Pharmacokinetic/Pharmacodynamic modelling of Saxagliptin and its active metabolite, 5-hydroxy Saxagliptin in rats with Type 2 Diabetes Mellitus.

BACKGROUND AND PURPOSES: It is unclear whether the parent Saxagliptin (SAX) in vivo is the same as that in vitro, which is twice that of 5-hydroxy Saxagliptin (5-OH SAX). This study is to construct a Pharmacokinetic-Pharmacodynamic (PK-PD) link model to evaluate the genuine relationship between the concentration of parent SAX in vivo and the effect. METHODS: First, we established a reliable Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS/MS) method and DPP-4 inhibition ratio determination method. Then, the T2DM rats were randomly divided into four groups, intravenous injection of 5-OH SAX (0.5 mg/kg) and saline group, intragastric administration of SAX (10 mg/kg) and Sodium carboxymethyl cellulose (CMC-Na) group. Plasma samples were collected at different time points for subsequent testing. Finally, we used the measured concentrations and inhibition ratios to construct a PK-PD link model for 5-OH SAX and parent SAX. RESULTS: A two-compartment with additive model showed the pharmacokinetic process of SAX and 5-OH SAX, the concentration-effect relationship was represented by a sigmoidal Emax model and sigmoidal Emax with E0 model for SAX and 5-OH SAX, respectively. Fitting parameters showed SAX was rapidly absorbed after administration (Tmax=0.11 h, t1/2, ka=0.07 h), widely distributed in the body (V ≈ 20 L/kg), plasma exposure reached 3282.06 ng*h/mL, and the elimination half-life was 6.13 h. The maximum plasma dipeptidyl peptidase IV (DPP-4) inhibition ratio of parent SAX was 71.47%. According to the final fitting parameter EC50, EC50, 5-OH SAX=0.46EC50, SAX(parent), it was believed that the inhibitory effect of 5-OH SAX was about half of the parent SAX, which is consistent with the literature. CONCLUSIONS: The PK-PD link model of the parent SAX established in this study can predict its pharmacokinetic process in T2DM rats and the strength of the inhibitory effect of DPP-4 based on non-clinical data.

In vitro gastrointestinal stability and intestinal absorption of ACE-1 and DPP4 inhibitory peptides from poultry by-product hydrolysates.

Bioactive peptides derived from food are promising health-promoting ingredients that can be used in functional foods and nutraceutical formulations. In addition to the potency towards the selected therapeutic target, the bioavailability of bioactive peptides is a major factor regarding clinical efficacy. We have previously shown that a low molecular weight peptide fraction (LMWPF) from poultry by-product hydrolysates possesses angiotensin-1-converting enzyme (ACE-1) and dipeptidyl-peptidase 4 (DPP4) inhibitory activities. The present study aimed to investigate the bioavailability of the bioactive peptides in the LMWPF. Prior to the investigation of bioavailability, a dipeptide YA was identified from this fraction as a dual inhibitor of ACE-1 and DPP4. Gastrointestinal (GI) stability and intestinal absorption of the bioactive peptides (i.e., YA as well as two previously reported bioactive dipeptides (VL and IY)) in the LMWPF were evaluated using the INFOGEST static in vitro digestion model and intestinal Caco-2 cell monolayer, respectively. Analysis of peptides after in vitro digestion confirmed that the dipeptides were resistant to the simulated GI conditions. After 4 hours of incubation, the concentration of the peptide from the apical side of the Caco-2 cell monolayer showed a significant decrease. However, the corresponding absorbed peptides were not detected on the basolateral side, suggesting that the peptides were not transported across the intestinal monolayer but rather taken up or metabolized by the Caco2 cells. Furthermore, when analyzing the gene expression of the Caco-2 cells upon peptide stimulation, a down-regulation of peptide transporters, the transcription factor CDX2, and the tight junction protein-1 (TJP1) was observed, suggesting the specific effects of the peptides on the Caco-2 cells. The study demonstrated that bioactive dipeptides found in the LMWPF were stable through in vitro GI digestion; however, the overall bioavailability may be hindered by inadequate uptake across the intestinal barrier.

Concentration-QTc Modeling of the DPP-4 Inhibitor HSK7653 in a First-in-Human Study of Chinese Healthy Volunteers.

