Mechanism-based population pharmacokinetic modelling in diabetes: vildagliptin as a tight binding inhibitor and substrate of dipeptidyl peptidase IV

AIMS

To assess the pharmacokinetics of vildagliptin at different doses and build a mechanism-based population model that simultaneously describes vildagliptin pharmacokinetics and its effects on DPP-4 activity based on underlying physiology and biology.

METHODS

Vildagliptin concentrations and DPP-4 activity vs. time from 13 type 2 diabetic patients after oral vildagliptin 10, 25 or 100 mg and placebo twice daily for 28 days were co-modelled. NONMEM VI and S-ADAPT were utilized for population modelling.

RESULTS

A target-mediated drug disposition (TMDD) model accounting for capacity-limited high affinity binding of vildagliptin to DPP-4 in plasma and tissues had good predictive performance. Modelling the full time course of the vildagliptin-DPP-4 interaction suggested parallel vildagliptin dissociation from DPP-4 by a slow first-order process and hydrolysis by DPP-4 to an inactive metabolite as a disposition mechanism. Due to limited amounts of DPP-4, vildagliptin concentrations increased slightly more than dose proportionally. This newly proposed model and the parameter estimates are supported by published in vitro studies. Mean parameter estimates (inter-individual coefficient of variation) were: non-saturable clearance 36 l h⁻¹ (25%), central volume of distribution 22 l (37%), half-life of dissociation from DPP-4 1.1 h (94%) and half-life of hydrolysis 6.3 h (81%).

CONCLUSIONS

Vildagliptin is both an inhibitor and substrate for DPP-4. By utilizing the TMDD approach, slow dissociation of vildagliptin from DPP-4 was found in patients and the half-life of hydrolysis by DPP-4 estimated. This model can be used to predict DPP-4 inhibition effects of other dosage regimens and be modified for other DPP-4 inhibitors to differentiate their properties.     

Hormonal and metabolic effects of morning or evening dosing of the dipeptidyl peptidase IV inhibitor vildagliptin in patients with type 2 diabetes

AIM

This randomized, double-blind, crossover study compared post-prandial hormonal and metabolic effects of vildagliptin, (an oral, potent, selective inhibitor of dipeptidyl peptidase IV [DPP-4]) administered morning or evening in patients with type 2 diabetes.

METHODS

Forty-eight patients were randomized to once daily vildagliptin 100 mg administered before breakfast or before dinner for 28 days then crossed over to the other dosing regimen. Blood was sampled frequently after each dose at baseline (day −1) and on days 28 and 56 to assess pharmacodynamic parameters.

RESULTS

Vildagliptin inhibited DPP-4 activity (>80% for 15.5 h post-dose), and increased active glucagon-like peptide-1 compared with placebo. Both regimens reduced total glucose exposure compared with placebo (area under the 0–24 h effect–time curve [AUE(0,24 h)]: morning −467 mg dl⁻¹ h, P = 0.014; evening −574 mg dl⁻¹ h, P = 0.003) with no difference between regimens (P = 0.430). Reductions in daytime glucose exposure (AUE(0,10.5 h)) were similar between regimens. Reduction in night-time exposure (AUE(10.5,24 h) was greater with evening than morning dosing (−336 vs. −218 mg dl⁻¹ h, P = 0.192). Only evening dosing significantly reduced fasting plasma glucose (−13 mg dl⁻¹, P = 0.032) compared with placebo. Insulin exposure was greater with evening dosing (evening 407 µU ml⁻¹ h; morning 354 µU ml⁻¹ h, P = 0.050).

CONCLUSIONS

Both morning and evening dosing of once daily vildagliptin 100 mg significantly reduced post-prandial glucose in patients with type 2 diabetes; only evening dosing significantly decreased fasting plasma glucose. Although evening dosing with vildagliptin 100 mg tended to decrease night-time glucose exposure more than morning dosing, both regimens were equally effective in reducing 24 h mean glucose exposure (AUE(0,24 h)) in patients with type 2 diabetes.     

