Yibin Wang

Treatment of Pituitary-Dependent Cushing’s Disease with the Multireceptor Ligand Somatostatin Analog Pasireotide (SOM230): A Multicenter, Phase II Trial

CONTEXT There is currently no medical therapy for Cushings disease that targets the pituitary adenoma. Availability of such a medical therapy would be a valuable therapeutic option for the management of this disorder. OBJECTIVE Our objective was to evaluate the short-term efficacy of the novel multireceptor ligand somatostatin analog pasireotide in patients with de novo, persistent, or recurrent Cushings disease. DESIGN We conducted a phase II, proof-of-concept, open-label, single-arm, 15-d multicenter study. PATIENTS Thirty-nine patients with either de novo Cushings disease who were candidates for pituitary surgery or with persistent or recurrent Cushings disease after surgery without having received prior pituitary irradiation. INTERVENTION Patients self-administered sc pasireotide 600 microg twice daily for 15 d. MAIN OUTCOME MEASURE Normalization of urinary free cortisol (UFC) levels after 15 d treatment was the main outcome measure. RESULTS Of the 29 patients in the primary efficacy analysis, 22 (76%) showed a reduction in UFC levels, of whom five (17%) had normal UFC levels (responders), after 15 d of treatment with pasireotide. Serum cortisol levels and plasma ACTH levels were also reduced. Steady-state plasma concentrations of pasireotide were achieved within 5 d of treatment. Responders appeared to have higher pasireotide exposure than nonresponders. CONCLUSIONS Pasireotide produced a decrease in UFC levels in 76% of patients with Cushings disease during the treatment period of 15 d, with direct effects on ACTH release. These results suggest that pasireotide holds promise as an effective medical treatment for this disorder.

FTY720: Placebo‐Controlled Study of the Effect on Cardiac Rate and Rhythm in Healthy Subjects

The purpose of this double‐blind, placebo‐controlled study was to measure the effects of FTY720, a novel immunomodulator, on heart rate and rhythm in healthy volunteers. Subjects (n = 66) were randomized to FTY720 1.25 mg or 5 mg or placebo administered once daily for 7 days. Continuous telemetry revealed an acute, dose‐dependent decrease in mean heart rate (10‐bpm decrease vs placebo) following the first dose of FTY720, with a nadir generally 4 hours postdose. Although a persistent FTY720‐related decrease in heart rate was measured from day 2 to day 7, additional doses of FTY720 after day 2 resulted in no further incremental decreases. Mean PR interval increased by approximately 8 to 10 msec in FTY720‐treated subjects on day 1. FTY720 did not increase the QRS or QT interval. These results confirm that the first dose of FTY720 has a mild to moderate negative chronotropic effect.

Pharmacodynamics of Vildagliptin in Patients With Type 2 Diabetes During OGTT

This randomized, open‐label, placebo‐controlled, 7‐period crossover study assessed dose‐response relationships following single oral doses (10–400 mg) of vildagliptin in 16 patients with type 2 diabetes mellitus. Plasma levels of parent drug, dipeptidyl peptidase‐4 activity, glucose, insulin, and glucagon were measured during 75‐g oral glucose tolerance tests performed after an overnight fast, 30 minutes after drug administration. The tmax for parent drug was observed between 0.5 and 1.5 hours postdose. Both Cmax and AUC0–8 h increased dose proportionately. Both onset and duration of dipeptidyl peptidase‐4 inhibition were dose dependent, but >90% inhibition occurred within 45 minutes and was maintained for ≥4 hours after each dose. Glucose excursions and glucagon levels during oral glucose tolerance tests were significantly and similarly decreased after each dose of vildagliptin, and insulin levels were significantly and similarly increased after each dose level. Unlike findings during mixed‐meal challenges, vildagliptin increases plasma insulin levels during oral glucose tolerance tests in patients with type 2 diabetes mellitus.

