Unveiling Pharmacokinetics and Drug Interaction of Linagliptin and Pioglitazone HCl in Rat Plasma Using LC-MS/MS.

The linagliptin (LIN) and pioglitazone HCl (PIO) combination, currently undergoing phase III clinical trials for diabetes mellitus treatment, demonstrated significant improvements in glycemic control. However, the absence of an analytical method for simultaneous determination in biological fluids highlights a crucial gap. This underscores the pressing need for sensitive bioanalytical methods, emphasizing the paramount importance of developing such tools to advance diabetes management strategies and enhance patient care. Herein, a sensitive reverse-phase high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry method was developed for simultaneous determination of LIN and PIO in rat plasma using alogliptin as an internal standard. Chromatographic separation was performed on an Agilent Eclipse Plus C18 (4.6 × 100 mm, 3.5 µm) using an isocratic mobile phase system consisting of ammonium formate (pH 4.5) and methanol using an acetonitrile-induced protein precipitation technique for sample preparation. Multiple reaction monitoring in positive ion mode was used for quantitation of the precursor to production at m/z 473.2 → 419.9 for LIN, 357.1 → 134.2 for PIO, and 340.3 → 116.1 for ALO. The linearity range was 0.5 to 100 and 1 to 2000 ng/mL for LIN and PIO, respectively. The developed method was validated as per US-FDA guidelines and successfully applied to clinical pharmacokinetic and drug-drug interaction studies with a single oral administration of LIN and PIO in rat plasma. Pharmacokinetic parameters of LIN were significantly influenced by the concomitant administration of PIO and vice versa. Molecular modeling revealed the significant interaction of LIN and PIO with P-glycoprotein. Therefore, the drug-drug interaction between LIN and PIO deserves further study to improve drug therapy and prevent dangerous adverse effects.

Target-mediated exposure enhancement: a previously unexplored limit of TMDD.

Target-mediated drug disposition (TMDD) is often observed for targeted therapeutics, and manifests as decreases in clearance and volume of distribution with increasing dose as a result of saturable, high affinity target binding. In the present work, we demonstrate that classically defined TMDD is just one of the characteristic features of the system. In fact, for molecules with rapid non-specific elimination relative to target-mediated elimination, binding to target may actually lead to improved exposure at sub-saturating doses. This feature, which we refer to as target-mediated exposure enhancement (TMEE), produces the opposite trend to classical TMDD, i.e., with increasing dose levels, clearance and volume of distribution will also increase. The general model of TMDD was able to well-characterize the pharmacokinetics of two molecules that display TMEE, ALX-0081 and linagliptin. Additional fittings using the commonly reported TMDD model approximations revealed that both the quasi-equilibrium and quasi-steady-state approximations were able to well-describe TMEE; however, the Michaelis-Menten approximation was unable to describe this behavior. With the development of next-generation therapeutics with high affinity for target and rapid non-specific elimination, such as antibody fragments and peptides, this previously unexplored limit of TMDD is anticipated to become increasingly relevant for describing pharmacokinetics of investigational therapeutics.

Relative bioavailability of an empagliflozin 25-mg/linagliptin 5-mg fixed-dose combination tablet
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OBJECTIVE: This relative bioavailability study compared a fixed-dose combination (FDC) tablet of empagliflozin 25 mg/linagliptin 5 mg with the corresponding individual components. In addition, the effect of food on the bioavailability of the FDC was studied, and the standard-dissolving formulation FDC was compared with a slow-dissolving side batch. METHODS: An open-label, randomized, crossover study design was used (ClinicalTrials.gov Identifier NCT01189201). Healthy volunteers (n = 42) each received three single-dose treatments: FDC standard dissolution, individual tablets, and either FDC standard dissolution with food or FDC slow dissolution. Primary endpoints for relative bioavailability comparisons were area under the plasma concentration-time curve (AUC) over time 0 to the last time point with the plasma concentration above the quantification limit (AUC0-tz) for empagliflozin, AUC from 0 to 72 hours (AUC0-72) for linagliptin, and maximum plasma concentration (Cmax) for both drugs. RESULTS: In all three comparisons, the 90% confidence intervals for the ratios of AUCs were within the standard acceptance range (80 - 125%) for bioequivalence. Empagliflozin and linagliptin both showed reductions in Cmax after food compared with the fasted state, although overall exposure remained similar. The empagliflozin/linagliptin combinations were well tolerated. CONCLUSIONS: This study shows that the FDC of empagliflozin 25 mg/linagliptin 5 mg can be regarded as bioequivalent to the individual tablets. Administering the tablet after food or a tablet with a slow-dissolution profile did not have a clinically-relevant impact on the bioavailability of empagliflozin/linagliptin FDC tablets.
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Cubosomal functionalized block copolymer platform for dual delivery of linagliptin and empagliflozin: Recent advances in synergistic strategies for maximizing control of high-risk type II diabetes.