Pharmacokinetics of lipoyl vildagliptin,a novel dipeptidyl peptidase IV inhibitor after oral administration in rats

1. The pharmacokinetics of lipoyl vildagliptin, a novel dipeptidyl peptidase IV (DPP IV) inhibitor, was studied in rats after oral administration for developing it as an antidiabetic agent.

2. A liquid chromatography-tandem mass spectroscopy (LC-MS/MS) method was developed to determine lipoyl vildagliptin in rat plasma. After an overnight fasting, rats were orally given lipoyl vildagliptin. Following a single oral dose of 25, 50, and 100?mg·kg^?1, T_max values were from 1.25 to 1.84?h, CL/F values were around 100?l h^?1 kg^?1. In the dose range, C_max values (63.9–296?μg·l^?1) and AUC_0–∞values (260–1214?μg·h·l^?1) were proportional to the doses.

3. In conclusion, this LC-MS/MS method for the determination of lipoyl vildagliptin in rat plasma was selective and sensitive. In rats, lipoyl vildagliptin displayed linear pharmacokinetics after a single oral dose in the range of 25–100?mg·kg^?1. Lipoyl vildagliptin might have very high CL/F values and V_d/F values, which indicated that the bioavailability of this drug might be low or lipoyl vildagliptin might distribute extensively or accumulate in tissues in view of its high liposolubility.

     

Dose proportionality and the effect of food on vildagliptin, a novel dipeptidyl peptidase IV inhibitor, in healthy volunteers

Vildagliptin is a potent and selective dipeptidyl peptidase IV inhibitor in development for the treatment of type 2 diabetes that improves glycemic control by enhancing alpha- and beta-cell responsiveness to glucose. Two open-label, single-dose, randomized, crossover studies in healthy subjects (ages 18-45 years) investigated the dose proportionality of vildagliptin pharmacokinetics (n = 20) and the effect of food (n = 24) on vildagliptin pharmacokinetics. There was a linear relationship (r(2) = 0.999) between vildagliptin doses of 25, 50, 100, and 200 mg and area under the plasma concentration-time curve from time zero to infinity (AUC(0-infinity)) and maximum plasma concentration (C(max)). Dose proportionality was assessed using a statistical power model [X = alpha x (dose)(beta)]. The 90% confidence intervals of the proportionality coefficient, beta, for AUC(0-infinity) (1.15-1.19) and C(max) (1.04-1.14) indicated that deviations from dose proportionality were small (<7.7%). Doubling of dose led to 2.1- to 2.3-fold increases in AUC(0-infinity) and C(max) but no dose-dependent changes in time to reach C(max) or terminal elimination half-life. Administration of vildagliptin 100 mg following a high-fat meal decreased C(max) by 19% and AUC(0-infinity) by 10%. Vildagliptin displays approximately dose-proportional pharmacokinetics over the 25- to 200-mg dose range, and administration with food has no clinically relevant effect on vildagliptin pharmacokinetics.     

Study of the pharmacokinetic interaction of vildagliptin and metformin in patients with type 2 diabetes*

ABSTRACT

Objective: Metformin is widely used for treating patients with type 2 diabetes, often as first-line therapy; however, many patients with type 2 diabetes are unable to maintain adequate glycemic control with metformin alone. Vildagliptin, an orally active, potent and selective dipeptidyl peptidase IV (DPP-4) inhibitor, may represent an appropriate antihyperglycemic agent for combination with metformin to improve glycemic control in such patients. This study assessed the effects of coadministration of vildagliptin and metformin on the steady-state pharmacokinetics of each drug.

Research design and methods: In this open-label, single-center, randomized, three-period, three-treatment crossover study, 17 patients with type 2 diabetes received vildagliptin 100?mg once daily; metformin 1000?mg once daily; or vildagliptin 100?mg once daily plus metformin 1000?mg once daily. Blood samples for pharmacokinetic sampling were taken frequently on the final day (Day 5) of each treatment period. Lack of pharmacokinetic interaction was defined as the ratio of geometric mean (GMR) and 90% confidence interval (CI) for combination:monotherapy being within the range 0.80–1.25.

