cumulative EMP excretion in urine, the predicted values fell within a range of 0.5-2.0 when compared to observed data. Additionally, the simulated UGE data also matched well with the clinical data, further validating the accuracy of the model. According to the simulations, SGLT1 and SGLT2 contributed approximately 13% and 87%, respectively, to RGR in the absence of EMP. However, in the presence of EMP at doses of 2.5 and 10 mg, the contribution of SGLT1 to RGR significantly increased to approximately 76%-82% and 89%-93%, respectively, in patients with type 2 diabetes mellitus. Furthermore, the model supported the understanding that the compensatory effect of SGLT1 is the underlying mechanism behind the moderate inhibition observed in total RGR. The PBPK-UGE model has the capability to accurately predict the PK and UGE time profiles in humans. Furthermore, it provides a comprehensive analysis of the specific contributions of SGLT1 and SGLT2 to RGR in the presence or absence of EMP.

Pharmacokinetic Variables of Dapagliflozin/Metformin Extended-release Fixed-dose Combination in Healthy Chinese Volunteers and Regional Comparison.

PURPOSE: A fixed-dose combination (FDC) product combining dapagliflozin and metformin may increase medication adherence in patients with type 2 diabetes mellitus (T2DM) by minimizing pill burden associated with co-administration of individual component (IC) formulations and, consequently, improve cost-efficiency and compliance. This study evaluated the bioequivalence of the dapagliflozin/metformin FDC product versus IC administration in healthy volunteers from a Chinese population and assessed the safety profile of the FDC product. In addition, pharmacokinetic (PK) and safety comparisons of dapagliflozin and metformin across different regions were conducted to evaluate regional differences. METHODS: This single-center, open-label, parallel-cohort, randomized, 2-period, crossover study enrolled Chinese adults (aged 18-55 years). Volunteers in cohort 1 received either a single FDC tablet of dapagliflozin/metformin extended release (XR) (5/500 mg) or IC tablets (dapagliflozin [5 mg] and metformin XR [500 mg]). Volunteers in cohort 2 received a higher dosage in a similar manner (dapagliflozin [10 mg] and metformin XR [1000 mg]). Volunteers in each cohort were subsequently crossed over to receive the alternate cohort treatment. Plasma concentrations of dapagliflozin and metformin were determined, and bioequivalence analyses were performed under standard fed conditions. FINDINGS: Eighty healthy Chinese volunteers (89.9% male; mean age, 28.7 years) were randomized into cohort 1 (n = 40) and cohort 2 (n = 39; 1 volunteer withdrew before receiving study treatment). The mean plasma concentration-time profiles of the dapagliflozin and metformin FDC and IC formulations for both doses were found to be nearly superimposable. Dapagliflozin and metformin XR FDC were bioequivalent to the IC tablets, with 90% CIs for each pairwise comparison contained within the 80% to 125% bioequivalence limits. Both the FDC and IC formulations were well tolerated, with no serious adverse events/death. PK parameters for dapagliflozin in the Chinese volunteers were slightly to moderately higher than those from studies conducted in Brazil, Russia, and the United States, and the safety profile of the dapagliflozin/metformin FDC product was consistent with that of other studies. The difference in PK parameters among the 4 regions was not clinically meaningful. IMPLICATIONS: The bioequivalence of the dapagliflozin/metformin FDC and IC formulations in healthy Chinese adults was established without any new safety concerns. Notably, the observed bioequivalence may be extrapolated to patients with T2DM as the PK parameters of dapagliflozin and metformin in healthy adults are similar to those reported in patients with T2DM. CLINICALTRIALS: gov identifier: NCT04856007.

Pharmacokinetic and Pharmacodynamic Interactions Between Henagliflozin, a Novel Selective SGLT-2 Inhibitor, and Warfarin in Healthy Chinese Subjects.

