Plasma Dipeptidyl Peptidase-4 Inhibition Research Articles

Pharmacokinetic-pharmacodynamic (dipeptidyl peptidase-4 inhibition) model to support dose rationale in diabetes patients, including those with renal impairment, for once-weekly administered omarigliptin.

To characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of the once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor omarigliptin in healthy subjects and patients with type 2 diabetes mellitus, and use these models to support the dosing recommendation for patient labelling including patients with renal impairment. PK and PD were assessed from a total of 9827 omarigliptin concentrations collected from 1387 healthy subjects and patients participating in Phase 1, 2 and 3 studies examining single- or multiple-dose weekly administration of omarigliptin at doses ranging from 0.25 to 400 mg. Population PK and PD analyses were performed using nonlinear mixed effect modelling. A semi-mechanistic 2-compartment model with linear unbound clearance and concentration-dependent binding of omarigliptin to the DPP-4 enzyme in both the central and peripheral compartments adequately described omarigliptin PK. Key covariates on omarigliptin PK included reduced unbound clearance with renal impairment. A direct effect sigmoid maximum inhibitory efficacy model adequately described the relationship between omarigliptin plasma concentrations and DPP-4 inhibition. These models supported the current Japan label instructions that the approved omarigliptin 25-mg once-weekly dose be halved in patients with severe renal impairment and in those with end-stage renal disease. Also, if patients missed a dose, the next dose of omarigliptin should be taken as soon as remembered up to and including the day before the next scheduled dose. No other clinically important covariates were identified. The models in the present analysis adequately described PK and PD characteristics of omarigliptin and supported the dosing and administration section of the omarigliptin label.

Contribution of intestinal dipeptidyl peptidase-4 inhibition for incretin-dependent improved glucose tolerance in mice

Dipeptidyl peptidase-4 (DPP-4) inhibitors prevent the degradation of glucagon-like peptide-1 (GLP-1) and improve glycemic control. The GLP-1 insulinotropic effect involves a pathway through vagus nerve GLP-1 receptors in the gut, in addition to a direct effect on the pancreas. Therefore, this study verified whether DPP-4 inhibition in the gut contributed to the improvement of glycemic control. Anagliptin, a DPP-4 inhibitor, was administered orally or subcutaneously (with or without passing through the gastrointestinal tract, respectively) to mice. The association between blood glucose suppression following oral glucose challenge and DPP-4 inhibition in the small intestine and plasma was assessed. Oral administration of anagliptin (0.03–0.3 mg/kg) in normal mice significantly suppressed blood glucose, which was associated with an increase in insulin secretion at a dose of ≥0.1 mg/kg (P < 0.05). Subcutaneous administration of anagliptin (0.01–0.1 mg/kg) produced similar results. However, plasma DPP-4 inhibition following oral administration was weaker than that following subcutaneous administration; blood glucose suppression was significantly correlated with small intestinal DPP-4 inhibition (r = 0.949, P < 0.01), but not with plasma DPP-4 inhibition. Additionally, similar results were observed in a type 2 diabetes model (r = 0.975, P < 0.001). Thus, these results demonstrated that an improvement in glycemic control was dependent upon small intestinal DPP-4 inhibition. As these effects were accompanied by the elevation of intact GLP-1 in the portal, this suggests that improvement in glucose tolerance after anagliptin treatment might be related to an increase in GLP-1 receptor signaling in the small intestine and portal vein.

Beneficial Effects of Evogliptin, a Novel Dipeptidyl Peptidase 4 Inhibitor, on Adiposity with Increased Ppargc1a in White Adipose Tissue in Obese Mice.

