Leveraging a Clinical Phase Ib Proof-of-Concept Study for the GPR40 Agonist MK-8666 in Patients With Type 2 Diabetes for Model-Informed Phase II Dose Selection.

GPR40 mediates free fatty acid-induced insulin secretion in beta cells. We investigated the safety, pharmacokinetics, and glucose response of MK-8666, a partial GPR40 agonist, after once-daily multiple dosing in type 2 diabetes patients. This double-blind, multisite, parallel-group study randomized 63 patients (placebo, n = 18; 50 mg, n = 9; 150 mg, n = 18; 500 mg, n = 18) for 14-day treatment. The results showed no serious adverse effects or treatment-related hypoglycemia. One patient (150-mg group) showed mild-to-moderate transaminitis at the end of dosing. Median MK-8666 Tmax was 2.0-2.5 h and mean apparent terminal half-life was 22-32 h. On Day 15, MK-8666 reduced fasting plasma glucose by 54.1 mg/dL (500 mg), 36.0 mg/dL (150 mg), and 30.8 mg/dL (50 mg) more than placebo, consistent with translational pharmacokinetic/pharmacodynamic model predictions. Maximal efficacy for longer-term assessment is projected at 500 mg based on exposure-response analysis. In conclusion, MK-8666 was generally well tolerated with robust glucose-lowering efficacy.

A thorough QT study to evaluate the effects of singledose exenatide 10 µg on cardiac repolarization in healthy subjects.

OBJECTIVE: This was a singledose, randomized, positive- and placebo-controlled, double-dummy, double-blinded, 3-period crossover thorough QT study of exenatide, a glucagon-like peptide-1 receptor agonist for the treatment of Type 2 diabetes that enhances insulin secretion in a glucose- dependent fashion. METHODS: Healthy subjects (n = 70) underwent an initial tolerability screening, receiving subcutaneous exenatide 10 µg daily for 3 consecutive days. Subjects who passed tolerability screening (n = 62) received exenatide 10 µg, placebo, and moxifloxacin (400 mg orally; positive control) separated by washout periods of approximately 5 days. Twelve-lead electrocardiograms and blood samples for plasma exenatide, glucose, and insulin were collected. QT intervals were heart rate-corrected using Fridericia's correction (QTcF) and an individual correction (QTcI) and were analyzed as change from predose (ΔQTcF, or ΔQTcI). The relationships between the QTc interval and plasma exenatide, glucose, and insulin concentrations were also explored. RESULTS: Based on ΔQTcF and ΔQTcI assessments, exenatide 10 µg did not show a clinically significant prolongation of QT compared with placebo; the upper bound of the 2-sided 90% confidence interval (CI) for the largest mean difference from placebo was < 10 msec with both corrections. A positive slope was observed between plasma exenatide and ΔΔQTcF (0.02 (95% CI 0.01, 0.03), p < 0.001); no significant slope was observed between plasma exenatide concentrations and ΔΔQTcI (0.01 (95% CI 0.00, 0.02), p = 0.064). The plasma exenatide versus QTc analyses may be confounded by exenatide's glucose-lowering effect. A negative slope was observed between plasma glucose and [delta]QTcF (-1.5 (95% CI -2.2, -0.7), p < 0.001) and between plasma glucose and ΔQTcI (-1.6 (95% CI -2.3, -0.9), p < 0.0001). Plasma insulin and ΔQTcF were not correlated. CONCLUSION: This study demonstrated that single-dose exenatide 10 µg was not associated with clinically meaningful prolongation of the QTc interval.

Exenatide - pharmacokinetics, pharmacodynamics, safety and tolerability in patients ≥ 75 years of age with Type 2 diabetes.

OBJECTIVE: This study evaluated pharmacokinetics, pharmacodynamics,safety, and tolerability of single doses of exenatide in elderly Type 2 diabetes (T2D)patients. METHODS: This placebo-controlled,patient-blind, crossover study compared elderly patients (≥ 75 y, n = 15) to controls( ≥ 45 to ≤ 65y, n = 15) with T2D. Patients were randomized to single subcutaneous doses of exenatide 5µg, placebo or exenatide 10 µg (Sequence 1) or placebo, exenatide 5 µg or exenatide 10 µg (Sequence 2) before a standardized breakfast over three consecutive days. Serial blood samples were collected for plasma exenatide and serum glucose concentrations.Pharmacokinetic data from this study were also integrated with those from six other clinical pharmacology studies to further evaluate the impact of age on plasma exenatide apparent clearance (CL/F) (139 controls ( ≤ 65 y); 28 elderly patients (> 65 y)). RESULTS: Mean ± SD ages for control and elderly patients were 57 ± 6 y and 78 ± 3 y, respectively.All elderly patients had renal impairment at baseline, as compared with one third of controls. Dose-normalized plasma exenatide maximum concentration and exposure were greater in elderly patients, but between-age group differences were neither statistically significant nor considered clinically relevant. The integrated pharmacokinetic analysis showed a significant linear relationship between plasma exenatide CL/F and renal clearance (test of slope = 0, p < 0.001),with no additional effect from age. Exenatide dose-dependently blunted postprandial serum glucose excursions in both age groups. No hypoglycemia or serious adverse events were reported, and exenatide was generally well tolerated in both age groups. CONCLUSIONS: Exenatide dose adjustments should be determined by renal function rather than age in elderly T2D patients.