Cofrogliptin (HSK7653) is a long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus with a twice-monthly dosing regimen. This study included 62 participants (48 without food effect, 14 with food effect) receiving single doses of HSK7653 (5, 10, 25, 50, 100, and 150 mg) or placebo. Pharmacokinetic samples were collected over 24 hours postdosing and sampling times are aligned with 12-lead electrocardiograms (ECGs) which were derived from continuous ECG recordings. For the concentration-QT interval corrected for heart rate (C-QTc) analysis, we used linear mixed-effects modeling to characterize the correlation between plasma concentrations of HSK7653 and the change from baseline in the QT interval which was corrected by Fridericia's formula (ΔQTcF). The result showed that a placebo-corrected Fridericia corrected QT interval (ΔΔQTcF) prolongation higher than 10 milliseconds is unlikely at the mean maximum observed concentration (Cmax) (411 ng/mL) associated with the recommended therapeutic doses (25 mg twice-monthly), even at the highest supratherapeutic concentration (2425 ng/mL). Thus, HSK7653 does not significantly affect QT prolongation at either recommended doses or the highest supratherapeutic concentration.

Biotransformation and disposition characteristics of HSK7653, a novel long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes.

AIM: To investigate the metabolism and disposition characteristics of HSK7653 in healthy male Chinese participants. METHODS: A single oral dose of 80 µCi (25 mg) [14C]HSK7653 capsules was administered to six healthy participants, and blood, plasma, urine and faeces were collected. Quantitative and qualitative analysis was conducted to investigate the pharmacokinetics, blood-to-plasma ratio, mass balance and metabolism of HSK7653. RESULTS: The drug was well absorbed and reached a maximum concentration at 1.25 h. The drug-related components (HSK7653 and its metabolites) were eliminated slowly, with a half-life (t1/2) of 111 h. Unchanged HSK7653 contributed to more than 97% of the total radioactivity in all plasma samples. The blood-to-plasma ratio (0.573-0.845) indicated that HSK7653 did not tend to distribute into blood cells. At 504 h postdose, up to 95.9% of the dose was excreted, including 79.8% in urine and 16.1% in faeces. Most of the radioactivity (75.5% dose) in excreta was unchanged HSK7653. In addition, nine metabolites were detected in urine and faeces. The most abundant metabolite was M6-2, a dioxidation product of HSK7653, which accounted for 4.73% and 2.63% of the dose in urine and faeces, respectively. The main metabolic pathways of HSK7653 in vivo included oxidation, pyrrole ring opening and sulphonamide hydrolysation. CONCLUSION: HSK7653 was well absorbed, slightly metabolized and slowly excreted in humans. The high plasma exposure and long t1/2 of HSK7653 may contribute to its long-lasting efficacy as a long-acting dipeptidyl peptidase-4 inhibitor.

Differential inhibition of sildenafil and macitentan on saxagliptin metabolism.

The development of diabetes mellitus (DM) is generally accompanied by erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), which increases the use of combination drug therapy and the risk of drug-drug interactions. Saxagliptin for the treatment of DM, sildenafil for the treatment of ED and PAH, and macitentan for the treatment of PAH are all substrates of CYP3A4, which indicates their potential involvement in drug-drug interactions. Therefore, we investigated potential pharmacokinetic interactions between saxagliptin and sildenafil/macitentan. We investigated this speculation both in vitro and in vivo, and explored the underlying mechanism using in vitro hepatic metabolic models and molecular docking assays. The results showed that sildenafil substantially inhibited the metabolism of saxagliptin by occupying the catalytic site of CYP3A4 in a competitive manner, leading to the alterations in the pharmacokinetic properties of saxagliptin in terms of increased maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time 0 to 24 h (AUC(0-t)), area under the plasma concentration-time curve from time 0 extrapolated to infinite time (AUC(0-∞)), decreased clearance rate (CLz/F), and prolonged terminal half-life (t1/2). In contrast, a slight inhibition was observed in saxagliptin metabolism when concomitantly used with macitentan, as no pharmacokinetic parameters were altered, except for CLz/F. Thus, dosage adjustment of saxagliptin may be required in combination with sildenafil to achieve safe therapeutic plasma concentrations and reduce the risk of potential toxicity, but it is not necessary for co-administration with macitentan.

