Development and optimization of sitagliptin and dapagliflozin loaded oral self-nanoemulsifying formulation against type 2 diabetes mellitus.

Control of hyperglycemia and prevention of glucose reabsorption (glucotoxicity) are important objectives in the management of type 2 diabetes. This study deals with an oral combined dosage form design for two anti-diabetic drugs, sitagliptin and dapagliflozin using self-nanoemulsifying drug delivery systems (SNEDDS). The SNEDDS were developed using naturally obtained bioactive medium-chain/long-chain triglycerides oil, mixed glycerides and nonionic surfactants, and droplet size was measured followed by the test for antioxidant activities. Equilibrium solubility and dynamic dispersion experiments were conducted to achieve the maximum drug loading. The in vitro digestion, in vivo bioavailability, and anti-diabetic effects were studied to compare the representative SNEDDS with marketed product Dapazin®. The representative SNEDDS containing black seed oil showed excellent self-emulsification performance with transparent appearance. Characterization of the SNEDDS showed nanodroplets of around 50-66.57 nm in size (confirmed by TEM analysis), in addition to the high drug loading capacity without causing any precipitation in the gastro-intestinal tract. The SNEDDS provided higher antioxidant activity compared to the pure drugs. The in vivo pharmacokinetic parameters of SNEDDS showed significant increase in C max (1.99 ± 0.21 µg mL-1), AUC (17.94 ± 1.25 µg mL-1), and oral absorption (2-fold) of dapagliflozin compared to the commercial product in the rat model. The anti-diabetic studies showed the significant inhibition of glucose level in treated diabetic mice by SNEDDS combined dose compared to the single drug therapy. The combined dose of sitagliptin-dapagliflozin using SNEDDS could be a potential oral pharmaceutical product for the improved treatment of type 2 diabetes mellitus.

Mechanistic evaluation of the effect of sodium-dependent glucose transporter 2 inhibitors on delayed glucose absorption in patients with type 2 diabetes mellitus using a quantitative systems pharmacology model of human systemic glucose dynamics.

Sodium-dependent glucose transporter (SGLT) 2 is specifically expressed in the kidney, while SGLT1 is present in the kidneys and small intestine. SGLT2 inhibitors are a class of oral antidiabetic drugs that lower elevated plasma glucose levels by promoting the urinary excretion of excess glucose through the inhibition of renal glucose reuptake. The inhibition selectivity for SGLT2 over SGLT1 (SGLT2/1 selectivity) of marketed SGLT2 inhibitors is diverse, while SGLT2/1 selectivity of canagliflozin is relatively low. Although canagliflozin suppresses postprandial glucose levels, the degree of contribution for SGLT1 inhibition to this effect remains unproven. To analyze the effect of SGLT2 inhibitors on postprandial glucose level, we constructed a novel quantitative systems pharmacology (QSP) model, called human systemic glucose dynamics (HSGD) model, integrating intestinal absorption, metabolism, and renal reabsorption of glucose. This HSGD model reproduced the postprandial plasma glucose concentration-time profiles during a meal tolerance test under different clinical trial conditions. Simulations after canagliflozin administration showed a dose-dependent delay of time (Tmax,glc ) to reach maximum concentration of glucose (Cmax,glc ), and the delay of Tmax,glc disappeared when inhibition of SGLT1 was negated. In addition, contribution ratio of intestinal SGLT1 inhibition to the decrease in Cmax,glc was estimated to be 23%-28%, when 100 and 300 mg of canagliflozin are administered. This HSGD model enabled us to provide the partial contribution of intestinal SGLT1 inhibition to the improvement of postprandial hyperglycemia as well as to quantitatively describe the plasma glucose dynamics following SGLT2 inhibitors.

Simple and rapid LC-MS/MS method for determination of sitagliptin in human plasma and application to bioequivalence study.