Multiple-Dose FTY720: Tolerability, Pharmacokinetics, and Lymphocyte Responses in Healthy Subjects

FTY720 is a sphingosine‐1‐phosphate receptor agonist being developed as an immunomodulator for acute rejection prophylaxis after organ transplantation. This study was performed to characterize the pharmacokinetics of and lymphocyte response to multiple‐dose FTY720. In this randomized, double‐blind study, three groups of 20 healthy subjects each received either placebo, 1.25 mg/day FTY720, or 5 mg/day FTY720 for 7 consecutive days. FTY720 blood concentrations and lymphocyte counts were assessed over the weeklong treatment phase and over a month‐long washout phase. The relationship between FTY720 blood concentrations and lymphocyte counts was explored by an inhibitory Emax model. First‐dose exposure was consistent with dose proportionality between the low‐ and high‐dose groups. Blood levels accumulated fivefold over the treatment period. Exposure on day 7 was dose proportional for Cmax (5.0 ± 1.0 vs. 18.2 ± 4.1 ng/mL) and for AUC (109 ± 24 vs. 399 ±85 ng•h/ mL). Washout pharmacokinetics after the last dose indicated an elimination half‐life averaging 8 days. Lymphocyte counts decreased by 80% in subjects receiving the lower dose to a nadir of 0.4 ± 0.1 × 109/L and by 88% in subjects receiving the upper dose to a nadir of 0.2 ±0.1 ×109/L. Descriptive exposure‐response modeling estimated that the lymphocyte response at 5 mg/day is near the maximal response achievable. By the end‐of‐study evaluation on day 35, lymphocyte counts had recovered to within 75% and 50% of baseline in the low‐ and high‐dose groups, respectively. In summary, systemic exposure to FTY720 was consistent with dose‐proportionality after both single‐ and multiple‐dose administration. Total lymphocyte counts decreased from baseline by 80% and 88% at regimens of 1.25 and 5 mg/day, respectively. Exposure‐response modeling provided evidence that 5 mg/day FTY720 resulted in a near‐maximal dynamic effect of this drug on lymphocytes.

Pharmacokinetics and pharmacodynamics of vildagliptin in patients with type 2 diabetes mellitus.

BackgroundVildagliptin is a dipeptidyl peptidase IV (DPP-4) inhibitor currently under development for the treatment of type 2 diabetes mellitus.ObjectivesTo assess the pharmacokinetic and pharmacodynamic characteristics and tolerability of vildagliptin at doses of 10mg, 25mg and l00mg twice daily following oral administration in patients with type 2 diabetes.MethodsThirteen patients with type 2 diabetes were enrolled in this randomised, double-blind, double-dummy, placebo-controlled, four-period, crossover study. Patients received vildagliptin 10mg, 25mg and l00mg as well as placebo twice daily for 28 days.ResultsVildagliptin was absorbed rapidly (median time to reach maximum concentration 1 hour) and had a mean terminal elimination half-life ranging from 1.32 to 2.43 hours. The peak concentration and total exposure increased in an approximately dose-proportional manner. Vildagliptin inhibited DPP-4 (>90%) at all doses and demonstrated a dose-dependent effect on the duration of inhibition. The areas under the plasma concentration-time curves of glucagon-like peptide-1 (GLP-1) [p < 0.001] and glucose-dependent insulinotropic peptide (GIP) [p < 0.001] were increased whereas postprandial glucagon was significantly reduced at the 25mg (p = 0.006) and l00mg (p = 0.005) doses compared with placebo. As compared with placebo treatment, mean plasma glucose concentrations were decreased by 1.4 mmol/L with the vildagliptin 25mg dosing regimen and by 2.5 mmol/L with the lOOmg dosing regimen, corresponding to a 10% and 19% reduction, respectively. Vildagliptin was generally well tolerated.ConclusionVildagliptin is likely to be a useful therapy for patients with type 2 diabetes based on the inhibition of DPP-4 and the subsequent increase in incretin hormones, GLP-1 and GIP, and the decrease in glucose and glucagon levels.

QT and QTc Interval With Standard and Supratherapeutic Doses of Darifenacin, a Muscarinic M3 Selective Receptor Antagonist for the Treatment of Overactive Bladder

Prolongation of QT interval on an electrocardiogram is a valuable predictor of a drugs ability to cause potentially fatal ventricular tachyarrhythmia (torsades de pointes). Darifenacin is a muscarinic M3 selective receptor antagonist developed for the treatment of overactive bladder, a debilitating condition that is particularly prevalent in the older population. This 7‐day, randomized, parallel‐group study (n = 188) measured QT/QTc interval in healthy volunteers receiving once‐daily darifenacin at steady‐state therapeutic (15 mg) and supratherapeutic (75 mg) doses, alongside controls receiving placebo or moxifloxacin (positive control, 400 mg) once daily. There was no significant increase in QTcF interval with darifenacin treatment compared with placebo. Mean changes from baseline at pharmacokinetic Tmax versus placebo were −0.4 and −2.2 milliseconds in the darifenacin 15 mg and 75 mg groups, respectively, compared with +11.6 milliseconds in the moxifloxacin group (P <.01). This study demonstrates that darifenacin does not prolong QT/QTc interval.