A Phase I Clinical Study of the Pharmacokinetics and Safety of Prusogliptin Tablets in Subjects with Mild to Moderate Hepatic Insufficiency and Normal Liver Function.

BACKGROUND: Prusogliptin is a potent and selective DPP-4 inhibitor. In different animal models, Prusogliptin showed potential efficacy in the treatment of type 2 diabetes. However, the knowledge of its pharmacokinetics and safety in patients with liver dysfunction is limited. OBJECTIVES: The present study evaluated the pharmacokinetics and safety of Prusogliptin in subjects with mild or moderate hepatic impairment compared with healthy subjects. METHODS: According to the liver function of the subjects, we divided them into a mild liver dysfunction group, a moderate liver dysfunction group and a normal liver function group. All subjects in three groups received a single oral dose of Prusogliptin 100-mg tablets. Pharmacokinetics and safety index collection was carried out before and after taking the drug. Plasma pharmacokinetics of Prusogliptin were evaluated, and geometric least- -squares mean (GLSM) and associated 90% confidence intervals for insufficient groups versus the control group were calculated for plasma exposures. RESULTS: After a single oral administration of 100 mg of Prusogliptin tablets, the exposure level of Prusogliptin in subjects with mild liver dysfunction was slightly higher than that in healthy subjects. The exposure level of Prusogliptin was significantly increased in subjects with moderate liver dysfunction. There were no adverse events in this study. CONCLUSION: The exposure level of Prusogliptin in subjects with liver dysfunction was higher than that in healthy subjects. No participant was observed of adverse events. Prusogliptin tablets were safe and well tolerated in Chinese subjects with mild to moderate liver dysfunction and normal liver function.

Pharmacokinetics, Pharmacodynamics, and Safety of Single Dose HSK7653 Tablets in Chinese Subjects with Normal or Impaired Renal Function.

OBJECTIVE: HSK7653 is a novel, ultralong-acting dipeptidyl peptidase-4 (DPP-4) inhibitor, promising for type 2 diabetes mellitus with a dosing regimen of once every 2 weeks. This trial investigates the pharmacokinetics (PKs), pharmacodynamics (PDs),and safety of HSK7653 in outpatients with normal or impaired renal function. METHODS: This is a multicenter, open-label, nonrandomized, parallel-controlled phase I clinical study that investigates the pharmacokinetic profiles of HSK7653 after a single oral administration in 42 subjects with mild (n = 8), moderate (n = 10), severe renal impairment (n = 10), and end-stage renal disease (without dialysis, n = 5) compared with matched control subjects with normal renal function (n = 9). Safety was evaluated throughout the study, and the pharmacodynamic effects were assessed on the basis of a DPP-4 inhibition rate. RESULTS: HSK7653 exposure levels including the maximum plasma concentration (Cmax), area under the plasma concentration-time curve from zero to last time of quantifiable concentration (AUC0-t), and area under the plasma concentration-time curve from zero to infinity (AUC0-inf) showed no significant differences related to the severity of renal impairment. Renal clearance (CLR) showed a certain downtrend along with the severity of renal impairment. The CLR of the group with severe renal impairment and the group with end-stage renal disease were basically similar. The DPP-4 inhibition rate-time curve graph was similar among the renal function groups. All groups had favorable safety, and no serious adverse events occurred. CONCLUSIONS: HSK7653 is a potent oral DPP-4 inhibitor with a long plasma half-life, supporting a dosing regimen of once every 2 weeks. Impaired renal function does not appear to impact the pharmacokinetic and pharmacodynamic properties of HSK7653 after a single administration in Chinese subjects. HSK7653 is also well tolerated without an increase in adverse events with increasing renal impairment. These results indicate that dose adjustment of HSK7653 may not be required in patients with renal impairment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05497297.

A Quantitative Systems Pharmacology Model of the Incretin Hormones GIP and GLP1, Glucagon, Glucose, Insulin, and the Small Molecule DPP-4 Inhibitor, Linagliptin.