A well-made chitosan-PVP block copolymer platform was equipped with highly ordered and uniform nano-channels. This highly adhesive block copolymer platform was designed to ensure the efficient co-delivery of two synergistic-acting hypoglycemic drugs. Linagliptin oral bioavailability is 30% due to poor permeability and intestinal degradation. Its pharmacokinetics shows a non-linear profile. Empagliflozin exhibited decreased permeability and decreased solubility in aqueous media between pH 1 and 7.5. Cubosomes were functionalized as a good microdomain to guest and improve the physicochemical characteristics of drug molecules with decreased permeability and solubility. Cubosomes loaded with linagliptin (linagliptin cubosomes (LCs)) and empagliflozin (empagliflozin cubosomes ECs) were separately prepared using the top-down method and optimized by applying 23 factorial design. Optimized cubosomal systems LCs (F3) and ECs (F4) were incorporated into a chitosan-PVP gel to obtain dual cubosome-loaded platforms (LECF) optimized through 22 factorial design. The permeation study from the optimized LECF (C1) ensured enhanced empagliflozin permeation alongside continued efflux for linagliptin, resolving potential risks due to its non-linear plasma profile. The in-vivo study revealed that AUC(0-∞) of linagliptin and empagliflozin was enhanced by 2- and threefold, respectively. Therefore, the chitosan-PVP block copolymer platform buccal application for the co-delivery of linagliptin and empagliflozin could contribute to enhanced clinical effectiveness in treating diabetes.

Elucidation of DPP-4 involvement in systemic distribution and renal reabsorption of linagliptin by PBPK modeling with a cluster Gauss-Newton method.

The dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (LNG) exhibits target-mediated drug disposition (TMDD) in clinical settings, characterized by saturable binding to plasma soluble DPP-4 (sDPP-4) and tissue transmembrane DPP-4 (tDPP-4). Previous studies have indicated that saturable renal reabsorption of LNG contributes to its nonlinear urinary excretion observed in humans and wild-type mice, but not in Dpp-4 knockout mice. To elucidate the mechanisms underlying these complex phenomena, including DPP-4-related renal reabsorption of LNG, we employed physiologically-based pharmacokinetic (PBPK) modeling combined with a cluster Gauss-Newton method (CGNM). The CGNM facilitated the exploration of parameters in rat and human PBPK models for LNG and the determination of parameter identifiability. Through PBPK-CGNM analysis using reported autoradiography data ([14C]-LNG) in wild-type and Dpp-4-deficient rats, DPP-4-specific distributions of LNG in various tissues were clearly differentiated from nonspecific parts. By fitting to human plasma concentrations and urinary and fecal excretions of LNG after intravenous and oral administrations, multiple unknown PBPK parameters were simultaneously estimated by the CGNM. Notably, the amount of tDPP-4 and the reabsorption clearance for LNG-DPP-4 complexes were identifiable, indicating their critical role in explaining the complex nonlinear pharmacokinetics of LNG. Compared with previous PBPK analyses, the CGNM allowed us to incorporate greater model complexity (e.g., consideration of tDPP-4 expressions and in vitro binding kinetics), ultimately resulting in a more accurate reproduction of LNG's TMDD. In conclusion, by considering LNG as a high-affinity probe for DPP-4, comprehensive PBPK-CGNM analyses suggested a dynamic whole-body distribution of DPP-4, including its involvement in the renal reabsorption of LNG.

Transdermal Drug Delivery System of Linagliptin Sustained-release Microparticle Gels: In vitro Characterization and In vivo Evaluation.