Results: Coadministration with metformin had no effect on vildagliptin AUC_0–24 (GMR, 0.94; 90% CI 0.90, 0.99) although there was an 18% decrease in vildagliptin C_max (GMR 0.82; 90% CI 0.73, 0.91). Coadministration with vildagliptin had no effect on metformin C_max (GMR 1.04; 90% CI 0.94, 1.16). but caused a 15% increase in AUC_0–24 (GMR 1.15; 90% CI 1.06, 1.25). Both monotherapies and combination therapy were well tolerated. Seven patients reported a total of 10 adverse events; none was serious.

Conclusions: Coadministration of vildagliptin and metformin had a small effect on the pharmacokinetics of each drug in patients with type 2 diabetes; however, this is not likely to be clinically relevant. This small, open-label trial suggests that vildagliptin could be coadministered with metformin without any dose adjustment for either agent.     

Inhibition of dipeptidyl peptidase IV activity as a therapy of Type 2 diabetes

Dipeptidyl peptidase IV (DPP IV) is a ubiquitous, multifunctional, serine protease enzyme and receptor with roles in the control of endocrine and immune function, cell metabolism, growth and adhesion. As an enzyme, DPP IV cleaves the N-terminal dipeptide from the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. This inactivates the hormones, thereby cancelling their prandial insulinotropic effect. One approach to restore incretin activity as a therapy for Type 2 diabetes has been the development of DPP IV inhibitors. Inhibitors of DPP IV have shown efficacy and tolerability when used to control the hyperglycaemia of noninsulin-dependent animal models and human Type 2 diabetes. These DPP IV inhibitors prolong active incretin hormone concentrations and may exert additional antidiabetic effects. If long-term clinical trials confirm sustained and safe control of blood glucose, DPP IV inhibitors (known as ‘gliptins’) may be expected to provide a new treatment modality for Type 2 diabetes.     

Thorough QT study of the effects of vildagliptin,a dipeptidyl peptidase IV inhibitor,on cardiac repolarization and conduction in healthy volunteers

Abstract

Objective:

This randomized, double-blind study evaluated the effects of vildagliptin, a dipeptidyl peptidase IV inhibitor for treating type 2 diabetes, on cardiac repolarization and conduction.     

The influence of hepatic impairment on the pharmacokinetics of the dipeptidyl peptidase IV (DPP-4) inhibitor vildagliptin

Objective Vildagliptin is a potent and selective dipeptidyl peptidase-IV (DPP-4) inhibitor that improves glycemic control in patients with type 2 diabetes mellitus by increasing α- and β-cell responsiveness to glucose. This study investigated the pharmacokinetics of vildagliptin in patients with hepatic impairment compared with healthy subjects. Methods This was an open-label, parallel-group study in patients with mild (n = 6), moderate (n = 6) or severe (n = 4) hepatic impairment and healthy subjects (n = 6). All subjects received a single 100-mg oral dose of vildagliptin, and plasma concentrations of vildagliptin and its main pharmacologically inactive metabolite LAY151 were measured up to 36 h post-dose. Results Exposure to vildagliptin (AUC_0–∞ and C_max) decreased non-significantly by 20 and 30%, respectively, in patients with mild hepatic impairment [geometric mean ratio (90% CI): AUC_0–∞, 0.80 (0.60, 1.06), p = 0.192; C_max, 0.70 (0.46, 1.05), p = 0.149]. Exposure to vildagliptin was also decreased non-significantly in patients with moderate hepatic impairment [−8% for AUC_0–∞, geometric mean ratio (90% CI): 0.92 (0.69, 1.23), p = 0.630; −23% for C_max, geometric mean ratio (90% CI): 0.77 (0.51, 1.17), p = 0.293]. In patients with severe hepatic impairment, C_max was 6% lower than that in healthy subjects [geometric mean ratio (90% CI): 0.94 (0.59, 1.49), p = 0.285], whereas AUC_0–∞ was increased by 22% [geometric mean ratio (90% CI): 1.22 (0.89, 1.68), p = 0.816). Across the hepatic impairment groups, LAY151 AUC_0–∞ and C_max were increased by 29–84% and 24–63%, respectively, compared with healthy subjects. The single 100-mg oral dose of vildagliptin was well tolerated by patients with hepatic impairment. Conclusions There was no significant difference in exposure to vildagliptin in patients with mild, moderate or severe hepatic impairment; therefore, no dose adjustment of vildagliptin is necessary in patients with hepatic impairment.     