In the current study, we established a comprehensive quantitative systems pharmacology (QSP) model using linagliptin as the model drug, where drug disposition, drug intervention on dipeptidyl peptidase-4 (DPP-4), glucose-dependent insulinotropic peptide (GIP), Glucagon-like peptide-1 (GLP-1), glucagon, glucose, and insulin are integrated together with the cross talk and feedback loops incorporated among the whole glycemic control system. In the final linagliptin QSP model, the complicated disposition of linagliptin was characterized by a 2-compartment pharmacokinetic (PK) model with an enterohepatic cycling (EHC) component as well as target-mediated drug disposition (TMDD) processes occurring in both tissues and plasma, and the inhibitory effect of linagliptin on DPP-4 was determined by the linagliptin-DPP-4 complex in the central compartment based on target occupancy principle. The integrated GIP-GLP1-glucagon-glucose-insulin system contains five indirect response models as the "skeleton" structure with 12 feedback loops incorporated within the glucose control system. Our model adequately characterized the substantial nonlinear PK of linagliptin, time course of DPP-4 inhibition, as well as the kinetics of GIP, GLP-1, glucagon, and glucose simultaneously in humans. Our model provided valuable insights on linagliptin pharmacokinetics/pharmacodynamics and complicated glucose homeostasis. Since the glucose regulation modeling framework within the QSP model is "drug-independent", our model can be easily adopted by others to evaluate the effect of other DPP-4 inhibitors on the glucose control system. In addition, our QSP model, which contains more components than other reported glucose regulation models, can potentially be used to evaluate the effect of combination antidiabetic therapy targeting different components of glucose control system.

A systematic review on the clinical pharmacokinetics of vildagliptin in healthy and disease populations.

INTRODUCTION: Vildagliptin, a dipeptidyl peptidase-4 inhibitor, is indicated to cure type 2 diabetes mellitus (T2DM). This systematic literature search aims to assess the current knowledge about the clinical pharmacokinetics (PK) of vildagliptin to provide recommendations for clinical use to prevent the harmful effects of this drug. METHODS: The PubMed, Science Direct, EBSCO, Cochrane Central Register of Controlled Trials, and Google Scholar databases were screened for articles related to the clinical PK of vildagliptin using systematic search strategies. RESULTS: The literature search identified 2118 records, among which 28 were subsumed in this systematic review that fulfilled the inclusion standards. CONCLUSIONS: This systematic review can help dose optimization among critically ill patients (e.g. renal impairment) without exposing them to the drug's toxic effects.

Dose decision of HSK7653 oral immediate release tablets in specific populations clinical trials based on mechanistic physiologically-based pharmacokinetic model.

HSK7653, an oral dipeptidyl peptidase-4 inhibitor administered every 2 weeks, is a candidate for the treatment of type 2 diabetes mellitus. The major elimination pathway of HSK7653 in vivo is renal excretion, and hepatic metabolism and fecal excretion of unchanged compound contribute less to the systemic clearance of HSK7653. Considering the disposition characteristics and the potential indication population of HSK7653, evaluating the HSK7653 exposure in patients with renal impairment and geriatric populations is a prerequisite for bringing more benefits to the patients. Here, a PBPK model was developed based on in vitro experimental results, such as dissolution, permeability, and metabolism, and the in vivo renal clearance, to evaluate the effects of physiological factors and food on HSK7653 exposure in specific populations, including adult and elder individuals with renal impairment and geriatric populations. Simulation results showed that the AUC of HSK7653 increased by 46%, 82%, and 129% in adult patients with mild, moderate, and severe renal impairment, and by 56%, 78%, and 101% in patients aged 65-75, 75-85 and 85-95 years, respectively. The AUC increased in the range of 62%-83%, 98%-133%, and 153%-195% in elderly patients (65-95 years) with mild, moderate, and severe renal impairment, respectively. Moreover, two different absorption model development methods (dissolution profile method and the diffusion layer model method) predicted that food had no effect on the exposure of the same simulated population. Since the predicted AUC of HSK7653 at the 10 mg dose in various specific populations was still within the relatively flat results of the exposure-response analysis, the 10 mg dose of HSK7653 was first used to explore the exposure in the renal impairment population (CTR20221952).