The Absolute Oral Bioavailability and Population-Based Pharmacokinetic Modelling of a Novel Dipeptidylpeptidase-IV Inhibitor, Vildagliptin, in Healthy Volunteers

Background and objectiveVildagliptin is a potent, selective, orally active inhibitor of dipeptidylpeptidase-IV being developed for the treatment of type 2 diabetes mellitus. The objective of this study was to assess the absolute oral bioavailability of vildagliptin by comparing the systemic exposure after oral and intravenous administration in healthy volunteers.MethodsThis was an open-label, randomised, two-period, two-treatment, crossover study in 11 healthy volunteers. Subjects received vildagliptin 50mg orally or 25mg as a 30-minute intravenous infusion on two occasions separated by a 72-hour washout period. Vildagliptin concentrations were determined by a specific assay in urine (lower limit of quantification [LLQ] = 5 ng/mL) and serial plasma samples (LLQ = 2 ng/mL) obtained up to 24 hours after dosing. Noncompartmental analysis and population pharmacokinetic modelling were performed.ResultsBoth noncompartmental analysis and population pharmacokinetic modelling estimated the absolute oral bioavailability of vildagliptin to be 85%. Renal elimination of unchanged vildagliptin accounted for 33% and 21% of the administered dose 24 hours after intravenous and oral administration, respectively. Renal clearance (13 L/h) was approximately one-third of the total systemic clearance (41 L/h). Two peaks were observed in plasma concentrations at 1 and 3 hours after oral administration in nine of 11 subjects. Modelling based on the population approach identified two absorption sites with lag-times of 0.225 and 2.46 hours. Both absorption rate constants were slower than the elimination rate constant, indicating ‘flip-flop’ kinetics after oral administration. Bodyweight was identified as a factor with an impact on the volume of distribution of the peripheral compartment. Clearance was 24% greater in males (44.6 L/h) than in females (36.1 L/h).ConclusionsVildagliptin is rapidly and well absorbed with an estimated absolute bioavailability of 85%. Two possible sites of absorption were identified, and the absorption rates were slower than the elimination rate, indicating a flip-flop phenomenon after oral dosing.

Effect of Terbinafine on the Pharmacokinetics and Pharmacodynamics of Desipramine in Healthy Volunteers Identified as Cytochrome P450 2D6 (CYP2D6) Extensive Metabolizers

Terbinafine‐CYP2D6 inhibition was evaluated by assessing 48‐hour concentration‐time profiles of the tricyclic antidepressant desipramine in 12 healthy volunteers identified as extensive cytochrome P450 2D6 (CYP2D6) metabolizers by genotyping and phenotyping. Pharmacokinetics was evaluated at baseline (50 mg oral desipramine given alone), steady state (after 250 mg oral terbinafine for 21 days), and 2 and 4 weeks after terbinafine discontinuation. Pharmacodynamics was evaluated before and 2 hours after each desipramine administration, using Mini‐Mental Status Examination (MMSE) and ECG. Terbinafine administration inhibited CYP2D6 metabolism, as indicated by the significant increase in desipramine Cmax (19 ng/ml vs. 36 ng/ml) and AUC0‐∞ (482 ng•h/ml vs. 2383 ng•h/ml) and decrease in AUC0–24 and Cmax of the CYP2D6‐mediated metabolite, 2‐hydroxydesipramine. In addition, the Cmax and AUC0‐∞ of desipramine and metabolite were still elevated 4 weeks after terbinafine discontinuation. Caution should be exercised when coprescribing terbinafine and drugs metabolized by CYP2D6, particularly those with a narrow therapeutic index.

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.

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 α‐ and β‐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 (r2 = 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 (AUC0–∞) and maximum plasma concentration (Cmax). Dose proportionality was assessed using a statistical power model [X = α·(dose)β]. The 90% confidence intervals of the proportionality coefficient, β, for AUC0–∞ (1.15–1.19) and Cmax (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 AUC0–∞ and Cmax but no dose‐dependent changes in time to reach Cmax or terminal elimination half‐life. Administration of vildagliptin 100 mg following a high‐fat meal decreased Cmax by 19% and AUC0–∞ 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.