BACKGROUND: Linagliptin (LNG) exhibits poor bioavailability and numerous side effects, significantly limiting its use. Transdermal drug delivery systems (TDDS) offer a potential solution to overcome the first-pass effect and gastrointestinal reactions associated with oral formulations. OBJECTIVE: The aim of this study was to develop LNG microparticle gels to enhance drug bioavailability and mitigate side effects. METHODS: Linagliptin hyaluronic acid (LNG-HA) microparticles were prepared by spray drying method and their formulation was optimized via a one-factor method. The solubility and release were investigated using the slurry method. LNG-HA microparticle gels were prepared and optimised using in vitro transdermal permeation assay. The hypoglycaemic effect of the LNG-HA microparticle gel was examined on diabetic mice. RESULTS: The results indicated that the LNG-HA microparticle encapsulation rate was 84.46%. Carbomer was selected as the gel matrix for the microparticle gels. Compared to the oral API, the microparticle gel formulation demonstrated a distinct biphasic release pattern. In the first 30 minutes, only 43.56% of the drug was released, followed by a gradual release. This indicates that the formulation achieved a slow-release effect from a dual reservoir system. Furthermore, pharmacodynamic studies revealed a sustained hypoglycemic effect lasting for 48 hours with the LNG microparticle gel formulation. CONCLUSION: These findings signify that the LNG microparticle gel holds significant clinical value for providing sustained release and justifies its practical application.

A Pharmacokinetic Drug Interaction Between Fimasartan and Linagliptin in Healthy Volunteers.

OBJECTIVE: Fimasartan, an angiotensin II type 1 receptor blocker, and linagliptin, a dipeptidyl-peptidase-4 inhibitor, are frequently coadministered to treat patients with hypertension and diabetes, respectively. This study sought to evaluate the pharmacokinetic interactions between fimasartan and linagliptin after co-administration in healthy Korean subjects. METHODS: The overall study was divided into two separate parts, with each part designed as an open-label, multiple-dose, two-period, and single-sequence study. In Part A, to investigate the effect of linagliptin on fimasartan, 25 subjects received 120 mg fimasartan alone once daily for seven days during Period I, and 120 mg fimasartan with 20 mg linagliptin for seven days during Period II. In Part B, to examine the effect of fimasartan on linagliptin, 12 subjects received only linagliptin once daily for seven days during Period I, followed by concomitant administration of fimasartan for seven days during Period II, at the same doses used in Part A. Serial blood samples were collected at scheduled intervals for up to 24 h after the last dose to determine the steady-state pharmacokinetics of both drugs. RESULTS: Thirty-six subjects completed the study. The geometric mean ratio and 90% confidence intervals for maximum plasma concentration at steady state (Cmax,ss) and area under the concentration-time curve at steady state (AUCτ,ss) of fimasartan with or without linagliptin were 1.2633 (0.9175-1.7396) and 1.1740 (1.0499-1.3126), respectively. The corresponding values for Cmax,ss and AUCτ,ss of linagliptin with or without fimasartan were 0.9804 (0.8480-1.1336) and 0.9950 (0.9322-1.0619), respectively. A total of eight adverse events (AEs) were reported and the incidence of AEs did not increase significantly with co-administration of the drugs. CONCLUSION: Our results suggest that there are no clinically significant pharmacokinetic interactions between fimasartan and linagliptin when co-administered. Treatments were well tolerated during the study, with no serious adverse effects. CLINICAL TRIAL REGISTRY: http://clinicaltrials.gov, NCT03250052.

Incorporating Pharmacological Target-Mediated Drug Disposition (TMDD) in a Whole-Body Physiologically Based Pharmacokinetic (PBPK) Model of Linagliptin in Rat and Scale-up to Human.