PURPOSE: While controlling blood glucose, patients with diabetes and abnormal coagulation should be treated with positive anticoagulation because the hypercoagulable state of their blood is the primary cause of macroangiopathy. The goal of this study was to evaluate the pharmacokinetic and pharmacodynamic (PK/PD) interactions between henagliflozin, a novel selective sodium-glucose cotransporter 2 inhibitor, and warfarin in healthy subjects. METHODS: This single-center, open-label, single-arm clinical study was conducted in 16 healthy male Chinese subjects. According to the study protocol, the PK properties of henagliflozin 10 mg/d and warfarin 5 mg/d were collected and tabulated in accordance with sampling time. All study drugs were given with once-daily administration. Subjects were monitored for adverse reactions and their severity, outcomes, and relationship to study drug. This influences of warfarin on the PK properties of henagliflozin (Cmax,ss and AUCτ,ss), the effects of henagliflozin on the PK properties of warfarin (Cmax, AUC0-t, and AUC0-∞), and the influences of henagliflozin on the PD properties of warfarin (PTmax, PTAUC, INRmax, and INRAUC) were evaluated. FINDINGS: The geometric mean ratios (GMRs; 90% CIs) of henagliflozin Cmax,ss and AUCτ,ss were 101.75% (96.11%-107.72%) and 102.21% (100.04%-104.42%), respectively. The GMRs (90% CIs) of S- and R-warfarin Cmax, AUC0-t, and AUC0-∞ were as follows: Cmax, 114.31% (106.30%-122.91%) and 115.09% (109.46%-121.01%), respectively; AUC0-t, 120.15% (116.71%-123.69%) and 119.01% (116.32%-121.76%); and AUC0-∞, 120.81% (117.17%-124.58%) and 121.94% (118.90%-125.05%). The GMRs (90% CIs) of warfarin PTmax and PTAUC were 92.73% (91.25%-94.22%) and 97.42% (96.61%-98.24%). The GMRs (90% CIs) of warfarin INRmax and INRAUC were 92.66% (91.17%-94.17%) and 97.36% (96.52%-98.21%). A total of 32 cases of mild adverse events were reported, and were recovered/resolved. There were no serious adverse events reported. IMPLICATIONS: No significant clinically relevant effects on the PK/PD properties of henagliflozin or warfarin were found with coadministration of the two drugs in these healthy male Chinese subjects. Based on these findings, it is expected that henagliflozin and warfarin can be used in combination without dose adjustment. Chinadrugtrials.org.cn identifier: CTR20190240.

Pharmacokinetic Interactions between Canagliflozin and Sorafenib or Lenvatinib in Rats.

Hepatocellular carcinoma (HCC) and type 2 diabetes mellitus (T2DM) are common clinical conditions, and T2DM is an independent risk factor for HCC. Sorafenib and lenvatinib, two multi-targeted tyrosine kinase inhibitors, are first-line therapies for advanced HCC, while canagliflozin, a sodium-glucose co-transporter 2 inhibitor, is widely used in the treatment of T2DM. Here, we developed an ultra-performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of canagliflozin, sorafenib, and lenvatinib, and investigated the pharmacokinetic drug interactions between canagliflozin and sorafenib or lenvatinib in rats. The animals were randomly divided into five groups. Groups I-III were gavage administrated with sorafenib, lenvatinib, and canagliflozin, respectively. Group IV received sorafenib and canagliflozin; while Group V received lenvatinib and canagliflozin. The area under the plasma concentration-time curves (AUC) and maximum plasma concentrations (Cmax) of canagliflozin increased by 37.6% and 32.8%, respectively, while the apparent volume of distribution (Vz/F) and apparent clearance (CLz/F) of canagliflozin significantly decreased (30.6% and 28.6%, respectively) in the presence of sorafenib. Canagliflozin caused a significant increase in AUC and Cmax of lenvatinib by 28.9% and 36.2%, respectively, and a significant decrease in Vz/F and CLz/F of lenvatinib by 52.9% and 22.7%, respectively. In conclusion, drug interactions exist between canagliflozin and sorafenib or lenvatinib, and these findings provide a reference for the use of these drugs in patients with HCC and T2DM.

Relative bioavailability of ertugliflozin tablets containing the amorphous form versus tablets containing the cocrystal form.