Although dipeptidyl peptidase 4 (DPP4) is an adipokine known to positively correlate with adiposity, the effects of pharmacological DPP4 inhibition on body composition have not been fully understood. This study was aimed to assess the effects of DPP4 inhibitors on adiposity for the first time in the established obese mice model. The weight loss effects of multiple DPP4 inhibitors were compared after a 4 week treatment in diet-induced obese mice. In addition, a 2 week study was performed to explore and compare the acute effects of evogliptin, a novel DPP4 inhibitor, and exenatide, a glucagon-like peptide-1 (GLP-1) analogue, on whole body composition, energy consumption, various plasma adipokines and gene expression in white adipose tissue (WAT). After the 4 week treatment, weight loss and blood glucose reductions were consistently observed with multiple DPP4 inhibitors. Moreover, after 2-week treatment, evogliptin dose-dependently reduced whole body fat mass while increasing the proportion of smaller adipocytes. However, insulin sensitivity or plasma lipid levels were not significantly altered. In addition to increased active GLP-1 levels by plasma DPP4 inhibition, evogliptin also enhanced basal metabolic rate without reduction in caloric intake, in contrast to exenatide; this finding suggested evogliptin's effects may be mediated by pathways other than via GLP-1. Evogliptin treatment also differentially increased Ppargc1a expression, a key metabolic regulator, in WAT, but not in skeletal muscle and brown adipose tissue. The increased expression of the downstream mitochondrial gene, Cox4i1, was also suggestive of the potential metabolic alteration in WAT by DPP4 inhibitors. We are the first to demonstrate that pharmacological DPP4 inhibition by evogliptin directly causes fat loss in established obese mice. In contradistinction to exenatide, the fat-loss effect of DPP4 inhibitor is partly attributed to enhanced energy expenditure along with metabolic changes in WAT. These results provide insight into the regulation of energy storage in WAT caused by DPP4 inhibition.

A novel, potent, and long-lasting dipeptidyl peptidase-4 inhibitor, teneligliptin, improves postprandial hyperglycemia and dyslipidemia after single and repeated administrations

Dipeptidyl peptidase-4 (DPP-4) inhibitors have been demonstrated to improve glycemic control, in particular postprandial hyperglycemic control, in patients with type 2 diabetes. Teneligliptin is a novel chemotype prolylthiazolidine-based DPP-4 inhibitor. The present study aimed to characterize the pharmacological profiles of teneligliptin in vitro and in vivo. Teneligliptin competitively inhibited human plasma, rat plasma, and human recombinant DPP-4 in vitro, with IC50 values of approximately 1nmol/l. Oral administration of teneligliptin in Wistar rats resulted in the inhibition of plasma DPP-4 with an ED50 of 0.41mg/kg. Plasma DPP-4 inhibition was sustained even at 24h after administration of teneligliptin. An oral carbohydrate-loading test in Zucker fatty rats showed that teneligliptin at ≥0.1mg/kg increased the maximum increase in plasma glucagon-like peptide-1 and insulin levels, and reduced glucose excursions. This effect was observed over 12h after a dose of 1mg/kg. An oral fat-loading test in Zucker fatty rats also showed that teneligliptin at 1mg/kg reduced triglyceride and free fatty acid excursions. In Zucker fatty rats, repeated administration of teneligliptin for two weeks reduced glucose excursions in the oral carbohydrate-loading test and decreased the plasma levels of triglycerides and free fatty acids under non-fasting conditions. The present studies indicate that teneligliptin is a potent, competitive, and long-lasting DPP-4 inhibitor that improves postprandial hyperglycemia and dyslipidemia by both single and repeated administrations.