A simple, rapid, sensitive, and reproducible liquid chromatography-tandem mass spectrometry method was developed to determine sitagliptin in human plasma. Diphenhydramine HCl was used as internal standard (IS). The chromatographic separation was achieved using Agilent Poroshell 120 EC-C18 - Fast LC column (100 × 2.1mmID, 2.7) fitted with UHPLC Guard Poroshell 120 EC-C18 (5 × 2.1mmID, 2.7 µm). The mobile phase consisted of 0.1% v/v formic acid and methanol (45:55, v/v) run at a flow rate of 0.45 mL/min at 30 °C. Methanol produced relatively cleaner plasma sample as deproteinization agent. Polytetrafluoroethylene membrane was preferred over nylon membrane as the former produced clear plasma samples. The standard calibration curve was linear over the concentration range of 5-500.03 ng/mL. The within-run precision was 0.53-7.12% and accuracy 87.09-105.05%. The between-run precision was 4.74-11.68% and accuracy 95.02-97.36%. The extended run precision was 3.60-6.88% and accuracy 93.18-95.82%. The recovery of analyte and IS was consistent. Sitagliptin in plasma was stable at benchtop (short term) for 24 h, in autosampler tray for 48 h, in instrumentation room for 48 h (post-preparative), after 7 freeze-thaw cycles (-20 ± 10 °C), and 62 days in the freezer (-20 ± 10 °C). Both sitagliptin (analyte) and IS stock solutions were stable for 62 days when kept at room temperature (25 ± 4 °C) and in chiller (2-8 °C). The validated method was successfully applied to a bioequivalence study of two sitagliptin formulations involving 26 healthy Malaysian volunteers.

A Physiologically-Based Quantitative Systems Pharmacology Model of the Incretin Hormones GLP-1 and GIP and the DPP4 Inhibitor Sitagliptin.

Incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play a major role in regulation of postprandial glucose and the development of type 2 diabetes mellitus. The incretins are rapidly metabolized, primarily by the enzyme dipeptidyl-peptidase 4 (DPP4), and the neutral endopeptidase (NEP), although the exact metabolization pathways are unknown. We developed a physiologically-based (PB) quantitative systems pharmacology model of GLP-1 and GIP and their metabolites that describes the secretion of the incretins in response to intraduodenal glucose infusions and their degradation by DPP4 and NEP. The model describes the observed data and suggests that NEP significantly contributes to the metabolization of GLP-1, and the traditional assays for the total GLP-1 and GIP forms measure yet unknown entities produced by NEP. We further extended the model with a PB pharmacokinetics/pharmacodynamics model of the DPP4 inhibitor sitagliptin that allows predictions of the effects of this medication class on incretin concentrations.

An Assessment of Pharmacokinetic Interaction Between Lobeglitazone and Sitagliptin After Multiple Oral Administrations in Healthy Men.

PURPOSE: Patients with type 2 diabetes mellitus require strict blood glucose control, and combination therapy with a thiazolidinedione and dipeptidyl peptidase-4 inhibitors, such as lobeglitazone and sitagliptin, is one of the recommended treatments. The objective of this study was to investigate a possible pharmacokinetic interaction between lobeglitazone and sitagliptin after multiple oral administrations in healthy Korean men. METHODS: Two randomized, open-label, multiple-dose, 2-way crossover studies were conducted simultaneously in healthy men. In study 1, men were randomly assigned to 1 of 2 sequences, and 1 of the following treatments was administered in each period: 1 tablet of lobeglitazone sulfate (0.5 mg) once daily for 5 days and or 1 tablet each of lobeglitazone sulfate (0.5 mg) and sitagliptin (100 mg) once daily for 5 days. In study 2, men were also randomly assigned to 1 of 2 sequences and the treatments were as follows: 1 tablet of sitagliptin (100 mg) once daily for 5 days or 1 tablet each of sitagliptin (100 mg) and lobeglitazone sulfate (0.5 mg) once daily for 5 days. Serial blood samples were collected up to 48 h after dosing on the fifth day. Plasma drug concentrations were measured by LC-MS/MS. Pharmacokinetic parameters, including Cmax,ss and AUC0-τ , were determined by noncompartmental analysis. The geometric least-square mean (GLSM) ratios and associated 90% CIs of log-transformed Cmax,ss and AUC0-τ for separate or coadministration were calculated to evaluate pharmacokinetic interactions. FINDINGS: Nineteen men from study 1 and 17 from study 2 completed the pharmacokinetic sampling and were included in the analyses. The GLSM ratios of Cmax,ss and AUC0-τ were 0.9494 (95% CI, 0.8798-1.0243) and 1.0106 (95% CI, 0.9119-1.1198) for lobeglitazone (from study 1) and 1.1694 (95% CI, 1.0740-1.2732) and 1.0037 (95% CI, 0.9715-1.0369) for sitagliptin (from study 2), respectively. IMPLICATIONS: Except for the slight 17% increase in the sitagliptin Cmax,ss value, the pharmacokinetic parameters of lobeglitazone and sitagliptin met the pharmacokinetic equivalent criteria when administered separately or in combination. The increase in Cmax of sitagliptin when coadministered with lobeglitazone would not be clinically significant in practice. ClinicalTrials.gov Identifier: NCT02824874 and NCT02827890.