Linagliptin demonstrates substantial nonlinear pharmacokinetics due to its saturable binding to its pharmacological target dipeptidyl peptide 4 (DPP-4), a phenomenon known as target-mediated drug disposition (TMDD). In the current study, we established a novel whole-body physiologically-based pharmacokinetic (PBPK)-TMDD model for linagliptin. This comprehensive model contains plasma and 14 tissue compartments, among which TMDD binding process was incorporated in 9 of them, namely the plasma, kidney, liver, spleen, lung, skin, salivary gland, thymus, and reproductive organs. Our final model adequately captured the concentration-time profiles of linagliptin in both plasma and various tissues in both wildtype rats and DPP4-deficient rats following different doses. The association rate constant (kon) in plasma and tissues were estimated to be 0.943 and 0.00680 nM-1 h-1, respectively, and dissociation rate constant (koff), in plasma and tissues were estimated to be 0.0698 and 0.00880 h-1, respectively. The binding affinity of linagliptin to DPP-4 (Kd) was predicted to be higher in plasma (0.0740 nM) than that in tissue (1.29 nM). When scaled up to a human, this model captured the substantial and complex nonlinear pharmacokinetic behavior of linagliptin in human adults that is characterized by less-than dose-proportional increase in plasma exposure, dose-dependent clearance and volume of distribution, as well as long terminal half-life with minimal accumulation after repeated doses. Our modeling work is not only novel but also of high significance as the whole-body PBPK-TMDD model platform developed using linagliptin as the model compound could be applied to other small-molecule compounds exhibiting TMDD to facilitate their optimal dose selection. Graphical abstract.

Does Rabeprazole Sodium Alleviate the Anti-diabetic Activity of Linagliptin? Drug-Drug Interaction Analysis by In vitro and In vivo Methods.

Drug interaction has turned into the preeminent regarding issues for a prescriber during polypharmacy. The foremost objective of this research was to form a complex between linagliptin and rabeprazole sodium by in vitro interactions. The interactions between the drugs have been examined by monitoring some chromatographic and spectroscopic analyses viz. TLC, HPLC, FT-IR, UV, Job's plot, conductometric titrations, and Ardon's spectrophotometric strategy. Rabeprazole sodium formed a stable complex with linagliptin, which was ensured from the insight of these analytical data. The developed complex's bright spot was clearly watched in the TLC plate. The retention time (Rt) of the formed complex was 5.303 min, where the Rt were 3.364 and 3.103 min for linagliptin and rabeprazole sodium, respectively, in HPLC chromatograms. In FT-IR and UV spectra of the formed complex revealed some disappearance of characteristic peaks that affirmed the complexation. All of the variations of the spectrophotometric and chromatographic properties from the antecedent drugs indicated the drug-drug interaction. Another crucial fact for the experimental aim was to affirm the assumed drug interaction by in vivo model examination. The assessment of anti-diabetic property on alloxan-induced Swiss albino mice proved significant in vivo interaction between the drugs. It was outlined from the animal study that the hypoglycemic activity of linagliptin might be significantly affected due to the complex formation of the drug with a proton pump inhibitor (PPI). Nonetheless, it is the primary outcome of the interaction, which recommends the bigger in vivo study or clinical monitoring on the human model.

Pharmacokinetic interaction between linagliptin and tadalafil in healthy Egyptian males using a novel LC-MS method.

Aim: Assessment of pharmacokinetic interaction between linagliptin (LNG) and tadalafil (TDL) in healthy males. Methods: First, a novel LC-MS method was developed; second, a Phase IV, open-label, cross-over study was performed. Volunteers took single 20-mg TDL dose on day 1 followed by wash out period of 2 weeks then multiple oral dosing of 5-mg/day LNG for 13 days. On day 13, volunteers were co-administered 20-mg TDL. Results: LNG and TDL single doses did not affect QTc interval. Smoking did not alter pharmacokinetics/pharmacodynamics of LNG and TDL. Co-administration of LNG with TDL resulted in TDL longer time to reach maximum plasma concentration (Tmax), decreased oral clearance (Cl/F) and oral volume of distribution (Vd/F), increased its maximum plasma concentration (Cmax), area under concentration-time curve (AUC), muscle pain and QTc prolongation. Conclusion: LNG and TDL co-administration warrants monitoring and/or TDL dose adjustment.

A validated LC-MS/MS method for simultaneous determination of linagliptin and metformin in spiked human plasma coupled with solid phase extraction: Application to a pharmacokinetic study in healthy volunteers.