Mechanistic Study on the Effect of Renal Impairment on the Pharmacokinetics of Vildagliptin and its Carboxylic Acid Metabolite.

PURPOSE: To clarify the mechanism of renal impairment leading to different degrees of increased plasma exposure to dipeptidyl peptidase 4 inhibitor vildagliptin and its major metabolite, M20.7. METHODS: The 5/6 nephrectomized (5/6 Nx) rat model, to simulate chronic renal failure (CRF) patients, combined with kidney slices and transporter studies in vitro were used to assess this pharmacokinetic differences. RESULTS: After intragastric administration to 5/6 Nx rats, vildagliptin showed increased plasma levels by 45.8%, and M20.7 by 7.51 times, which was similar to patients with severe renal impairment. The recovery rate of M20.7 in urine and feces increased by less than 20%, showing limited effect of renal impairment on vildagliptin metabolism. In vitro studies found M20.7 to be the substrate for organic anion transporter 3 (OAT3). However, the active uptake of M20.7 in renal slices showed no difference between the 5/6 Nx and normal rats. In OAT3 overexpressed cells, the protein-bound uremic toxins, 3-carboxy-4-methyl-5propyl-2-furanpropionate (CMPF), hippuric acid (HA) and indoxyl sulfate (IS), which accumulate in CRF patients, inhibited M20.7 uptake with IC50 values of 5.75, 29.0 and 69.5 µM respectively, far lower than plasma concentrations in CRF patients, and showed a mixed inhibition type. CONCLUSIONS: The large increase in plasma exposure of M20.7 could be attributed to the accumulation of uremic toxins in CRF patients, which inhibited OAT3 activity and blocked renal excretion of M20.7, while vildagliptin, with high permeability, showed a slight increase in plasma exposure due to reduced glomerular filtration.

DBPR108, a novel dipeptidyl peptidase-4 inhibitor with antihyperglycemic activity.

AIMS: Dipeptidyl peptidase 4 (DPP-4) is a valid molecular drug target from which its inhibitors have been developed as medicines for treating diabetes. The present study evaluated a new synthetic DPP-4-specific inhibitor of small molecule DBPR108 for pharmacology and pharmacokinetic profiles. MAIN METHODS: DBPR108 of various doses was orally administered to rats, diabetic mice, and dogs and the systemic circulating DPP-4 activities in the animals were measured to demonstrate the pharmacological mechanisms of action via DPP-4 inhibition. Upon an oral administration of DBPR108, the serum active GLP-1 and insulin levels of the rats challenged with an oral glucose ingestion were measured. Oral glucose tolerance test in diet-induced obese mice was performed to examine if DBPR108 increases the glucose tolerability in animals. KEY FINDINGS: Orally administered DBPR108 inhibited the systemic plasma DPP-4 activities in rats, dogs and diabetic mice in a dose-dependent manner. DBPR108 caused elevated serum levels of active GLP-1 and insulin in the rats. DBPR108 dose-dependently increased the glucose tolerability in diet-induced obese (DIO) mice and, furthermore, DIO mice treated with DBPR108 (0.1 mg/kg) in combination with metformin (50 or 100 mg/kg) showed a prominently strong increase in the glucose tolerability. SIGNIFICANCE: DBPR108 is a novel DPP-4-selective inhibitor of small molecule that demonstrated potent in vivo pharmacological effects and good safety profiles in animals. DBPR108 is now a drug candidate being further developed in the clinical studies as therapeutics for treating diabetes.

Safety and pharmacokinetic interaction between fotagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin in healthy subjects.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors have significant clinical efficacy for type 2 diabetes mellitus (T2DM). The combination of fotagliptin (FOT) with metformin (MET) is a promising therapeutic approach in MET-resistant patients. The aim of the present study was to evaluate the pharmacokinetic (PK) interaction between FOT and MET in healthy subjects after multiple-dose administration. METHODS: Eighteen participants received a randomized open-label, three period treatment that included MET 1000 mg alone, co-administration of FOT 24 mg and MET, followed by FOT 24 mg alone. Serial blood samples were collected for PK analysis, which included geometric mean ratios (GMRs) with 90% confidence intervals (CIs), area under the concentration-time curve (AUC), and maximum plasma concentration (Cmax). RESULTS: Analysis results showed that for FOT alone or combination therapy, the 90% CIs of the GMR for AUC0-24,ss and Cmax,ss were 102.08% (98.9%, 105.36%) and 110.65% (102.19%, 119.82%), respectively. For MET, they were 113.41% (100.32%, 128.22%) and 97.11% (83.80%, 112.55%) for AUC0-12,ss and Cmax,ss, respectively. FOT or MET monotherapy and the combination therapy with both drugs were well tolerated. CONCLUSIONS: No PK drug-drug interactions were found in the combination therapy with FOT and MET. Therefore, FOT can be co-administered with MET without dose adjustment. TRIAL REGISTRATION: The trial is registered at http://www.chinadrugtrials.org.cn/(Registration No. CTR20190221).