Imeglimin Does Not Induce Clinically Relevant Pharmacokinetic Interactions When Combined with Either Metformin or Sitagliptin in Healthy Subjects.

BACKGROUND AND OBJECTIVES: Imeglimin (IMEG) is the first in a novel class of oral glucose-lowering agents with a unique mechanism of action targeting mitochondrial bioenergetics. We assessed whether repeated co-administration of IMEG and either metformin (MET) or sitagliptin (SITA) would influence the pharmacokinetics of either MET or SITA in healthy Caucasian men. METHODS: Healthy Caucasian men received either MET 850 mg twice daily with placebo (n = 16) or SITA 100 mg once daily with placebo (n = 16) on days 1-6, followed by MET 850 mg twice daily with IMEG 1500 mg twice daily or SITA 100 mg once daily with IMEG 1500 mg twice daily on days 7-12. Pharmacokinetic parameters were determined from blood and urine; levels of all compounds were evaluated using liquid chromatography with tandem mass spectrometry. RESULTS: Systemic exposure (AUC0-τ area under the plasma concentration-time curve over a dosing interval and maximum concentration) to MET was 14% and 10% lower, respectively, when administered with IMEG. Approximately 40% of MET was excreted unchanged in urine, decreasing to 34% when given with IMEG. The 90% confidence intervals for AUC0-τ and maximum concentration indicated no effect of co-administration on systemic exposure to MET. Mean AUC0-τ and maximum concentration of SITA were similar with or without IMEG. Median times to maximum concentration were 0.7 and 1.0 h and mean elimination half-lives were 8.2 and 8.7 h with and without IMEG, respectively. Systemic exposure to IMEG was similar to previous phase I studies. CONCLUSIONS: Co-administration of IMEG with MET or SITA did not result in clinically relevant changes in systemic exposure to MET or SITA, although minor reductions in exposure (AUC0-τ and maximum concentration) and renal elimination were noted when MET was given with IMEG vs placebo. CLINICAL TRIAL REGISTRATION: EudraCT2009-014520-40 (MET-IMEG DDI) and EudraCT2010-022926-34 (SITA-IMEG DDI).

A Clinical Drug-Drug Interaction Study Assessing a Novel Drug Transporter Phenotyping Cocktail With Adefovir, Sitagliptin, Metformin, Pitavastatin, and Digoxin.

A new probe drug cocktail containing substrates of important drug transporters was tested for mutual interactions in a clinical trial. The cocktail consisted of (predominant transporter; primary phenotyping metric): 10 mg adefovir-dipivoxil (OAT1; renal clearance (CLR )), 100 mg sitagliptin (OAT3; CLR ), 500 mg metformin (several renal transporters; CLR ), 2 mg pitavastatin (OATP1B1; clearance/F), and 0.5 mg digoxin (intestinal P-gp, renal P-gp, and OATP4C1; peak plasma concentration (Cmax ) and CLR ). Using a randomized six-period, open change-over design, single oral doses were administrated either concomitantly or separately to 24 healthy male and female volunteers. Phenotyping metrics were evaluated by noncompartmental analysis and compared between periods by the standard average bioequivalence approach (boundaries for ratios 0.80-1.25). Primary metrics supported the absence of relevant interactions, whereas secondary metrics suggested that mainly adefovir was a victim of minor drug-drug interactions (DDIs). All drugs were well tolerated. This cocktail may be another useful tool to assess transporter-based DDIs in vivo.