Combination therapy has a pivotal role in type II diabetes mellitus management in patients unable to maintain normal glycemic level using metformin alone. Addition of linagliptin, dipeptidyl peptidase-IV inhibitor, to metformin improves glycemic control. This study is concerned with the development of an HPLC-MS/MS method for simultaneous quantification of linagliptin and metformin in spiked human plasma. The method was applied to evaluate the potential pharmacokinetic interactions between the cited drugs in healthy volunteers. Solid phase extraction was applied using Strata™ X cartridge. Separation was carried out on Symmetry® C18 column using methanol: 10 mM ammonium formate buffer (containing 0.2% formic acid) in a ratio of (95: 5, v/v) as mobile phase at flow rate 0.25 mL min-1. Quantification was performed with multiple reaction monitoring in positive ionization mode. The monitored transitions were set at m/z 473.24 → 419.94, 130.14 → 60.18 and 340.27 → 116.07 for linagliptin, metformin and alogliptin (internal standard), respectively. The method was validated according to FDA guidelines. The method showed excellent linearity over concentration ranges 0.25-10 and 25-2000 ng mL-1 for linagliptin and metformin, respectively. The validated HPLC-MS/MS method was successfully applied to pharmacokinetic study of linagliptin and metformin in healthy volunteers after oral administration of Jentadueto® tablets.

Pharmacokinetic drug evaluation of empagliflozin plus linagliptin for the treatment of type 2 diabetes.

INTRODUCTION: Type 2 diabetes mellitus has become a growing epidemic and therefore efficient treatment strategies that target its management are needed. The treatment of diabetic patients often requires the combination of antidiabetic drug classes. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) block glucose reabsorption in the proximal renal tubules. Dipeptidyl peptidase-4 inhibitors (DPP-4i) improve glucose metabolism by blocking the enzyme that degrades incretins leading to increased insulin secretion. Areas covered: The aim of the review is to present the available data on pharmacokinetic properties/pharmacodynamics, metabolic and cardiovascular effects of empagliflozin plus linagliptin combination. Expert opinion: Both empagliflozin and linagliptin have established safety and efficacy in the treatment of diabetes. Available data demonstrate the absence of pharmacological interactions when the two drugs are given together. The complementary mechanisms of action would be expected to provide additive benefits on carbohydrate metabolism variables, but the results from clinical trials have shown that the empagliflozin/linagliptin combination provides only mild improvements of glycated hemoglobin compared with either monotherapy. However, the single-tablet formulation of empagliflozin/linagliptin is expected to provide better compliance and thus improved glycaemic control coupled with a favourable safety profile. Thus, the fixed-dose combination of empagliflozin/linagliptin has the capacity to both effectively and safely manage diabetic patients.

Phase 1 and Pharmacokinetic Drug-Drug Interaction Study of Metformin, Losartan, and Linagliptin Coadministered With DW1029M in Healthy Volunteers.

We investigated botanical drug-pharmaceutical drug interactions between DW1029M (a botanical extract of Morus alba linne root bark and Puerariae radix) and metformin, losartan, and linagliptin in the steady state. Three studies were conducted as randomized, open-label, 2-period, 2-treatment, multiple-dose, 2-way crossover designs. Eligible subjects received metformin (500 mg twice daily), losartan (50 mg once daily), or linagliptin (5 mg once daily) with DW1029M (300 mg × 2T twice daily) every 12 hours on days 1 through 6 and a single dose on the morning of day 7. Coadministration of DW1029M with metformin, losartan, or linagliptin had no clinically relevant effects based on the area under the plasma concentration-time curve (AUCτ ) geometric least-squares mean ratio (GMR) - AUCτ GMR, 89.7; 90% confidence interval (CI), 81.0-99.4 for metformin; AUCτ GMR, 96.2; 90%CI, 86.3-107.1 for losartan; and AUCτ GMR, 89.7; 90%CI, 83.2-96.6 for linagliptin. In addition, coadministration of DW1029M did not have any clinically meaningful effect on the maximum plasma concentration (Cmax,ss ) - Cmax,ss GMR, 87.3; 90%CI, 76.2-100.0 for metformin; Cmax,ss GMR, 90.5; 90%CI, 78.3-104.6 for losartan; and Cmax,ss GMR, 81.4; 90%CI, 69.5-95.3 for linagliptin. Coadministration of DW1029M with metformin, losartan, or linagliptin was well tolerated.