OBJECTIVES: Ertugliflozin is a selective sodium-glucose cotransporter 2 inhibitor approved for the treatment of type 2 diabetes in adults. In its natural form, ertugliflozin exists as an amorphous solid with physicochemical properties that prevent commercial manufacture. The commercial product was developed as an immediate-release tablet, consisting of an ertugliflozin-L-pyroglutamic acid cocrystal of 1 : 1 molar stoichiometry as the active pharmaceutical ingredient. The ertugliflozin cocrystal may partially dissociate when exposed to high humidity for extended periods, leading to the formation of free amorphous ertugliflozin. Therefore, a study was conducted to estimate the relative bioavailability of ertugliflozin when administered in non-commercial formulated tablets containing the amorphous form vs. the cocrystal form. MATERIALS AND METHODS: In this phase 1, open-label, randomized, two-period, two-sequence, single-dose crossover study, 16 healthy subjects received 15 mg immediate-release ertugliflozin in its amorphous and cocrystal forms under fasted conditions, separated by a washout period of ≥ 7 days. Blood samples were collected post-dose for 72 hours to determine plasma ertugliflozin concentrations. RESULTS: Mean ertugliflozin plasma concentration-time profiles were nearly superimposable following administration of the amorphous and cocrystal forms. The 90% confidence intervals for the geometric mean ratios for AUCinf and Cmax were wholly contained within the pre-specified criteria for similarity (70 - 143%), as well as the acceptance range for bioequivalence (80 - 125%). Most adverse events were mild in intensity. CONCLUSION: Any dissociation of ertugliflozin to the amorphous form that occurs in tablets containing the cocrystal will not have any clinically meaningful impact on the oral bioavailability of ertugliflozin.

No apparent pharmacokinetic interactions were found between henagliflozin: A novel sodium-glucose co-transporter 2 inhibitor and glimepiride in healthy Chinese male subjects.

WHAT IS KNOWN AND OBJECTIVE: Henagliflozin is a novel selective sodium-glucose co-transporter 2 (SGLT2) inhibitor with similar inhibitory effect to ertugliflozin. Glimepiride is widely used to treat type 2 diabetes mellitus (T2DM) with few cardiovascular side effects. In the present study, we aimed at evaluating the pharmacokinetic (PK) interactions between henagliflozin and glimepiride. METHODS: An open-label, single-centre, single-arm, 3-period, 3-treatment, self-control study was conducted in twelve healthy Chinese male subjects. During each study period, subjects received a single oral dose of glimepiride 2 mg, multiple oral doses of henagliflozin 10 mg or a combination of the two drugs. Serial blood samples were collected 24 h post-dosing for PK analyses. Finger-tip blood glucose was also tested for safety evaluation. RESULTS AND DISCUSSION: Co-administration of henagliflozin with glimepiride did not affect their plasma PK profiles. For henagliflozin, the 90% confidence intervals for the geometric mean ratio (GMR) for the maximum plasma concentrations at steady-state (Cmax ss ) and the area under the plasma concentration-time curve during a dosing interval at steady-state (AUCτ, ss ) of combination therapy to henagliflozin alone were 1.00 (0.93-1.08) and 1.00 (0.98-1.02), respectively. For glimepiride, the corresponding values of combination therapy to glimepiride alone were 1.00 (0.88-1.13) for maximum plasma concentrations (Cmax ), 0.91 (0.84-0.99) for the area under the plasma concentration-time curve from 0-24 h (AUC0-24h ) and 0.91 (0.83-1.00) for the plasma concentration-time curve from 0 h to infinite (AUC0-inf ), respectively. All values fell within the equivalence range of 0.8-1.25. All monotherapies and combination therapy led to no serious adverse events and were well tolerated. WHAT IS NEW AND CONCLUSION: Multiple doses of henagliflozin did not exert a significant change on glimepiride PK profiles and a single dose of glimepiride had little effect on henagliflozin blood concentration. Thus, henagliflozin can be co-administered with glimepiride without dose adjustment of either drug.