Pharmacokinetics of linagliptin in subjects with hepatic impairment

• Linagliptin is an oral, highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that was approved in the United States, Europe and elsewhere in 2011 for the treatment of type 2 diabetes mellitus. • The elimination of linagliptin is primarily non-renal. Therefore, a potential effect of hepatic impairment on the elimination of linagliptin may have important implications for dosing recommendations. • This study shows that mild, moderate or severe hepatic impairment did not result in an increase in linagliptin exposure after single and multiple dosing as compared with normal hepatic function. • No linagliptin dose adjustment is required in patients with any degree of hepatic impairment. To investigate whether hepatic impairment affects linagliptin pharmacokinetics, pharmacodynamics and tolerability. This open label, parallel group, single centre study enrolled patients with mild (n= 8), moderate (n= 9) or severe (n= 8) hepatic impairment and healthy subjects (n= 8). Groups were matched with regard to age, weight and gender. Primary endpoints were linagliptin exposure following 5 mg linagliptin once daily for 7 days in patients with mild and moderate hepatic impairment vs. healthy subjects or after a single 5 mg dose for patients with severe hepatic impairment vs. healthy subjects. In mild hepatic impairment, steady-state linagliptin exposure was slightly lower than in healthy subjects [AUC(τ,ss) geometric mean ratio (GMR) 75.5%, 90% confidence interval (CI) 61.6%, 92.5%, and C(max,ss) GMR 64.4%, 90% CI 43.2%, 96.0%]. Exposure also tended to be lower in moderate hepatic impairment (AUC(τ,ss) GMR 85.5%, 90% CI 70.2%, 104.2% and C(max,ss) GMR 92.3%, 90% CI 62.8%, 135.6%). After a single dose, AUC(0,24 h) in patients with severe hepatic impairment was similar to that in healthy subjects (GMR 100.4%, 90% CI 75.0%, 134.3%) and C(max) was lower (GMR 77.0%, 90% CI 44.9%, 132.3%). Accumulation based on AUC or C(max) and renal excretion of unchanged linagliptin (≤ 7%) were comparable across groups. Median plasma DPP-4 inhibition was similar in healthy subjects (91%), and patients with mild (90%) and moderate (89%) hepatic impairment at steady-state trough concentrations, and in patients with severe hepatic impairment 24 h after a single dose (84%). Linagliptin was well tolerated. Mild, moderate or severe hepatic impairment did not result in an increase in linagliptin exposure after single and multiple dosing compared with normal hepatic function. Dose adjustment with linagliptin is not required in patients with hepatic impairment.

The concentration-dependent binding of linagliptin (BI 1356) and its implication on efficacy and safety

Linagliptin (BI 1356) is a dipeptidyl peptidase-4 (DPP-4) inhibitor for treatment of Type 2 diabetes which recently gained approval in the US, Europe, and Japan. Linagliptin showed nonlinear pharmacokinetics after intravenous and oral administration, which is due to a concentration-dependent protein binding of linagliptin to its target enzyme DPP-4. The aim of this analysis was to investigate this target-mediated binding of linagliptin and its implication on efficacy and safety. Pharmacokinetic modeling and simulations were performed using a two-compartment model with concentration-dependent binding in the central and in one peripheral compartment. The optimum therapeutic dose with minimal off-target side effects was simulated assuming that an antidiabetic effect of linagliptin was due to the linagliptin concentration bound to DPP-4 and that off-target side effects were related to free linagliptin. The difference between steady state AUCs of specifically bound and free linagliptin was maximized at oral doses of 2 - 5 mg. Since plasma DPP-4 inhibition increased slightly from 2.5 to 10 mg, pharmacokinetic simulations and the pharmacodynamic measurements taken together suggest that 5 mg linagliptin could be considered an optimum dose. Simulations with missed doses and additional doses at steady state showed the effect on DPP-4 bound linagliptin and change in DPP-4 inhibition was minimal after missing one 5 mg oral dose of linagliptin while two doses of 5 mg linagliptin resulted in a less than proportional increase of steady state AUC of free linagliptin. Results from modeling and simulation support a stable antidiabetic effect of linagliptin over 24 h at steady state and further indicate a low risk for off-target side effects.

Evaluation of pharmacokinetic parameters and dipeptidyl peptidase‐4 inhibition following single doses of sitagliptin in healthy, young Japanese males

Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 (DPP-4) used to treat type 2 diabetes. The present aim was to evaluate pharmacokinetic (PK), pharmacodynamic (PD) and safety characteristics of sitagliptin following single doses in healthy, young Japanese males. In this alternating two-panel, randomized, controlled double-blind study, six healthy Japanese male subjects (aged 20-46 years) in each panel received single oral doses of 5-400mg sitagliptin and two received placebo. Plasma and urine drug concentrations were measured from 0-48h post dose and plasma DPP-4 inhibition from 0-24h post dose. The results were compared with historical data from young, healthy non-Japanese males. Plasma concentrations of sitagliptin increased approximately in proportion to dose; maximum concentrations occurred 2-6h post-dose. The mean apparent terminal half-life for plasma sitagliptin was 9-14h, with the half-life slightly decreasing as the dose increased. The mean dose fraction excreted unchanged in the urine was 0.73-1.00. Ingestion of a traditional Japanese breakfast prior to dosing had only a minor effect on PK parameters. After correction for dilution and competition effects during assay, doses of sitagliptin ≥50mg resulted in weighted average DPP-4 inhibition from 0-24h post-dose >94% (without correction, >78%). No clinically meaningful differences in PK and DPP-4 inhibition parameters were found between Japanese and non-Japanese subjects. Sitagliptin was generally well tolerated and there were no serious adverse experiences or episodes of hypoglycaemia. The PK and PD findings from this study are consistent with once daily dosing of sitagliptin in Japanese patients with type 2 diabetes.