Effect of the novel oral dipeptidyl peptidase IV inhibitor vildagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects*

ABSTRACT

Objective: Vildagliptin is a potent and selective dipeptidyl peptidase?IV (DPP?4) inhibitor that improves glycemic control in patients with type 2 diabetes by increasing alpha and beta-cell responsiveness to glucose. This study assessed the effect of multiple doses of vildagliptin 100?mg once daily on warfarin pharmacokinetics and pharmacodynamics following a single 25?mg oral dose of warfarin sodium.

Research design and methods: Open-label, randomized, two-period, two-treatment crossover study in 16 healthy subjects.

Results: The geometric mean ratios (co-administration vs. administration alone) and 90% confidence intervals (CIs) for the area under the plasma concentration-time curve (AUC) of vildagliptin, R- and S?warfarin were 1.04 (0.98, 1.11), 1.00 (0.95, 1.04) and 0.97 (0.93, 1.01), respectively. The 90% CI of the ratios for vildagliptin, R- and S?warfarin maximum plasma concentration (C_max) were also within the equivalence range 0.80–1.25. Geometric mean ratios (co-administration vs. warfarin alone) of the maximum value and AUC for prothrombin time (PT_max, 1.00 [90% CI 0.97, 1.04]; AUC_PT, 0.99 [0.97, 1.01]) and international normalized ratios (INR_max, 1.01 [0.98, 1.05]; AUC_INR, 0.99 [0.97, 1.01]) were near unity with the 90% CI within the range 0.80–1.25. Vildagliptin was well tolerated alone or co-administered with warfarin; only one adverse event (upper respiratory tract infection in a subject receiving warfarin alone) was reported, which was judged not to be related to study medication.

Conclusions: Co-administration of warfarin with vilda­gliptin did not alter the pharmacokinetics and pharmaco­dynamics of R- or S?warfarin. The pharmacokinetics of vildagliptin were not affected by warfarin. No dosage adjustment of either warfarin or vildagliptin is necessary when these drugs are co-medicated.     

选择性二肽基肽酶抑制剂维格列汀与关节痛/骨关节炎发病风险相关性的系统评价

目的 系统评价选择性二肽基肽酶（DPP）-4抑制剂维格列汀与关节痛/骨关节炎发病风险的相关性。方法 利用计算机检索PubMed（1978.01-2016.02）、Cochrane Library（2015年第4期）、EMbase（1974.01-2016.02）、CBM（1978.01-2016.02）、CNKI（1978.01-2016.02）、VIP（1989.01-2016.02）的所有相关文献。根据Cochrane系统评价方法筛选维格列汀治疗2型糖尿病发生关节痛/骨关节炎的所有中、英文随机对照试验（RCT）,对纳入文献进行数据提取和质量评价后,采用RevMan 5.3软件进行荟萃（Meta）分析。结果 共纳入10篇文献。Meta分析结果显示：使用维格列汀与使用其他降糖药或安慰剂相比,发生关节痛/骨关节炎的风险更高,差异有统计学意义[RR=1.24,95% CI（1.08,1.44）,P=0.003]。进一步分析表明,各种剂量维格列汀组关节痛/骨关节炎的发病风险高于安慰剂组,差异有统计学意义[RR=1.35,95% CI（1.02,1.78）,P=0.04]。尤其50 mg,1次/d维格列汀致关节痛/骨关节炎的发病风险显著高于安慰剂组,差异有统计学意义[RR=3.04,95% CI（1.44,6.44）,P=0.004]。与其他降糖药比较,发现维格列汀组关节痛/骨关节炎的发病风险更高,差异有统计学意义[RR=1.19,95% CI（1.01,1.41）,P=0.04]。结论 维格列汀可增加关节痛/骨关节炎的发病风险。尤其50 mg,1次/d维格列汀可使关节痛/骨关节炎的发病风险增加2倍。但其远期的安全性还需进行更多大样本、高质量、长期随访的RCT加以验证。     

