Srikanth Neelakantham

Differential effects of vildagliptin and glimepiride on glucose fluctuations in patients with type 2 diabetes mellitus assessed using continuous glucose monitoring.

To assess whether there is a difference in the effects of vildagliptin and glimepiride on glucose fluctuation in patients with type 2 diabetes mellitus (T2DM) using continuous glucose monitoring (CGM).

Pharmacokinetic and pharmacodynamic drug–drug interaction assessment between pradigastat and digoxin or warfarin

Pradigastat, a novel diacylglycerol acyltransferase‐1 inhibitor, was evaluated for both pharmacokinetic (PK) and pharmacodynamic (PD) drug–drug interactions when co‐administered with digoxin or warfarin in healthy subjects. This open‐label study included two parallel subject cohorts each with three sequential treatment periods. Forty subjects were enrolled in the study with 20 subjects allocated to each cohort. PK and PD (PT/INR for warfarin only) samples were collected in each period. The statistical analysis results showed that the 90% CIs of the geometric mean ratios of digoxin, R‐warfarin, and S‐warfarin PK parameters (AUC and Cmax) were all within 0.80–1.25 interval. The 90% CIs of the geometric mean ratios of pradigastat PK parameters (AUC and Cmax) were within 0.80–1.25 interval when co‐administered with warfarin; while co‐administration with digoxin slightly reduced pradigastat exposure (∼15%). The results also showed that 90% CIs of the geometric mean ratios of warfarin PD parameters (AUCPT, PTmax, AUCINR, and INRmax) were within 0.80–1.25 interval. Pradigastat and digoxin or warfarin had no relevant clinical PK or PD drug–drug interactions. Administration of pradigastat and warfarin or pradigastat and digoxin as a mono or combined treatment appears to be safe and tolerated.

Pharmacokinetic drug-drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel-ethinyl estradiol in healthy subjects.

LCZ696 is a novel angiotensin receptor neprilysin inhibitor in development for the treatment of cardiovascular diseases. Here, we assessed the potential for pharmacokinetic drug‐drug interaction of LCZ696 (400 mg, single dose or once daily [q.d.]) when co‐administered with omeprazole 40 mg q.d. (n = 28) or metformin 1000 mg q.d. (n = 27) or levonorgestrel‐ethinyl estradiol 150/30 μg single dose (n = 24) in three separate open‐label, single‐sequence studies in healthy subjects. Pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan), metformin, and levonorgestrel‐ethinyl estradiol were assessed. Omeprazole did not alter the AUCinf of sacubitril and pharmacokinetics of LBQ657; however, 7% decrease in the Cmax of sacubitril, and 11% and 13% decreases in AUCinf and Cmax of valsartan were observed. Co‐administration of LCZ696 with metformin had no significant effect on the pharmacokinetics of LBQ657 and valsartan; however, AUCtau,ss and Cmax,ss of metformin were decreased by 23%. Co‐administration of LCZ696 with levonorgestrel‐ethinyl estradiol had no effect on the pharmacokinetics of ethinyl estradiol and LBQ657 or AUCinf of levonorgestrel. The Cmax of levonorgestrel decreased by 15%, and AUCtau,ss and Cmax,ss of valsartan decreased by 14% and 16%, respectively. Co‐administration of LCZ696 with omeprazole, metformin, or levonorgestrel‐ethinyl estradiol was not associated with any clinically relevant pharmacokinetic drug interactions.

Bimagrumab improves body composition and insulin sensitivity in insulin‐resistant individuals

To test the hypothesis that an improving body composition in insulin‐resistant individuals could enhance insulin sensitivity.

Pharmacokinetics, Safety, and Tolerability of Fevipiprant (QAW039), a Novel CRTh2 Receptor Antagonist: Results From 2 Randomized, Phase 1, Placebo‐Controlled Studies in Healthy Volunteers

We evaluated the pharmacokinetics (PK), safety, and tolerability of a novel oral CRTh2 antagonist, fevipiprant (QAW039), in healthy subjects. Peak concentrations of fevipiprant in plasma were observed 1‒3 hours postdosing. Concentrations declined in a multiexponential manner, followed by an apparent terminal phase (t1/2, ∼20 hours). Steady state was achieved in 4 days with <2‐fold accumulation. Elimination was partly by renal excretion (≤30% of the dose) and glucuronidation. Food had minimal impact on the PK of fevipiprant, and it was well tolerated at single and multiple oral doses up to 500 mg/day. No dose‐dependent adverse events were observed, and all the events were mild or moderate in severity. Systemic concentrations were sufficiently high to achieve relevant target occupancy, considering in vitro pharmacology data. In summary, the data support further development as a once‐daily oral therapy for allergic diseases.