Bioequivalence of Ertugliflozin/Sitagliptin Fixed-Dose Combination Tablets and Coadministration of Respective Strengths of Individual Components.

A fixed-dose combination (FDC) tablet of ertugliflozin, a selective inhibitor of sodium-glucose cotransporter 2, and sitagliptin, a dipeptidyl peptidase-4 inhibitor, was developed for the treatment of patients with type 2 diabetes mellitus. Four studies were conducted under fasted conditions to demonstrate bioequivalence of ertugliflozin/sitagliptin FDC tablets and individual components at respective strengths when coadministered in healthy subjects. All studies had open-label, randomized, 2-period, 2-sequence, single-dose crossover designs. In each study 18 or 19 subjects were enrolled and received an ertugliflozin/sitagliptin FDC tablet (5 mg/50 mg, 5 mg/100 mg, 15 mg/50 mg, or 15 mg/100 mg) and corresponding strengths of ertugliflozin and sitagliptin coadministered as individual components. For both ertugliflozin and sitagliptin, the 90%CIs for the ratio (FDC:coadministration) of geometric means for area under the plasma concentration-time profile from time 0 extrapolated to infinite time, and maximum observed plasma concentration, were within acceptance criteria for bioequivalence (80% to 125%). All adverse events were mild in intensity. The 4 studies demonstrated that each strength of FDC tablet is bioequivalent to the respective dose of coadministered individual components. This indicates that the known efficacy and tolerability of ertugliflozin and sitagliptin when coadministered can be translated to the use of a FDC formulation.

Dried blood spot testing for estimation of renal function and analysis of metformin and sitagliptin concentrations in diabetic patients: a cross-sectional study.

PURPOSE: Dried blot spot (DBS) analysis of drugs or clinical parameters offers many advantages. We investigated the feasibility of using DBS for analysis of anti-diabetic drugs concomitantly with the estimated creatinine clearance (Clcrea). METHODS: The cross-sectional study involved physicians in an enabling analysis with 70 diabetic patients and community pharmacists in a field investigation with 84 participants. All 154 DBS samples were analyzed for creatinine, metformin, and sitagliptin. RESULTS: The diabetic patients revealed of a wide range of age (32-88 years), BMI values (19.8-54.7 kg/m2), and extent of polypharmacotherapy (1-21 drugs). A correlation factor to convert capillary blood creatinine from DBS into plasma concentrations was determined. Patients' Clcrea ranged from 21.6-155.9 mL/min. The results indicated statistically significant correlations (p < 0.05) between the use of two or three particular drug classes (diuretics, NSAIDs, renin-angiotensin system blockers) and a decreased renal function. DBS concentrations of metformin ranged between 0.23-4.99 µg/mL. The estimated elimination half-life (t ½) of metformin was 11.9 h in patients with a ClCrea higher than 60 mL/min and 18.5 h for diabetics with lower ClCrea. Sitagliptin capillary blood concentrations ranged between 11.12-995.6 ng/mL. Calculated t ½ of sitagliptin were 8.4 h and 13.0 h in patients with a ClCrea above and below 60 mL/min, respectively. CONCLUSIONS: DBS allow for the analysis of concentrations of predominantly renally eliminated drugs and community pharmacists can provide a valuable contribution to DBS sampling.

Effect of Food on the Pharmacokinetics of Ertugliflozin and Its Fixed-Dose Combinations Ertugliflozin/Sitagliptin and Ertugliflozin/Metformin.

Ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, is approved in the United States and European Union for the treatment of type 2 diabetes in adults, both as monotherapy and as part of fixed-dose combination (FDC) therapies with either sitagliptin or immediate-release metformin. The effect of a standard, high-fat breakfast on the pharmacokinetics of the highest strengths of ertugliflozin monotherapy (15 mg), ertugliflozin/sitagliptin FDC (15-/100-mg), and ertugliflozin/metformin FDC (7.5-/1000-mg) tablets was evaluated. In 3 separate open-label, 2-period, 2-sequence, single-dose, crossover studies, 14 healthy subjects per study were randomized to receive either ertugliflozin monotherapy or FDC tablets comprising ertugliflozin and sitagliptin or ertugliflozin and metformin under fasted and fed (or vice versa) conditions. Food did not meaningfully affect the pharmacokinetics of ertugliflozin, sitagliptin, or metformin. For FDCs, the effect of food was consistent with that described for individual components. All treatments were well tolerated. Ertugliflozin and ertugliflozin/sitagliptin FDC tablets can be administered without regard to meals. As metformin is administered with meals because of its gastrointestinal side effects, the ertugliflozin/metformin FDC should also be administered with meals.

A randomized clinical trial to evaluate the single-dose pharmacokinetics, pharmacodynamics, and safety of sitagliptin in pediatric patients with type 2 diabetes.

OBJECTIVE: To evaluate the single-dose pharmacokinetics (PK), pharmacodynamics (PD), and safety of sitagliptin in pediatric patients with type 2 diabetes mellitus (T2DM). STUDY DESIGN: This was a randomized, placebo-controlled, double-blind evaluation of sitagliptin in 35 patients 10 to 17 years old with T2DM at 7 clinical research sites. The safety, tolerability, PK, and PD (dipeptidyl peptidase-4 [DPP-4] inhibition and aspects of glucose metabolism) of single doses of 50, 100, and 200 mg were assessed. Appropriate transformations on the PK parameters were used and back-transformed summary statistics are reported. RESULTS: Adverse experiences were reported by eight study participants; all were of mild intensity except one (intravenous site pain of moderate intensity). PK characteristics in the young patients were comparable to reference adult data, with geometric mean ratios (youths/adults) for AUC0-∞ , Cmax , and C24hr of 0.82, 1.04, and 0.74, respectively. Single doses of 50, 100, and 200 mg sitagliptin inhibited 67.2%, 73.8%, and 81.2% of plasma DPP-4 activity over 24 hours, respectively. Least squares (LS) mean glucose concentrations 2 hours after an oral glucose tolerance test or a meal tolerance test decreased in study participants treated with sitagliptin, compared to placebo, while active LS mean glucagon-like peptide 1 concentrations increased significantly at all sitagliptin doses in both tests. CONCLUSIONS: Single doses of sitagliptin as high as 200 mg were generally well tolerated in 10- to 17-year-old male and female study participants with T2DM, and a daily sitagliptin dose of 100 mg is appropriate for evaluation in Phase III safety and efficacy studies in pediatric patients with T2DM. (ClinicalTrials.gov: NCT00730275).

UPLC-MS/MS method for the quantification of ertugliflozin and sitagliptin in rat plasma.

In the present study, an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) approach was designed to concurrently measure the levels of ertugliflozin and sitagliptin in rat plasma with diazepam as the internal standard (IS). Acetonitrile-based protein precipitation was applied for sample preparation, then analytes (ertugliflozin and sitagliptin) were subjected to gradient elution chromatography with a mobile phase composed of acetonitrile (A) and 0.1% formic acid in water (B). Ertugliflozin was monitored by m/z 437.2 → 329.0 transition for quantification and m/z 437.2 → 207.5 transition for qualification, and sitagliptin was determined by m/z 408.2 → 235.0 transition for quantification and m/z 408.2 → 174.0 transition for qualification by multiple reaction monitoring (MRM) in positive ion electrospray ionization (ESI) source. When the concentration of ertugliflozin ranged from 1 to 1000 ng/mL and sitagliptin ranged from 2 to 2500 ng/mL, the method exhibited good linearity. For both ertugliflozin and sitagliptin, the intra- and inter-day precision were determined with the values of 1.6-10.9% and 0.8-13.3%, respectively; and the accuracy ranged from -5.7% to 14.6%. Matrix effect, extraction recovery, and stability data were in line with the stipulated FDA guidelines for validating a bioanalytical method. The validity of the designed method was confirmed through the pharmacokinetic experiments.