Common UGT1A9 polymorphisms do not have a clinically meaningful impact on the apparent oral clearance of dapagliflozin in type 2 diabetes mellitus.

Dapagliflozin is an inhibitor of human renal sodium-glucose cotransporter 2 (SGLT2), first approved for the treatment of type 2 diabetes mellitus (T2DM). Dapagliflozin is primarily metabolized by uridine diphosphate glucuronosyltransferase 1A9 (UGT1A9). The effect of UGT1A9 polymorphisms on dapagliflozin apparent oral clearance (CL/F) was studied with dapagliflozin population pharmacokinetic data and UGT1A9 genotype data (I.399C>T, rs2011404, rs6759892, rs7577677, rs4148323, UGT1A9*2 and UGT1A9*3) from a Phase 2 study conducted in subjects with T2DM (n = 187). An analysis of covariance (ANCOVA) model accounting for known covariates influencing dapagliflozin CL/F was applied to these data to quantify the impact of each UGT1A9 polymorphism relative to the wildtype UGT1A9 genotype. The analysis showed that the geometric mean ratios of dapagliflozin CL/F for all of the UGT1A9 polymorphisms studied were within the range of wildtype UGT1A9 CL/F values. Consequently, the polymorphisms of UGT1A9 studied had no clinically meaningful impact on the CL/F of dapagliflozin.

Effects of Empagliflozin on Myocardial Flow Reserve in Patients With Type 2 Diabetes Mellitus: The SIMPLE Trial.

Background Sodium-glucose cotransporter 2 inhibitors reduce hospitalizations for heart failure and cardiovascular death, although the underlying mechanisms have not been resolved. The SIMPLE trial (The Effects of Empagliflozin on Myocardial Flow Reserve in Patients With Type 2 Diabetes Mellitus) investigated the effects of empagliflozin on myocardial flow reserve (MFR) reflecting microvascular perfusion, in patients with type 2 diabetes mellitus at high cardiovascular disease risk. Methods and Results We randomized 90 patients to either empagliflozin 25 mg once daily or placebo for 13 weeks, as add-on to standard therapy. The primary outcome was change in MFR at week 13, quantified by Rubidium-82 positron emission tomography/computed tomography. The secondary key outcomes were changes in resting rate-pressure product adjusted MFR, changes to myocardial flow during rest and stress, and reversible cardiac ischemia. Mean baseline MFR was 2.21 (95% CI, 2.08-2.35). There was no change from baseline in MFR at week 13 in either the empagliflozin: 0.01 (95% CI, -0.18 to 0.21) or placebo groups: 0.06 (95% CI, -0.15 to 0.27), with no treatment effect -0.05 (95% CI, -0.33 to 0.23). No effects on the secondary outcome parameters by Rubidium-82 positron emission tomography/computed tomography was observed. Treatment with empagliflozin reduced hemoglobin A1c by 0.76% (95% CI, 1.0-0.5; P<0.001) and increased hematocrit by 1.69% (95% CI, 0.7-2.6; P<0.001). Conclusions Empagliflozin did not improve MFR among patients with type 2 diabetes mellitus and high cardiovascular disease risk. The present study does not support that short-term improvement in MFR explains the reduction in cardiovascular events observed in the outcome trials. Registration URL: https://clinicaltrialsregister.eu/; Unique identifier: 2016-003743-10.

Population Pharmacokinetic Analyses of Ertugliflozin in Select Ethnic Populations.

Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, is approved for treatment of type 2 diabetes. Two population pharmacokinetic (PK) analyses were conducted, using data from up to 17 phase 1 to 3 studies, to characterize ertugliflozin PK parameters in select ethnic subgroups: (1) East/Southeast (E/SE) Asian vs non-E/SE Asian subjects; (2) Asian subjects from mainland China vs Asian subjects from the rest of the world and non-Asian subjects. A 2-compartment model with first-order absorption, lag time, and first-order elimination was fitted to the observed data. For the E/SE Asian vs non-E/SE Asian analysis (13 692 PK observations from 2276 subjects), E/SE Asian subjects exhibited a 17% increase in apparent clearance (CL/F) and 148% increase in apparent central volume of distribution (Vc/F) vs non-E/SE Asian subjects. However, individual post hoc CL/F values were similar between groups when body weight differences were considered. For the second analysis (16 018 PK observations from 2620 subjects), compared with non-Asian subjects, CL/F was similar while Vc/F increased by 44% in Asian subjects from mainland China and both CL/F and Vc/F increased in Asian subjects from the rest of the world (8% and 115%, respectively) vs non-Asian subjects. Increases in Vc/F would decrease the ertugliflozin maximum concentration but would not impact area under the concentration-time curve. Therefore, the differences in CL/F (area under the concentration-time curve) and Vc/F were not considered clinically relevant or likely to result in meaningful ethnic differences in the PK of ertugliflozin.

Inhibidores del cotransportador de sodio-glucosa tipo 2: Efecto de los mecanismos moleculares en el miocardio / Sodium-glucose cotransporter 2 inhibitors: Effect of molecular mechanisms on the myocardium

Resumen Los receptores del cotransportador de sodio-glucosa han demostrado una gran relevancia en la función miocárdica. Los receptores tipo 1 se encuentran en el miocardio en valores bajos, sin embargo, se elevan en patologías cardiacas por medio de distintos mecanismos moleculares. Por otra parte, los receptores tipo 2 están ausentes en el miocardio. Los fármacos que inhiben este receptor tienen beneficio cardiovascular evidente en estudios clínicos y experimentales, principalmente en pacientes con diabetes mellitus tipo 2 e insuficiencia cardiaca, en los que se ha demostrado una reducción de la mortalidad por causas cardiovasculares y reducción en hospitalización por insuficiencia cardiaca. Existen interrogantes sobre el mecanismo de acción directo de este grupo antihiperglicemiantes sobre el cardiomiocito y se han desarrollado hipótesis y teorías para explicar este efecto. El objetivo de este artículo es revisar y analizar los diferentes mecanismos metabólicos, estructurales, funcionales y mitocondriales en un contexto molecular de los inhibidores del cotransportador sodio-glucosa tipo 2. La acción fisiopatológica del receptor tipo 1 en el miocardio también es importante y se encuentran en desarrollo estudios clínicos para establecer el efecto de su inhibición a nivel cardíaco.

Abstract Sodium-glucose cotransporter receptors have demonstrated relevance in myocardial function. Type 1 receptors are found in the myocardium in low values, however, they are elevated in cardiac pathologies by means of different molecular mechanisms. On the other hand, type 2 receptors are absent in the myocardium. The drugs that inhibit this receptor have been shown to have a cardiovascular benefit demonstrated in clinical and experimental studies, mainly in patients with type 2 diabetes mellitus and heart failure, presenting a reduction in mortality due to cardiovascular causes and a reduction in hospitalization due to heart failure. Due to the above, many questions arise about the mechanism of direct action of this antihyperglycemic group on cardiomyocyte, which is why they have been developed from hypotheses and theories to clarify this action by medicines. The objective of this article is to analyze the different metabolic, structural, functional and mitochondrial mechanisms in a molecular context of the inhibitors of the sodium-glucose cotransporter type 2. On the other hand, to analyze the pathophysiological action of the type 1 receptor in the myocardium, since that future clinical studies will be developed to establish the effect with its inhibition at the cardiac level.

No Relevant Pharmacokinetic Drug-Drug Interaction Between the Sodium-Glucose Co-Transporter-2 Inhibitor Empagliflozin and Lobeglitazone, a Peroxisome Proliferator-Activated Receptor-γ Agonist, in Healthy Subjects.