Sitagliptin 100 mg daily effect on DPP-4 inhibition and compound-specific glycemic improvement

Objective:In clinical trials, the degree of glucose lowering with sitagliptin has been correlated with the magnitude of dipeptidyl peptidase-4 (DPP-4) inhibition over 24 h. Previous studies evaluating sitagliptin doses ranging from 25 to 200 mg/day demonstrated that the daily dose of 100 mg provided maximal glucose-lowering efficacy for this compound in patients with type 2 diabetes. However, sitagliptin 200 mg once daily provided numerically greater percent plasma DPP-4 inhibition compared with 100 mg once daily. The purpose of this study was to evaluate whether sitagliptin 200 mg once daily provides greater improvement in glycemic efficacy as assessed by weighted mean glucose (WMG) over 24 h relative to sitagliptin 100 mg once daily and to relate the percent DPP-4 inhibition achieved with these doses to any between-treatment differences in glycemic efficacy.Methods:In a double-blind crossover study, patients with type 2 diabetes (fasting plasma glucose [FPG] 130–250 mg/dL) were randomized to one of six treatment sequences over three treatment periods (placebo, sitagliptin 100 mg once daily, or sitagliptin 200 mg once daily). Each of the treatment periods was 7 days in duration, with 28-day washout periods between treatments. After each treatment period, patients underwent blood sampling at various time points over 24 h to determine 24-h WMG. Plasma DPP-4 activity was assessed at trough, 24 h following dosing on day 7; percent DPP-4 inhibition was corrected for sample assay dilution.Results:The 103 randomized patients had a baseline mean FPG of 172 mg/dL. Following a planned interim analysis, the study was stopped because the 24-h WMG values were not different between the sitagliptin doses. Furthermore, a significant carryover effect across periods was observed for FPG; thus, efficacy results from period 1 are presented herein. The 24-h WMG values were significantly (p < 0.01) lower with sitagliptin relative to placebo, but the difference between sitagliptin doses was not significant (p = 0.365). Corrected percent plasma DPP-4 inhibition at trough was not significantly (p = 0.791) different with sitagliptin 200 mg (LS mean [95% CI] 96.9% [90.0, 100.0]) compared with sitagliptin 100 mg (95.6% [88.4, 100.0]). The early termination and the carryover effect described above are limitations to this study.Conclusion:Across sitagliptin doses in this study, the similarity of the 24-h WMG concentrations and the similarity of the corrected DPP-4 inhibition values support prior findings that the maximal glucose-lowering efficacy of sitagliptin is achieved with once-daily dosing of 100 mg.Clinicaltrials.gov: NCT00541229

Pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel inhibitor of dipeptidyl peptidase-4, in rats, dogs, and monkeys

The aim of the present research was to characterize the pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel quinazolinone-based dipeptidyl peptidase-4 (DPP-4) inhibitor. Alogliptin potently inhibited human DPP-4 in vitro (mean IC50, ~ 6.9 nM) and exhibited > 10,000-fold selectivity for DPP-4 over the closely related serine proteases DPP-2, DPP-8, DPP-9, fibroblast activation protein/seprase, prolyl endopeptidase, and tryptase (IC50 > 100,000 nM). Absolute oral bioavailability of alogliptin in rats, dogs, and monkeys was 45%, 86%, and 72% to 88%, respectively. After a single oral dose of alogliptin, plasma DPP-4 inhibition was observed within 15 min and maximum inhibition was > 90% in rats, dogs, and monkeys; inhibition was sustained for 12 h in rats (43%) and dogs (65%) and 24 h in monkeys (> 80%). From Emax modeling, 50% inhibition of DPP-4 activity was observed at a mean alogliptin plasma concentration (EC50) of 3.4 to 5.6 ng/ml (10.0 to 16.5 nM) in rats, dogs, and monkeys. In Zucker fa/fa rats, a single dose of alogliptin (0.3, 1, 3, and 10 mg/kg) inhibited plasma DPP-4 (91% to 100% at 2 h and 20% to 66% at 24 h), increased plasma GLP-1 (2- to 3-fold increase in AUC0–20 min) and increased early-phase insulin secretion (1.5- to 2.6-fold increase in AUC0–20 min) and reduced blood glucose excursion (31%–67% decrease in AUC0–90 min) after oral glucose challenge. Alogliptin (30 and 100 mg/kg) had no effect on fasting plasma glucose in normoglycemic rats. In summary, these data suggest that alogliptin is a potent and highly selective DPP-4 inhibitor with demonstrated efficacy in Zucker fa/fa rats and potential for once-daily dosing in humans.