Evaluation of pharmacokinetic and pharmacodynamic parameters following single dose of sitagliptin in healthy Indian males.

PURPOSE: Sitagliptin, a dipeptidyl peptidase (DPP)-IV inhibitor approved for the treatment of type 2 diabetes, is reported to be more efficacious in Indian patients than non-Indian patient population. The objective of the study was to evaluate pharmacokinetic and pharmacodynamic (PK/PD) parameters of single-dose sitagliptin 100 mg (Januvia) in healthy Indian male participants. METHOD: In a randomised, single-dose, open-label, three-treatment, three-period, three-sequence, crossover bioavailability study, 18 healthy male participants received single-dose of sitagliptin under fasted and fed conditions. PK parameters (Cmax, Tmax, AUC0-∞ and t1/2) were determined using Phoenix WinNonlin software. PD parameters [DPP-IV inhibition, active glucagon-like peptide-1 (GLP-1) and insulin] were determined using established methods. RESULTS: PK parameters expressed in mean (SD) were Cmax 491.7 (135.9) ng/mL; AUC0-∞ 4256.1 (509.9) ng· hr/mL, Tmax 2.9 (1.0) hr and t1/2 10.4 (3.0) hr. The weighted average (WA) plasma DPP-4 inhibition over 24 h was 89.6% and WA of plasma active GLP-1 over 2 h after standardised meal (geometric mean ratio) was 11.1 (9.9) pM/L which is two- to- four fold higher compared to that reported in other populations. The mean average (SD) AUC of plasma insulin over 2 h of standardised meal was 47.9 (24.9) µIU/mL. CONCLUSION: Although, there are differences in pharmacokinetic parameters, no clinically meaningful differences were observed with respect to DPP-IV inhibition between Indian and non-Indian population.

Evaluation of Drug Efficacy of GLP-1 Receptor Agonists and DPP-4 Inhibitors Based on Target Molecular Binding Occupancy.

Glucagon-like peptide-1 (GLP-1) receptor agonists (liraglutide, exenatide, lixisenatide) have recently been used as anti-diabetes drugs. We examined relationships of the binding occupancy of GLP-1 receptors (Φ) and their clinical efficacy after administration of GLP-1 receptor agonists. Next, by focusing on changes of GLP-1 concentration after administration of dipeptidyl peptidase-4 (DPP-4) inhibitors (vildagliptin, alogliptin, sitagliptin, linagliptin), we analyzed the relationship between Φ and clinical efficacy. Furthermore, using Φ as a common parameter, we compared the clinical efficacy elicited by GLP-1 receptor agonists and DPP-4 inhibitors using a theoretical analysis method. The present results showed that GLP-1 receptor agonists produced their clinical effect at a relatively low level of Φ (1.1-10.7%) at a usual dose. Furthermore, it was suggested that the drugs might achieve their full effect at an extraordinarily low level of Φ. It was also revealed that the Φ value of DPP-4 inhibitors (0.83-1.3%) was at the lower end or lower than that of GLP-1 receptor agonists at a usual dose. Accordingly, the predicted value for hemoglobin A1c (HbA1c) reduction after administration of the GLP-1 receptor agonists was higher than that of DPP-4 inhibitors. We clarified the differences between the therapeutic effects associated with GLP-1 receptor agonists and DPP-4 inhibitors theoretically. Together, the present findings provide a useful methodology for proper usage of GLP-1 receptor agonists and DPP-4 inhibitors.

Using miniature MS system with automatic blood sampler for preclinical pharmacokinetics study.