PURPOSE: Combination therapy with insulin-independent sodium-glucose cotransporter 2 inhibitors and thiazolidinedione drugs, such as lobeglitazone, has been reported to elicit potential additive efficacy in glycemic control in type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetic (PK) drug-drug interactions between empagliflozin and lobeglitazone in healthy subjects. SUBJECTS AND METHODS: A randomized, open-label, multiple-dose study was conducted in 30 healthy subjects using a three-treatment, six-sequence, three-way crossover design. Subjects received one of the following treatments once daily for 5 days in each period: 25 mg empagliflozin, 0.5 mg lobeglitazone sulfate, or a combination. Serial blood sampling before every dose and up to 24 h after the last dose was performed during each treatment period. The PK parameters were estimated using noncompartmental methods with the plasma empagliflozin and lobeglitazone concentrations. The absence of a PK interaction was construed as the 90% confidence interval (90% CI) of maximum concentration at steady state (Cmax,ss) and area under the concentration-time curve over the dosing interval (AUCtau) for combination therapy-to-monotherapy ratios within the limits of 0.80-1.25. RESULTS: The steady-state plasma empagliflozin and lobeglitazone concentration-time profiles of combination therapy and monotherapy were comparable in the 25 subjects who completed the study. Coadministration of empagliflozin with lobeglitazone did not affect empagliflozin PK (with 90% CIs of 0.956-1.150 and 0.945-1.133 for Cmax,ss and AUCtau, respectively). Likewise, empagliflozin did not affect lobeglitazone Cmax,ss or AUCtau (with 90% CIs of 0.869-0.995 and 0.851-1.018, respectively). All treatment groups tolerated mild adverse events well. CONCLUSION: The lack of PK interactions between lobeglitazone and empagliflozin in combination therapy, along with their good tolerability, indicates that the two drugs can be coadministered without dose adjustment. TRIAL REGISTRATION NUMBER: NCT02854748, Registered on August 7, 2016.

End-to-end application of model-informed drug development for ertugliflozin, a novel sodium-glucose cotransporter 2 inhibitor.

Model-informed drug development (MIDD) is critical in all stages of the drug-development process and almost all regulatory submissions for new agents incorporate some form of modeling and simulation. This review describes the MIDD approaches used in the end-to-end development of ertugliflozin, a sodium-glucose cotransporter 2 inhibitor approved for the treatment of adults with type 2 diabetes mellitus. Approaches included (1) quantitative systems pharmacology modeling to predict dose-response relationships, (2) dose-response modeling and model-based meta-analysis for dose selection and efficacy comparisons, (3) population pharmacokinetics (PKs) modeling to characterize PKs and quantify population variability in PK parameters, (4) regression modeling to evaluate ertugliflozin dose-proportionality and the impact of uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A9 genotype on ertugliflozin PKs, and (5) physiologically-based PK modeling to assess the risk of UGT-mediated drug-drug interactions. These end-to-end MIDD approaches for ertugliflozin facilitated decision making, resulted in time/cost savings, and supported registration and labeling.

"The pharmacological profile of SGLT2 inhibitors: Focus on mechanistic aspects and pharmacogenomics".

Diabetes, characterized by high glucose levels, has been listed to be one of the world's major causes of death. Around 1.6 million deaths are attributed to this disease each year. Persistent hyperglycemic conditions in diabetic patients affect various organs of the body leading to diabetic complications and worsen the disease condition. Current treatment strategies for diabetes include biguanides, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, insulin and its analogs, DPP-4(dipeptidyl peptidase-4) and GLP-1 (glucagon-like peptide) analogs. However, many side effects contributing to the devastation of the disease are associated with them. Sodium glucose co-transporter-2 (SGLT2) inhibition has been reported to be new insulin-independent approach to diabetes therapy. It blocks glucose uptake in the kidneys by inhibiting SGLT2 transporters, thereby promoting glycosuria. Dapagliflozin, empagliflozin and canagliflozin are the most widely used SGLT2 inhibitors. They are effective in controlling blood glucose and HbA1c levels with few side effects including hypoglycemia or weight gain which makes them preferable to other anti-diabetic drugs. However, treatment is found to be associated with inter-individual drug response to SGLT2 inhibitors and adverse drug reactions which are also affected by genetic variations. There have been very few pharmacogenetics trials of these drugs. This review discusses the various SGLT2 inhibitors, their pharmacokinetics, pharmacodynamics and genetic variation influencing the inter-individual drug response.