Chronic administration of alogliptin, a novel, potent, and highly selective dipeptidyl peptidase-4 inhibitor, improves glycemic control and beta-cell function in obese diabetic ob/ob mice

Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes by increasing plasma active glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide levels. However, the effects of chronic DPP-4 inhibition on in vivo beta-cell function are poorly characterized. We thus evaluated the chronic effects of the DPP-4 inhibitor alogliptin benzoate (formerly SYR-322) on metabolic control and beta-cell function in obese diabetic ob/ob mice. Alogliptin (0.002%, 0.01%, or 0.03%) was administered in the diet to ob/ob mice for 2 days to determine effects on plasma DPP-4 activity and active GLP-1 levels and for 4 weeks to determine chronic effects on metabolic control and beta-cell function. After 2 days, alogliptin dose-dependently inhibited DPP-4 activity by 28–82% and increased active GLP-1 by 3.2–6.4-fold. After 4 weeks, alogliptin dose-dependently decreased glycosylated hemoglobin by 0.4–0.9%, plasma glucose by 7–28% and plasma triglycerides by 24–51%, increased plasma insulin by 1.5–2.0-fold, and decreased plasma glucagon by 23–26%, with neutral effects on body weight and food consumption. In addition, after drug washout, alogliptin (0.03% dose) increased early-phase insulin secretion by 2.4-fold and improved oral meal tolerance (25% decrease in glucose area under the concentration–time curve), despite the lack of measurable plasma DPP-4 inhibition. Importantly, alogliptin also increased pancreatic insulin content up to 2.5-fold, and induced intense insulin staining of islets, suggestive of improved beta-cell function. In conclusion, chronic treatment with alogliptin improved glycemic control, decreased triglycerides, and improved beta-cell function in ob/ob mice, and may exhibit similar effects in patients with type 2 diabetes.

Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor alogliptin: A randomized, double-blind, placebo-controlled, multiple-dose study in adult patients with type 2 diabetes