AIM: Preclinical pharmacokinetic studies are an essential part of modern drug development. In this work, we explored a new solution with onsite analysis using a miniature MS system, which can significantly improve the efficiency of the preclinical study. Materials & methods: A miniature mass spectrometer was used with an automatic blood sampler for onsite quantitation of drug compounds in whole blood samples. Slug-flow microextraction was used to replace the in-lab sample preparation. RESULTS & CONCLUSION: Animal studies were carried out using two drug compounds, using the auto sampler to take blood samples at preprogrammed time points. The miniature MS system was used to obtain drug concentrations, which were subsequently used to calculate the pharmacokinetic parameters.

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

Type 2 diabetes (T2D) generally requires a combination of several pharmacological approaches to control hyperglycaemia. Combining a sodium-glucose cotransporter type 2 inhibitor (SGLT2I, also known as gliflozin) and a dipeptidyl peptidase-4 inhibitor (DPP-4I, also 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 an SGLT2I (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, tofogliflozin) and 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 [AUC]) of either drug when they were administered together orally compared with corresponding values when each of them was absorbed alone. Two fixed-dose combinations (FDCs) are already available (dapagliflozin-saxagliptin, empagliflozin-linagliptin) and others are in development (ertugliflozin-sitagliptin). Preliminary results show bioequivalence of the two medications administered as FDC tablets when compared with coadministration 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.

Quantitative prediction of human pharmacokinetics and pharmacodynamics of imigliptin, a novel DPP-4 inhibitor, using allometric scaling, IVIVE and PK/PD modeling methods.

PURPOSE: To predict the pharmacokinetic/pharmacodynamic (PK/PD) profiles of imigliptin, a novel DPP-4 inhibitor, in first-in-human (FIH) study based on the data from preclinical species. METHODS: Imigliptin was intravenously and orally administered to rats, dogs, and monkeys to assess their PK/PD properties. DPP-4 activity was the PD biomarker. PK/PD profiles of sitagliptin and alogliptin in rats and humans were obtained and digitized from literatures. PK/PD profiles of all dose levels for each drug in each species were analyzed using modeling approach. Human CL, Vss and PK profiles of imigliptin were then predicted using Allometric Scaling (AS), in vitro in vivo extrapolation (IVIVE), and the steady-state plasma drug concentration - mean residence time (Css-MRT) methods. In vitro EC50 corrected by fu and in vivo EC50 in rats corrected by interspecies difference of sitagliptin and alogliptin were utilized separately to predict imigliptin human EC50. The prediction by integrating all above methods was evaluated by comparing observed and simulated PK/PD profiles in healthy subjects. RESULTS: Full PK/PD profiles in animal were summarized for imigliptin, sitagliptin and alogliptin. Imigliptin CL, Vss, and Fa were predicted to be 19.1L/h, 247L, and 0.81 in humans, respectively. Predicted imigliptin AUCs, AUECs, and Emax in humans were within 0.8-1.2 times of observed values whereas other predicted PK/PD parameters were within 0.5-1.5 times of observed values. CONCLUSIONS: By integrating available preclinical and clinical data, FIH PK/PD profiles of imigliptin could be accurately predicted.

A Pharmacokinetic/Pharmacodynamic Drug-Drug Interaction Study of Tofogliflozin (a New SGLT2 Inhibitor) and Selected Anti-Type 2 Diabetes Mellitus Drugs.

OBJECTIVE: Tofogliflozin is an oral hypoglycemic agent with a novel mechanism of action that reduces blood glucose levels by promoting glucose excretion in urine, achieved by selectively inhibiting sodium-glucose co-transporter 2 (SGLT2). We evaluated the effects of several selected anti-type 2 diabetes mellitus (T2DM) drugs-glimepiride, metformin, sitagliptin, pioglitazone, miglitol, nateglinide, and voglibose-on the pharmacokinetics and pharmacodynamics of tofogliflozin, and the effects of tofogliflozin on the pharmacokinetics of these anti-T2DM drugs in healthy male volunteers. METHODS: A single dose of either tofogliflozin alone, one of the anti-T2DM drugs alone, or co-administration of tofogliflozin and the anti-T2DM drug was administered to 108 healthy men. Cmax, AUCinf, and cumulative urine glucose excretion after co-administration of tofogliflozin and each of the anti-T2DM drugs was evaluated relative to the values of those parameters after administration of each drug alone. RESULTS: None of the anti-T2DM drugs had any effect on tofogliflozin exposure. Tofogliflozin had no or little effect on the exposure of any anti-T2DM drug. No anti-T2DM drug had any major effect on the cumulative urine glucose excretion induced by tofogliflozin. There were no safety concerns evident after administration of any drug alone or in co-administration. CONCLUSIONS: Neither the pharmacokinetics nor the pharmacodynamics of tofogliflozin was affected by any of the anti-T2DM drugs evaluated in this study, nor was the pharmacokinetics of any of the anti-T2DM drugs affected by tofogliflozin in healthy male volunteers.