Effect of Pradigastat, a Diacylglycerol Acyltransferase 1 Inhibitor, on the QTcF Interval in Humans

Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, has been studied in familial chylomicronemia syndrome. To evaluate the effects of supratherapeutic concentrations of pradigastat on the QTc interval, 2 studies were conducted. The first study assessed the safety, tolerability, and pharmacokinetics of single escalating intravenous doses of pradigastat (10, 30, 100, and 115 mg over 60 minutes) in healthy adults. Single intravenous doses were safe, well tolerated, and at the higher doses resulted in supratherapeutic pradigastat exposure. The second was a parallel, 3‐arm thorough QTc study in which healthy male subjects were randomized to pradigastat (115 mg intravenously), moxifloxacin (400 mg oral, positive control), or placebo. Following intravenous administration, pradigastat exposure peaked at 4 times the therapeutic concentration and did not prolong the baseline‐adjusted and placebo‐corrected QTc intervals. During the 60‐minute pradigastat infusion, a number of infusion reactions and a small mean decrease in QTc were observed. Both effects disappeared when the infusion was stopped, suggesting that an infusate excipient may have been responsible. As expected, moxifloxacin significantly increased the QTc interval at multiple points, confirming the studys sensitivity to detect a true positive effect. Pradigastat is therefore unlikely to increase the risk of dysrhythmias associated with QTc prolongation in humans.

Effect of pradigastat a diacylglycerol acyltransferase 1 inhibitor on the pharmacokinetics of a combination oral contraceptive in healthy female subjects.

OBJECTIVE We evaluated the potential pharmacokinetic interaction between pradigastat, a potent and selective diacylglycerol acyltransferase 1 inhibitor, and Levora-28®, a combination oral contraceptive (COC) containing 30 μg ethinylestradiol (EE) and 150 μg levonorgestrel (LVG). METHODS An open-label, single-sequence three-period (period 1, single dose of COC; period 2, pradigastat 100 mg x 3 days followed by 40 mg x 7 days; and period 3, both pradigastat 40 mg and a single dose of COC) study involving 24 healthy female subjects of childbearing potential was conducted. RESULTS The pharmacokinetic parameters of EE were similar when administered alone or in combination with pradigastat, as the 90% confidence interval (CI) of geometric mean ratios for EE exposure (AUC and C(max)) were all within the range of 0.80 - 1.25. The AUC(∞), AUC(last), and C(max) of LVG were slightly increased in the presence of pradigastat, the geometric mean ratios (90% CI) were 1.25 (1.16, 1.35), 1.24 (1.15, 1.34), and 1.16 (1.06, 1.27), respectively. CONCLUSIONS Pradigastat did not elicit clinically relevant changes in the magnitude of Levora-28® exposure. Therefore, dose adjustment is not required for Levora-28® when co-administered with pradigastat.

Bioavailability of valsartan oral dosage forms.

The oral bioavailability of valsartan from extemporaneous suspension and solution formulations were evaluated relative to tablet formulation in two separate open‐label, randomized crossover studies in healthy adults. In both studies, the plasma concentrations of valsartan after oral administration were analyzed using validated liquid chromatography‐tandem mass spectrometry (LC–MS/MS) methods, and the corresponding pharmacokinetic parameters were estimated using noncompartmental analysis. The peak plasma concentration (Cmax) and area under the concentration time‐curves (AUC(0–∞)) of valsartan from the extemporaneous suspension were higher by 1.93‐ and 1.56‐fold, respectively, relative to the tablet formulation (P < .001). The Cmax and AUC(0–∞) of valsartan from the oral solution were higher by 2.21‐ and 1.74‐fold, respectively, relative to the tablet formulation (P < .001). These results indicate that both rate and extent of absorption of valsartan are higher in the two liquid dosage forms (extemporaneous suspension and solution formulations) relative to the solid oral dosage form (tablet formulation).