Background: Alogliptin is a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes (T2D). Objectives: This study was conducted to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles and explore the efficacy of multiple oral doses of alogliptin in patients with T2D. Methods: In this randomized, double-blind, placebo-controlled, parallel-group study, patients with T2D between the ages of 18 and 75 years were assigned to receive a single oral dose of alogliptin 25, 100, or 400 mg or placebo (4:4:4:3 ratio) once daily for 14 days. PK profiles and plasma DPP-4 inhibition were assessed on days 1 and 14. Tolerability was monitored based on adverse events (AEs) and clinical assessments. Efficacy end points included 4-hour postprandial plasma glucose (PPG) and insulin concentrations, and fasting glycosylated hemoglobin (HbA 1c), C-peptide, and fructosamine values. Results: Of 56 enrolled patients (57% women; 93% white; mean age, 55.6 years; mean weight, 89.8 kg; mean body mass index, 31.7 kg/m 2), 54 completed the study. On day 14, the median T max was ~1 hour and the mean t 1/2 was 12.5 to 21.1 hours across all alogliptin doses. Alogliptin was primarily excreted renally (mean fraction of drug excreted in urine from 0 to 72 hours after dosing, 60.8%-63.4%). On day 14, mean peak DPP-4 inhibition ranged from 94% to 99%, and mean inhibition at 24 hours after dosing ranged from 82% to 97% across all alogliptin doses. Significant decreases from baseline to day 14 were observed in mean 4-hour PPG after breakfast with alogliptin 25 mg (-32.5 mg/dL; P = 0.008), 100 mg (-37.2; P = 0.002), and 400 mg (-65.6 mg/dL; P < 0.001) compared with placebo (+8.2 mg/dL). Significant decreases in mean 4-hour PPG were also observed for alogliptin 25, 100, and 400 mg compared with placebo after lunch (-15.8 mg/dL [ P = 0.030]; -29.2 mg/dL [ P = 0.002]; -27.1 mg/dL [ P = 0.009]; and +14.3 mg/dL, respectively) and after dinner (-21.9 mg/dL [ P = 0.017]; -39.7 mg/dL [ P < 0.001]; -35.3 mg/dL [ P = 0.003]; and +12.8 mg/dL). Significant decreases in mean HbA 1c from baseline to day 15 were observed for alogliptin 25 mg (-0.22%; P = 0.044), 100 mg (-0.40%; P < 0.001), and 400 mg (-0.28%; P = 0.018) compared with placebo (+0.05%). Significant decreases in mean fructosamine concentrations from baseline to day 15 were observed for alogliptin 100 mg (-25.6 μmol/L; P = 0.001) and 400 mg (-19.9 μmol/L; P = 0.010) compared with placebo (+15.0 μmol/L). No statistically significant changes were noted in mean 4-hour postprandial insulin or mean fasting C-peptide. No serious AEs were reported, and no patients discontinued the study because of an AE. The most commonly reported AEs for alogliptin 400 mg were headache in 6 of 16 patients (compared with 0/15 for alogliptin 25 mg, 1/14 for alogliptin 100 mg, and 3/11 for placebo), dizziness in 4 of 16 patients (compared with 1/15, 2/14, and 1/11, respectively), and constipation in 3 of 16 patients (compared with no patients in any other group). No other individual AE was reported by >2 patients receiving the 400-mg dose. Apart from dizziness, no individual AE was reported by >1 patient receiving either the 25- or 100-mg dose. Conclusions: In these adult patients with T2D, alogliptin inhibited plasma DPP-4 activity and significantly decreased PPG levels. The PK and PD profiles of multiple doses of alogliptin in this study supported use of a once-daily dosing regimen. Alogliptin was generally well tolerated, with no dose-limiting toxicity.

Pharmacokinetics, pharmacodynamics, and tolerability of single increasing doses of the dipeptidyl peptidase-4 inhibitor alogliptin in healthy male subjects

Background: Alogliptin is a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes. Objective: This study was conducted to characterize the pharmacokinetics, pharmacodynamics, and tolerability of single oral doses of alogliptin in healthy male subjects. Methods: This was a randomized, double-blinnd, placebo-controlled study in which healthy, nonobese male suubjects between the ages of 18 and 55 years were assigned to 1 of 6 cohorts: alogliptin 25, 50, 100, 200, 400, or 800 mg. One subject in each cohort received placebo. An ascending-dose strategy was used, in which each cohort received its assigned dose only after review of the safety data from the previous cohort. Blood and urine were collected over 72 hours after dosing for pharmacokinetic analysis and determination of plasma DPP-4 inhibition and active glucagon-like peptide -1(GLP-1) concentrations. Results: Thirty-six subjects (66 per cohort) were enrolled and completed the study (29/36 [81% ] white; mean age, 26.6 years; mean weight, 76.00 kg)..Alogliptin was rapidly absorbed (median T max, 1-2 hours) and eliminated slowly (mean t 1/2, 12.4-21.4 hours), primarily via urinary excretion (mean fraction of drug excreted in urine from 0 to 72 hours after dosing, 60%--71%). C max and AUC 0-∞ increased dose proportionally over the range from 25 to 100 mg. The metabolites M-I ( N-demethylated) and M-II ( N-acetylated) accounted for <2% and <6%, respectively, of alogliptin concentrations in plasma and urine. Across alogliptin doses, mean peak DPP-4 inhibition ranged from 93% to 99%, and mean inhibition at 24 hours after dosing ranged from 74% to 97%. Exposure to active GLP-1 was 2- to 4-fold greater for all alogliptin doses compared with placebo; no dose response was apparent. Hypoglycemia (asymptom matic) was reported in 5 subjects (11 receiving alogliptin 50 mg, 2 receiving alogliptin 200 mg, 1 receiving alogliptin 400 mg, 1 receiving placebo). Other adverse events were reported in 1 subject each: dizziness (alogliptin 100 mg), syncope (alogliptin 200 mg), constipation (alogliptin 200 mg), viral infection (alogliptin 400 mg), hot flush (placebo), and nausea (placebo). Conclusion: In these healthy male subjects, alogliptin at single doses up to 800 mg inhibited plasma DPP-4 activity, increased active GLP-1, and was generally well tolerated, with no dose-limiting toxicity.