Pharmacokinetic and pharmacodynamic evaluation of linagliptin for the treatment of type 2 diabetes mellitus, with consideration of Asian patient populations.

Our aims were to summarize the clinical pharmacokinetics and pharmacodynamics of the dipeptidyl-peptidase-4 inhibitor, linagliptin, and to consider how these characteristics influence its clinical utility. Differences between linagliptin and other dipeptidyl-peptidase-4 inhibitors were also considered, in addition to the influence of Asian race on the pharmacology of linagliptin. Linagliptin has a xanthine-based structure, a difference that might account for some of the pharmacological differences observed with linagliptin versus other dipeptidyl-peptidase-4 inhibitors. The long terminal half-life of linagliptin results from its strong binding to dipeptidyl-peptidase-4. Despite this, linagliptin shows a short accumulation half-life, as a result of saturable, high-affinity binding to dipeptidyl-peptidase-4. The pharmacokinetic characteristics of linagliptin make it suitable for once-daily dosing in a broad range of patients with type 2 diabetes mellitus. Unlike most other dipeptidyl-peptidase-4 inhibitors, linagliptin has a largely non-renal excretion route, and dose adjustment is not required in patients with renal impairment. Furthermore, linagliptin exposure is not substantially altered in patients with hepatic impairment, and dose adjustment is not necessary for these patients. The 5-mg dose is also suitable for patients of Asian ethnicity. Linagliptin shows unique pharmacological features within the dipeptidyl-peptidase-4 inhibitor class. Although most clinical trials of linagliptin have involved largely Caucasian populations, data on the pharmacokinetic/pharmacodynamic properties of linagliptin show that these features are not substantially altered in Asian populations. The 5-mg dose of linagliptin is suitable for patients with type 2 diabetes mellitus irrespective of their ethnicity or the presence of renal or hepatic impairment.

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.

The DPP4 Inhibitor Linagliptin Protects from Experimental Diabetic Retinopathy.

BACKGROUND/AIMS: Dipeptidyl peptidase 4 (DPP4) inhibitors improve glycemic control in type 2 diabetes, however, their influence on the retinal neurovascular unit remains unclear. METHODS: Vasculo- and neuroprotective effects were assessed in experimental diabetic retinopathy and high glucose-cultivated C. elegans, respectively. In STZ-diabetic Wistar rats (diabetes duration of 24 weeks), DPP4 activity (fluorometric assay), GLP-1 (ELISA), methylglyoxal (LC-MS/MS), acellular capillaries and pericytes (quantitative retinal morphometry), SDF-1a and heme oxygenase-1 (ELISA), HMGB-1, Iba1 and Thy1.1 (immunohistochemistry), nuclei in the ganglion cell layer, GFAP (western blot), and IL-1beta, Icam1, Cxcr4, catalase and beta-actin (quantitative RT-PCR) were determined. In C. elegans, neuronal function was determined using worm tracking software. RESULTS: Linagliptin decreased DPP4 activity by 77% and resulted in an 11.5-fold increase in active GLP-1. Blood glucose and HbA1c were reduced by 13% and 14% and retinal methylglyoxal by 66%. The increase in acellular capillaries was diminished by 70% and linagliptin prevented the loss of pericytes and retinal ganglion cells. The rise in Iba-1 positive microglia was reduced by 73% with linagliptin. In addition, the increase in retinal Il1b expression was decreased by 65%. As a functional correlate, impairment of motility (body bending frequency) was significantly prevented in C. elegans. CONCLUSION: Our data suggest that linagliptin has a protective effect on the microvasculature of the diabetic retina, most likely due to a combination of neuroprotective and antioxidative effects of linagliptin on the neurovascular unit.

Comparable pharmacodynamics, efficacy, and safety of linagliptin 5 mg among Japanese, Asian and white patients with type 2 diabetes.