Safety, Pharmacokinetics, and Pharmacodynamics of a Dipeptidyl Peptidase-4 Inhibitor: A Randomized, Double-Blinded, Placebo-Controlled Daily Administration of Fotagliptin Benzoate for 14 Days for Type 2 Diabetes Mellitus.

This study investigated the pharmacokinetics, pharmacodynamics, and safety of fotagliptin benzoate (fotagliptin), a dipeptidyl peptidase-4 (DPP-4) inhibitor, in Chinese patients with type 2 diabetes mellitus (T2DM). In a randomized, double-blinded, placebo-controlled study, 10 and 4 patients with T2DM were randomized and received, respectively, once-daily oral fotagliptin (24 mg) or placebo, for 14 days. The pharmacokinetics and pharmacodynamics were assessed throughout the study, including monitoring DPP-4, glucagon-like peptide-1 (GLP-1), glycosylated hemoglobin, and fasting blood glucose. Fotagliptin was rapidly absorbed, and the median time to maximum concentration value was ∼1.5 hours. Plasma fotagliptin levels were stable after 14 days of once-daily dosage. The accumulation ratios for the area under the plasma concentration-time curve of fotagliptin, M1, and M2-1, were 1.19 ± 0.10, 1.59 ± 0.27, and 1.39 ± 0.26, respectively. The durations for DPP-4 inhibition >80% in the fotagliptin group on days 1 and 14 were 23.5 and 24.0 hours, respectively. The concentrations of GLP-1 were higher on days 1 and 14 than at the baseline. No serious complications occurred. Fotagliptin showed favorable pharmacokinetics and pharmacodynamics and was well tolerated. Treatment with fotagliptin can achieve high DPP-4 inhibition and increase plasma GLP-1. A once-per-day dosing regimen may be recommended as clinically efficacious.

Development and validation of an ultrasensitive LC-MS/MS method for the quantification of cetagliptin in human plasma and its application in a microdose clinical trial.

This study established and validated an LC-MS/MS method for the ultrasensitive determination of cetagliptin in human plasma. Sample pretreatment was achieved by liquid-liquid extraction with ethyl acetate, and chromatographic separation was performed on an XB-C18 analytical column (50 × 2.1 mm, 5 µm) with gradient elution (0.1% formic acid in acetonitrile and 0.1% formic acid) at a flow rate of 1.0 mL/min. For mass spectrometric detection, multiple reaction monitoring was used, and the ion transitions monitored were m/z 421.2-86.0 for cetagliptin and m/z 424.2-88.0 for cetagliptin-d3. Method validation was performed according to the U.S. Food and Drug Administration Bioanalytical Method Validation Guidance, for which the calibration curve was linear in the range of 50.0-2000 pg/mL. All of the other results, such as selectivity, lower limit of quantitation, precision, accuracy, matrix effect, recovery, and stability, met the acceptance criteria. The validated method was successfully applied in a microdose clinical trial to systematically investigate the pharmacokinetic profile of cetagliptin in healthy subjects. Both rapid absorption and prolonged duration demonstrate the potential value of cetagliptin for diabetes treatment.

Pharmacokinetics of exogenous GIP(1-42) in C57Bl/6 mice; Extremely rapid degradation but marked variation between available assays.