Pharmacokinetic and Pharmacodynamic Assessments of the Dipeptidyl Peptidase-4 Inhibitor PHX1149: Double-Blind, Placebo-Controlled, Single- and Multiple-Dose Studies in Healthy Subjects

Background: PHX1149 is a dipeptidyl peptidase-4 (DPP4) inhibitor that is currently in clinical development for the treatment of type 2 diabetes mellitus. PHX1149 is a small (molecular weight = 241.16 Da), highly water-soluble (>2 g/mL), orally active molecule with a selectivity index of 15- to 319-fold relative to those of other members of the DPP family. The biochemical median inhibitory concentration of DPP4 is 2.5 nmol/L. Objective: The aim of these 2 double-blind, randomized, placebo-controlled studies was to examine the pharmacokinetic (PK) parameters and pharmacodynamic (PD) properties and tolerability of single and multiple ascending doses of PHX1149 in healthy human subjects. Methods: Healthy men and women aged 18 to 60 years were recruited to participate in a single- or a multiple-dose study in which sequential dose escalation paradigm was used. In the single-dose study, subjects were given a single oral dose of PHX1149 50 to 500 mg or placebo; in the multiple-dose study, subjects were given PHX1149 at doses from 50 to 400 mg or placebo QD for 13 days. There was no intrasubject dose escalation. Blood samples were collected from each subject at a series of time points ranging from 1 hour before to 24 hours after dosing on day 1 in the single- dose study and on days 1, 7, and 13 in the multiple-dose study. PK and PD analyses were performed in plasma samples to determine C max, T max, AUC 0-t, AUC 0-∞, and DPP4 enzymatic activity. The drug accumulation index was also calculated for each dose of PHX1149 in the multiple-dose study. Adverse events (AEs) were monitored in both studies through physical examinations, including measurement of vital signs, and clinical laboratory testing. In both studies, electrocardiography was performed. Results: The single- and multiple-dose studies enrolled 30 and 28 subjects, respectively, for a total enrollment in the 2 studies of 58 healthy adult subjects. The distribution of male and female subjects was 14 (47%) and 16 (53%), respectively, in the single- dose study and 16 (57%) and 12 (43%) in the multiple- dose study. In the single-dose study, 28 (93%) subjects were white; in the multidose study, all subjects were white. The mean (SD) ages in the 2 studies were 51 (10) and 51 (12) years, respectively; and mean (SD) body weights were 89.0 (10.8) and 81.1 (10.9) kg, respectively. PHX1149 exhibited dose-proportional increases in mean C max AUC 0-t, and AUC 0-∞ across the evaluated dose ranges. T max ranged from 2 to 4 hours, and t 1/2 ranged from ∼10 to 13 hours. No drug accumulation was observed. Plasma DPP4 inhibition at 24 hours was ≥50% in the multiple-dose study for doses of ≥100 mg. PHX1149 400 mg achieved ∼90% 24-hour plasma DPP4 inhibition in the multiple-dose study. All AEs were characterized as mild, with the exception of 1 case of moderate edema, which occurred 17 days after the end of dosing in the multiple-dose study (50-mg dose group) and was considered unrelated to the study drug. Adverse events were experienced by 47% of all subjects studied in the single-dose study and 93% of subjects in the multiple-dose study. The rates of AEs were comparable between the study and placebo groups. Conclusions: The PK parameters and PD properties of PHX1149 were suitable (eg, tl/2, DPP4 inhibition) for once-daily dosing in this group of 58 healthy subjects. All doses were well tolerated.