Meta-Analysis of Noncompartmental Pharmacokinetic Parameters of Ertugliflozin to Evaluate Dose Proportionality and UGT1A9 Polymorphism Effect on Exposure.

Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, is primarily metabolized via glucuronidation by the uridine 5'-diphospho-glucuronosyltransferase (UGT) isoform UGT1A9. This noncompartmental meta-analysis of ertugliflozin pharmacokinetics evaluated the relationship between ertugliflozin exposure and dose, and the effect of UGT1A9 genotype on ertugliflozin exposure. Pharmacokinetic data from 25 phase 1 studies were pooled. Structural models for dose proportionality described the relationship between ertugliflozin area under the plasma concentration-time curve (AUC) or maximum observed plasma concentration (Cmax ) and dose. A structural model for the UGT1A9 genotype described the relationship between ertugliflozin AUC and dose, with genotype information on 3 UGT1A9 polymorphisms (UGT1A9-2152, UGT1A9*3, UGT1A9*1b) evaluated as covariates from the full model. Ertugliflozin AUC and Cmax increased in a dose-proportional manner over the dose range of 0.5-300 mg, and population-predicted AUC and Cmax values for the 5- and 15-mg ertugliflozin tablets administered in the fasted state demonstrated good agreement with the observed data. The largest change in ertugliflozin AUC was in subjects carrying the UGT1A9*3 heterozygous variant, with population-predicted AUC (90% confidence interval) values of 485 ng·h/mL (458 to 510 ng·h/mL) and 1560 ng·h/mL (1480 to 1630 ng·h/mL) for ertugliflozin 5 and 15 mg, respectively, compared with 436 ng·h/mL (418 to 455 ng·h/mL) and 1410 ng·h/mL (1350 to 1480 ng·h/mL), respectively, in wild-type subjects. Overall, the mean effects of the selected UGT1A9 variants on ertugliflozin AUC were within ±10% of the wild type. UGT1A9 genotype did not have any clinically meaningful effects on ertugliflozin exposure in healthy subjects. No ertugliflozin dose adjustment would be required in patients with the UGT1A9 variants assessed in this study.

¿Son los inhibidores del receptor SGLT2 fármacos antidiabéticos o cardiovasculares? / Are the antidiabetic SGLT2 inhibitors a cardiovascular treatment?

Los inhibidores del cotransportador de sodio-glucosa tipo 2 (iSGLT2) fueron incialmente desarrollados para el tratamiento de la diabetes por su actividad hipoglucemiante. Sin embargo, a la luz de los estudios clínicos más recientes, están revolucionando el abordaje de la enfermedad cardiovascular (CV) en el paciente diabético. En el año 2015, el ensayo clínico EMPA-REG OUTCOME nos demuestra por primera vez que la empagliflozina -un fármaco considerado «antidiabético»- reduce la mortalidad CV y por cualquier causa, además de eventos CV mayores, hospitalización por IC y progresión de enfermedad renal. Posteriormente, otros estudios clínicos con agentes del mismo grupo farmacológico, CANVAS, con canagliflozina y DECLARE-TIMI-58 con dapagliflozina, corroboran la exitencia de los beneficios CV asociados a la inhibición del receptor SGLT2. Los beneficios observados los sitúan más allá de simples agentes hipoglucemiantes, con un demostrado efecto cardionefroprotector en la enfermedad aterosclerótica, insuficiencia cardiaca, mortalidad total, mortalidad cardiovascular y progresión de insuficiencia renal. Actualmente ya son una realidad en pacientes diabéticos de alto y muy alto riesgo cardiovascular, mientras su evidencia en el paciente no diabético es cada vez mayor. Asistimos, por tanto, a un cambio de paradigma y posiblemente al nacimiento de una nueva especialidad, la cardio-endocrinología, con la implicación de nuevos tratamientos que deben ser considerados más que sólo fármacos antidiabéticos