AIMS/INTRODUCTION: The efficacy and safety of drugs can vary between different races or ethnic populations because of differences in the relationship of dose to exposure, pharmacodynamic response or clinical efficacy and safety. In the present post-hoc analysis, we assessed the influence of race on the pharmacokinetics, pharmacodynamics, efficacy and safety of monotherapy with the dipeptidyl peptidase-4 inhibitor, linagliptin, in patients with type 2 diabetes enrolled in two comparable, previously reported randomized phase III trials. MATERIALS AND METHODS: Study 1 (with a 12-week placebo-controlled phase) recruited Japanese patients only (linagliptin, n = 159; placebo, n = 80); study 2 (24-week trial) enrolled Asian (non-Japanese; linagliptin, n = 156; placebo, n = 76) and white patients (linagliptin, n = 180; placebo, n = 90). RESULTS: Linagliptin trough concentrations were equivalent across study and race groups, and were higher than half-maximal inhibitory concentration, resulting in dipeptidyl peptidase-4 inhibition >80% at trough. Linagliptin inhibited plasma dipeptidyl peptidase-4 activity to a similar degree in study 1 and study 2. Linagliptin reduced fasting plasma glucose concentrations by a similar magnitude across groups, leading to clinically relevant reductions in glycated hemoglobin in all groups. Glycated hemoglobin levels decreased to a slightly greater extent in study 1 (Japanese) and in Asian (non-Japanese) patients from study 2. Linagliptin had a favorable safety profile in each race group. CONCLUSIONS: Trough exposure, pharmacodynamic response, and efficacy and safety of linagliptin monotherapy were comparable among Japanese, Asian (non-Japanese) and white patients, confirming that the recommended 5-mg once-daily dose of linagliptin is appropriate for use among different race groups.

Empagliflozin/Linagliptin: Combination therapy in patients with type 2 diabetes.

Glyxambi® (empagliflozin/linagliptin) is a fixed-dose, once-daily tablet combining a sodium glucose co-transporter-2 (SGLT2) inhibitor with a dipeptidyl peptidase-4 (DPP-4) inhibitor. Glyxambi® is served as an adjuvant to diet and exercise to improve glycemic control in adults with type 2 diabetes when both empagliflozin and linagliptin are appropriate treatments. Glyxambi® combines 10mg or 25mg empagliflozin with 5mg linagliptin, with different, complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes. Empagliflozin removes glucose through the urine by blocking blood glucose re-absorption in the kidney, and linagliptin exerts glucose-lowering activity by increasing hormones that stimulate the pancreas to produce more insulin and decreasing the levels of glucagon in the circulation. In addition, this combination therapy modestly reduces body weight and blood pressure without significant safety issues.

Population Pharmacokinetics and Pharmacodynamics of Linagliptin in Patients with Type 2 Diabetes Mellitus.

BACKGROUND AND OBJECTIVES: Linagliptin is a dipeptidyl peptidase (DPP)-4 inhibitor, used to treat type 2 diabetes mellitus (T2DM). Population pharmacokinetic and pharmacodynamic analyses were performed to characterize the impact of clinically relevant intrinsic/extrinsic factors (covariates) on linagliptin exposure and DPP-4 inhibition in patients with T2DM. METHODS: Linagliptin plasma concentrations and DPP-4 activities were obtained from four studies (two phase 1, two phase 2b). Non-linear mixed-effects modelling techniques were implemented using NONMEM software. The covariates that were studied comprised demographic information and laboratory values, including liver enzyme levels and creatinine clearance, as well as study-related factors such as metformin co-treatment. Covariate effects on parameters describing the pharmacokinetics and pharmacokinetic/pharmacodynamic relationship were investigated using stepwise forward inclusion/backward elimination. RESULTS: The pharmacokinetic analysis included 6,907 measurements of plasma linagliptin concentrations from 462 patients; the pharmacokinetic/pharmacodynamic analysis included 9,674 measurements of plasma DPP-4 activity and linagliptin plasma concentrations from 607 patients. The non-linear pharmacokinetics were described by a target-mediated drug disposition model accounting for the concentration-dependent binding of linagliptin to its target, DPP-4. The difference in exposure between the 5th and 95th percentiles of the covariate distributions and median was <20 % for each single covariate. Likewise, the impact of the covariates on both the half-maximum effect (EC50) and the concentration leading to 80 % DPP-4 inhibition was <20 %. CONCLUSION: These analyses show that the investigated factors do not alter the pharmacokinetics and DPP-4 inhibitory activity of linagliptin to a clinically relevant extent and that dose adjustment is not necessary on the basis of factors including age, sex and weight.