Like other peptide hormones, glucose-dependent insulinotropic polypeptide (GIP) is rapidly cleared from the circulation. Dipeptidyl peptidase-4 (DPP-4) is known to be involved. Information on the overall pharmacokinetics of GIP in rodents is, however, lacking. We investigated the pharmacokinetics of exogenous GIP after intravenous, subcutaneous and intraperitoneal injection with and without DPP-4 inhibition in conscious female C57Bl/6 mice. Secondly, we compared total and intact GIP levels measured by an in-house RIA and commercially available ELISA kits to determine the suitability of these methods for in vivo and in vitro measurements. GIP half-life following intravenous injection amounted to 93 ± 2 s, which was extended to 5 ± 0.6 min by inhibition of DPP-4. Intact GIP levels following subcutaneous and intraperitoneal GIP administration were approximately 15 % of total GIP. The area under the curve of intact GIP (GIP exposure) following GIP injection was significantly increased by DPP-4 inhibition, whereas total GIP levels remained unchanged. We found significant variation between measurements of total, but not intact GIP performed with our in-house RIA and ELISAs in samples obtained after in vivo administration of GIP. Different preanalytical sample preparation (EDTA plasma, heparin plasma, assay buffer and PBS) significantly influenced results for all ELISA kits used. Thus, in experiments involving exogenous GIP(1-42) administration in mice, it is important to consider that this will result in a very low ratio of intact:total peptide but co-administration of a DPP-4 inhibitor greatly elevates this ratio. Furthermore, for comparison of GIP levels, it is essential to maintain uniformity concerning assay methodology and sample preparation.

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.

Dipeptidyl peptidase-4 inhibition to prevent progression of calcific aortic stenosis.

OBJECTIVE: To evaluate whether the use of dipeptidyl peptidase-4 (DPP-4) inhibitors and their cardiac tissue distribution profile and anticalcification abilities are associated with risk of aortic stenosis (AS) progression. METHODS: Out of the five different classes of DPP-4 inhibitors, two had relatively favourable heart to plasma concentration ratios and anticalcification ability in murine and in vitro experiments and were thus categorised as 'favourable'. We reviewed the medical records of 212 patients (72±8 years, 111 men) with diabetes and mild-to-moderate AS who underwent echocardiographic follow-up and classified them into those who received favourable DPP-4 inhibitors (n=28, 13%), unfavourable DPP-4 inhibitors (n=69, 33%) and those who did not receive DPP-4 inhibitors (n=115, 54%). RESULTS: Maximal transaortic velocity (Vmax) increased from 2.9±0.3 to 3.5±0.7 m/s during follow-up (median, 3.7 years), and the changes were not different between DPP-4 users as a whole and non-users (p=0.143). However, the favourable group showed significantly lower Vmax increase than the unfavourable or non-user group (p=0.018). Severe AS progression was less frequent in the favourable group (7.1%) than in the unfavourable (29.0%; p=0.03) or the non-user (29.6%; p=0.01) group. In Cox regression analysis after adjusting for age, baseline renal function and AS severity, the favourable group showed a significantly lower risk of severe AS progression (HR 0.116, 95% CI 0.024 to 0.551, p=0.007). CONCLUSIONS: DPP-4 inhibitors with favourable pharmacokinetic and pharmacodynamic properties were associated with lower risk of AS progression. These results should be considered in the preparation of randomised clinical trials on the repositioning of DPP-4 inhibitors.

In Silico ADMET Evaluation of Natural DPP-IV Inhibitors for Rational Drug Design against Diabetes.

BACKGROUND: As a metabolic and lifestyle disorder, diabetes mellitus poses a prodigious health risk. Out of the many key targets, DPP-IV is one of the very imperative therapeutic targets for the treatment of diabetic patients. METHODS: In our current study, we have done the in silico simulations of ADME-T properties for naturally originated potent DPP-IV inhibitors like quinovic acid, stigmasterol, quinovic acid-3-beta-D-glycopyranoside, zygophyloside E, and lupeol. Structural topographies associated with different pharmacokinetic properties have been systematically assessed. RESULTS: Glycosylation on quinovic acid is found to be noteworthy for the improvement of pharmacokinetic and toxicological properties, which leads to the prediction that zygophyloside E can be further tailored down to get the lead DPP-IV inhibitor. CONCLUSION: This assessment provides useful insight into the future development of novel drugs for the treatment of diabetes mellitus.