The sodium-glucose co-transporter 2 inhibitors (SGLT2i) were first conceived to treat type 2 diabetes due to their hypoglycaemic effect. However, due to an increasing number of studies, SGLT2i are changing the way we treat, and understand, diabetes, and cardiovascular risk, in general. The EMPA-REG OUTCOME clinical trial, in 2015, showed for the first time that empagliflozine - a glucose lowering agent - lowers the risk of death from cardiovascular causes and death from any cause. Also, this SGLT2i lowered hospital admission for heart failure and delayed renal function worsening. From then on, other clinical trials with SGLT2i such as CANVAS (canagliflozin) and DECLARE-TIMI-58 (dapagliflozin) confirmed these positive effects. With a proven and non-related glucose-lowering effect on heart failure, overall death, cardiovascular death, and renal function, SGLT2i stands out among the rest of anti-diabetic drugs. Since its role in treating patients with heart failure and type 2 diabetes has been undoubtedly established, new studies are paving the way for non-diabetic patients as well. A potential paradigm shift is being witnessed and, probably, the dawn of a new field, cardio-endocrinology, which involves new and far-reaching pharmacological agents

Model-Informed Pediatric Dose Selection for Dapagliflozin by Incorporating Developmental Changes.

This analysis reports a quantitative modeling and simulation approach for oral dapagliflozin, a primarily uridine diphosphate-glucuronosyltransferase (UGT)-metabolized human sodium-glucose cotransporter 2 selective inhibitor. A mechanistic dapagliflozin physiologically based pharmacokinetic (PBPK) model was developed using in vitro metabolism and clinical pharmacokinetic (PK) data and verified for context of use (e.g., exposure predictions in pediatric subjects aged 1 month to 18 years). Dapagliflozin exposure is challenging to predict in pediatric populations owing to differences in UGT1A9 ontogeny maturation and paucity of clinical PK data in younger age groups. Based on the exposure-response relationship of dapagliflozin, twofold acceptance criteria were applied between model-predicted and observed drug exposures and PK parameters (area under the curve and maximum drug concentration) in various scenarios, including monotherapy in healthy adults (single/multiple dose), monotherapy in hepatically or renally impaired patients, and drug-drug interactions with UGT1A9 modulators, such as mefenamic acid and rifampin. The PBPK model captured the observed exposure within twofold of the observed monotherapy data in adults and adolescents and in special population. As a guide to determining dosing regimens in pediatric studies, the verified PBPK model, along with UGT enzyme ontogeny maturation understanding, was used for predictions of dapagliflozin monotherapy exposures in pediatric subjects aged 1 month to 18 years that best matched exposure in adult patients with a 10-mg single dose of dapagliflozin.

Pharmacokinetics and Pharmacodynamics of Ertugliflozin in Healthy Japanese and Western Subjects.

Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, is approved for treatment of type 2 diabetes. This randomized, double-blind (sponsor-open) study in healthy Japanese subjects and open-label study in Western subjects assessed ertugliflozin pharmacokinetics and pharmacodynamics. Cohort A received 3 ascending single doses of ertugliflozin (1, 5, and 25 mg; n = 6 Japanese, n = 6 Western) or placebo (n = 3 Japanese) under fasted conditions. Cohort B received multiple once-daily doses of ertugliflozin 25 mg (n = 6 Japanese) or placebo (n = 3 Japanese) for 7 days under fed conditions. For Japanese subjects in Cohort A, maximum plasma concentrations (Cmax ) were observed 1 to 1.5 hours after dosing, and apparent mean terminal half-life was 12.4 to 13.6 hours. The ratios of the geometric means (Japanese/Western) for ertugliflozin 1-, 5-, and 25-mg single doses were 95.94%, 99.66%, and 90.32%, respectively, for area under the plasma concentration-time curve and 107.59%, 97.47%, and 80.04%, respectively, for Cmax . Area under the plasma concentration-time curve and Cmax increased in a dose-proportional manner. For Cohort B, Cmax was observed 2.5 hours after dosing (days 1 and 7), and steady state was reached by day 4. The 24-hour urinary glucose excretion was dose dependent. Ertugliflozin was generally well tolerated. There were no meaningful differences in exposure, urinary glucose excretion, and safety between Japanese and Western subjects.