[Quantification of sitagliptin in human plasma and urine by LC-MS/MS method and its application].

A rapid and sensitive liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method for quantification of sitagliptin in human plasma and urine had been developed. This method was applied to the pharmacokinetics study of sitagliptin tablet after single- and multiple-dosing in Chinese population. Plasma samples were prepared by a liquid-liquid extracted method, and urine samples were diluted. Compounds were analyzed by multiple reaction monitoring (MRM) mode with a electrospray ionization (ESI) interface. Mobile phase consisted of methanol and water (85 : 15, v/v). The linear concentration range of calibration curve was 0.5-1 000 ng.mL-1. and 0.2-100 µg.mL , intra-run/between-run accuracy was 98.98%-103.69% and 97.63%-102.29%, intra-run/between-run precision was <5.51% and 4.26% for plasma and urine sample, respectively. The stability of sitagliptin stock solution was tested for 55 days at -30 °C. Sitagliptin was stable when stored under the following conditions: 24 hours in the autosampler after sample preparation; 24 hours at room temperature, after 3 freeze and thaw cycles (from -30 °C to room temperature), 40 days at -30 °C for plasma and urine samples. The absolute recovery in plasma was 71.1%, and no matrix effect was founded. This method was proved simple, specific, sensitive, rapid and suitable for pharmacokinetics study of sitagliptin in human being.

Retrospective and Prospective Human Intravenous and Oral Pharmacokinetic Projection of Dipeptidyl peptidase-IV Inhibitors Using Simple Allometric Principles - Case Studies of ABT-279, ABT-341, Alogliptin, Carmegliptin, Sitagliptin and Vildagliptin.

PURPOSE: The purpose of this exercise was to explore the utility of allometric scaling approach for the prediction of intravenous and oral pharmacokinetics of six dipeptidy peptidase-IV (DPP-IV) inhibitors viz. ABT-279, ABT-341, alogliptin, carmegliptin, sitagliptin and vildagliptin. METHODS: The availability of intravenous and oral pharmacokinetic data in animals enabled the allometry scaling of 6 DPP-IV inhibitors. The relationship between the main pharmacokinetic parameters [viz. volume of distribution (Vd) and clearance (CL)] and body weight was studied across three or four mammalian species, using double logarithmic plots to predict the human pharmacokinetic parameters of CL and Vd using simple allometry. RESULTS: A simply allometry relationship: Y = aWb was found to be adequate for the prediction of intravenous and oral human clearance/volume of distribution for DPP-IV inhibitors. The allometric equations for alogliptin, carmegliptin, sitagliptin, vildagliptin, ABT-279 and ABT-341 were 1.867W0.780, 1.170W0.756, 2.020W0.529, 1.959 W0.847, 0.672 W1.016, 1.077W 0.649, respectively, to predict intravenous clearance (CL) and the corresponding equations to predict intravenous volume of distribution (Vd) were: 3.313W0.987, 6.096W0.992, 7.140W0.805, 2.742W0.941, 1.299W0.695 and 5.370W0.803. With the exception of a few discordant values the exponent rule appeared to hold for CL (0.75) and Vd (1.0) for the predictions of various DPP-IV inhibitors. Regardless of the routes, the predicted values were within 2-3 fold of observed values and intravenous allometry was better than oral allometry. CONCLUSION: Simple allometry retrospectively predicted with reasonable accuracy the human reported values of gliptins and could be used as a prospective tool for this class of drugs.