新型糖尿病治疗药物二肽基肽酶IV抑制药的研究进展

二肽基肽酶IV(DPP-IV)抑制药是治疗2型糖尿病的一类新型口服降糖药。DPP-IV抑制药能抑制DDP-IV活性,从而减少胰高糖素样肽1(GLP-1)、葡萄糖依赖性促胰岛素肽(GIP)等的降解,并在GLP-1及GIP的作用下,促进胰岛素的分泌,在有效降低血糖的同时还具有保护胰岛β细胞的功能。本文就该类药物的研究现状及应用前景进行综述。     

Metabolism and disposition of the dipeptidyl peptidase IV inhibitor teneligliptin in humans

Abstract

1. The absorption, metabolism and excretion of teneligliptin were investigated in healthy male subjects after a single oral dose of 20?mg [¹⁴C]teneligliptin.

2. Total plasma radioactivity reached the peak concentration at 1.33?h after administration and thereafter disappeared in a biphasic manner. By 216?h after administration, ≥90% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 45.4% and 46.5%, respectively.

3. The most abundant metabolite in plasma was a thiazolidine-1-oxide derivative (designated as M1), which accounted for 14.7% of the plasma AUC (area under the plasma concentration versus time curve) of the total radioactivity. The major components excreted in urine were teneligliptin and M1, accounting for 14.8% and 17.7% of the dose, respectively, by 120?h, whereas in faeces, teneligliptin was the major component (26.1% of the dose), followed by M1 (4.0%).

4. CYP3A4 and FMO3 are the major enzymes responsible for the metabolism of teneligliptin in humans.

5. This study indicates the involvement of renal excretion and multiple metabolic pathways in the elimination of teneligliptin from the human body. Teneligliptin is unlikely to cause conspicuous drug interactions or changes in its pharmacokinetics patients with renal or hepatic impairment, due to a balance in the elimination pathways.     

Discovery of JANUVIA (Sitagliptin), a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

The emergence of glucagon-like peptide 1 (GLP-1) as a well validated approach to the treatment of type 2 diabetes and preclinical validation of dipeptidyl peptidase IV (DPP-4) inhibition as an alternate, oral approach to GLP-1 therapy prompted the initiation of a DPP-4 inhibitor program at Merck in 1999. DPP-4 inhibitors threo- and allo-isoleucyl thiazolidide were in-licensed to jump start the program; however, development was discontinued due to profound toxicity in rat and dog safety studies. The observation that both compounds inhibit the related proline peptidases DPP8 and DPP9 led to the hypothesis that inhibition of DPP8 and/or DPP9 could evoke severe toxicities in preclinical species. Indeed, the observed toxicities were recapitulated with a selective dual DPP8/9 inhibitor but not with an inhibitor selective for DPP-4. Thus, medicinal chemistry efforts focused on identifying a highly selective DPP-4 inibitor for clinical development. Initial work in an alpha-amino acid series related to isoleucyl thiazolidide was discontinued due to lack of selectivity; however, SAR studies on two screening leads led to the identification of a highly selective beta-amino acid piperazine series. In an effort to stabilize the piperazine moiety, which was extensively metabolized in vivo, a series of bicyclic derivatives were prepared, culminating in the identification of a potent and selective triazolopiperazine series. Unlike their monocyclic counterparts, these analogs typically showed excellent pharmacokinetic properties in preclinical species. Optimization of this series led to the discovery of JANUVIA (sitagliptin), a highly selective DPP-4 inhibitor for the treatment of type 2 diabetes.     

Evaluation of the pharmacodynamic and pharmacokinetic interaction between calcium antagonists and digoxin

Therapeutic uses of calcium antagonists have expanded to include not only ischemic heart disease but arrhythmias, systemic hypertension, congestive heart failure, and various pulmonary and gastrointestinal diseases. Many patients receiving a calcium antagonist concomitantly receive digoxin. Although the potential interaction between these agents has frequently been investigated, literature reports are confusing and inconsistent. We summarized the pharmacodynamics, pharmacokinetics, and mechanisms of interaction to help clinicians evaluate the potential calcium antagonist-digoxin interaction.     

Vildagliptin, a novel dipeptidyl peptidase IV inhibitor, has no pharmacokinetic interactions with the antihypertensive agents amlodipine, valsartan, and ramipril in healthy subjects

We conducted 3 open-label, multiple-dose, 3-period, randomized, crossover studies in healthy subjects to assess the potential pharmacokinetic interaction between vildagliptin, a novel dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes, and representatives of 3 commonly prescribed antihypertensive drug classes: (1) the calcium channel blocker, amlodipine; (2) the angiotensin receptor blocker, valsartan; and (3) the angiotensin-converting enzyme inhibitor, ramipril. Coadministration of vildagliptin 100 mg with amlodipine 5 mg, valsartan 320 mg, or ramipril 5 mg had no clinically significant effect on the pharmacokinetics of these drugs. The 90% confidence intervals of the geometric mean ratios for area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24h) and maximum plasma concentration (Cmax) for vildagliptin, amlodipine, and ramipril (and its active metabolite, ramiprilat) were contained within the acceptance range for bioequivalence (0.80-1.25). Valsartan AUC0-24h and Cmax increased by 24% and 14%, respectively, following coadministration of vildagliptin, but this was not considered clinically significant. Vildagliptin was generally well tolerated when given alone or in combination with amlodipine, valsartan, or ramipril in healthy subjects at steady state. No adjustment in dosage based on pharmacokinetic considerations is required should vildagliptin be coadministered with amlodipine, valsartan, or ramipril in patients with type 2 diabetes and hypertension.     

Long-term safety of pioglitazone versus glyburide in patients with recently diagnosed type 2 diabetes mellitus

STUDY OBJECTIVE: To evaluate the long-term safety and efficacy of glyburide versus pioglitazone in patients with a recent diagnosis of type 2 diabetes mellitus. DESIGN: Prospective, randomized, multicenter, double-blind trial with a 16-week titration period and a 40-week maintenance period. SETTING: Sixty-five investigative sites in the United States and Puerto Rico. PATIENTS: Five hundred two subjects with a recent diagnosis of type 2 diabetes that was unsuccessfully treated with diet and exercise were randomly assigned to study treatment. Of the 251 patients in each treatment group, 128 (51.0%) glyburide-treated patients and 134 (53.4%) pioglitazone-treated patients completed the study. INTERVENTIONS: Dosages of randomly assigned glyburide and pioglitazone were titrated every 4 weeks for 16 weeks in 5-mg/day and 15-mg/day increments, respectively, until a fasting plasma glucose level between 69 and 141 mg/dl was achieved. The optimized regimen was maintained during the subsequent 40-week double-blind phase. MEASUREMENTS AND MAIN RESULTS: At week 56, glyburide and pioglitazone improved glucose control comparably (change in hemoglobin A(1c) -2.02% and -2.07%, respectively, p=0.669). Withdrawal due to lack of efficacy or adverse events occurred more frequently with glyburide (20.8%) than pioglitazone (12.8%, p<0.032). Significantly higher percentages of glyburide- than pioglitazone-treated patients had a hypoglycemic (24.3% vs 4.4%, p=0.0001) or cardiac (8.8% vs 4.4%, p=0.0478) event. Edema (4.8% vs 7.9%, p=0.1443) and weight gain (4.4% vs 4.0%, p=0.8238) did not differ significantly between the glyburide and pioglitazone groups. Only a few patients discontinued study drug because of weight gain (one glyburide, one pioglitazone), edema (one pioglitazone), or a cardiac event (two glyburide). CONCLUSION: With long-term treatment, both glyburide and pioglitazone resulted in comparable glycemic control; however, pioglitazone was associated with less hypoglycemia and fewer withdrawals due to lack of efficacy or adverse events.