The effect of exenatide on lisinopril pharmacodynamics and pharmacokinetics in patients with hypertension.

OBJECTIVES: This study evaluated the potential effect of exenatide on the pharmacokinetics and pharmacodynamics of lisinopril in patients with mild-to-moderate hypertension. METHODS: 22 patients with mild-to-moderate primary hypertension participated in a double-blind, randomized, placebo-controlled, 2-period, 2-sequence crossover study. Patients on stable lisinopril therapy were randomly assigned to receive subcutaneous exenatide (10 microg b.i.d.) and placebo b.i.d. separated by at least 2 days washout period. The primary pharmacodynamic parameters were baseline-adjusted 24-hour mean systolic and diastolic blood pressure. Steady state plasma lisinopril concentration-time profiles were also assessed. RESULTS: Mean blood pressure changes were not significantly different between exenatide and placebo coadministered with lisinopril. The least squares mean differences (95% CI) between treatments were +1.38 mmHg (-1.41, 4.17) for diastolic and +1.38 mmHg (-1.95, 4.71) for systolic blood pressure. Exenatide delayed the time to attain maximum lisinopril concentration (tmax,ss) by 2 hours but did not significantly alter maximum lisinopril concentration (Cmax,ss) or area under the concentration-time profile (AUCtau,ss) over the 24-hour steady-state dosing interval. CONCLUSIONS: This study demonstrated that concurrent administration of exenatide did not produce clinically relevant changes in blood pressure and did not significantly alter lisinopril pharmacokinetics in patients with mild-to-moderate hypertension.

Exenatide pharmacokinetics in healthy Chinese subjects.

OBJECTIVES: Exenatide is an adjunctive treatment for Type 2 diabetes. This was the first study to evaluate the pharmacokinetics, safety and tolerability of therapeutic doses (5 microg and 10 microg) of exenatide after single and multiple subcutaneous injections in healthy adult Chinese subjects. METHODS: 24 healthy volunteers were randomized to receive either 5 microg or 10 microg of exenatide by subcutaneous injection. Subjects received a single injection of exenatide on Day 1, twice daily on Days 2 and 3, and once on Day 4. Serial blood samples were drawn for pharmacokinetic assessment at pre-dose and up to 12 h post dose on Day 1 and Day 4. Adverse events, vital signs, 12-lead ECG, body weight and clinical laboratory evaluations were assessed. RESULTS: Exenatide, 5 microg and 10 microg, was rapidly absorbed with a median tmax of 1 h after single and multiple doses. Exenatide Cmax and AUCtau,ss were (geometric mean (90% CI)) 145 (119 - 176) pg/ml and 370 (297 - 460) pg x h/ml, respectively, after multiple dosing with 5 microg. The Cmax and AUCtau,ss were 311 (271 - 357) pg/ml and 878 (785 - 983) pg x h/ml, respectively, for 10 microg. Mean half-life (t1/2, range 0.99 - 1.25 h), apparent volume of distribution (Vz/F, 19.2 - 22.3 l), and apparent clearance (CL/F, range 11.4 - 13.5 l/h) remained consistent between single and multiple doses and across the two dose levels. Both the accumulation ratios and linearity index approached 1.0. The most common adverse events were gastrointestinal in nature and mild in severity. The frequency of adverse events increased with dose, such that 8% of subjects who received 5 microg and 42% of subjects who received 10 microg experienced adverse events. CONCLUSIONS: Exenatide was rapidly absorbed, with similar pharmacokinetic properties following single and multiple doses. Exenatide exposure after multiple doses approximately doubled from 5 microg to 10 microg.

Exenatide effects on statin pharmacokinetics and lipid response.

OBJECTIVE: Exenatide is an adjunctive treatment for type 2 diabetes. Many patients with type 2 diabetes have dyslipidemia, which requires treatment with three hydroxy-3-methyl glutaryl coenzyme (HMG-CoA) reductase inhibitors (statins), hence, concurrent use of exenatide and statins is likely. Exenatide slows gastric emptying, which may alter the absorption rate of co-administered oral medications. Thus, the potential interaction between exenatide and statins was evaluated in two study settings. METHODS: In an open-label, fixed-sequence, clinical pharmacology study, the plasma pharmacokinetics of lovastatin (40 mg after breakfast) in the presence and absence of exenatide (10 microg before breakfast and dinner) was evaluated in 21 healthy subjects. In a second clinical setting, changes in lipid profiles and statin dosage over 30 weeks in patients with type 2 diabetes were retrospectively compared (n = 180 exenatide 10 microg twice daily (BID), n = 168 placebo BID) in a combined analysis of three placebo-controlled, randomized exenatide Phase 3 trials. RESULTS: In healthy subjects, exenatide decreased mean lovastatin area under the plasma concentration time curve from zero to infinity (AUC0-infinity) and maximum plasma concentration (Cmax) by 40 and 28%, respectively, and increased median time to maximum plasma concentration (tmax) by 4 hours. In the exenatide Phase 3 trials, 30-week changes from baseline for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol, triglycerides and statin dosage were not significantly different between the exenatide and placebo groups treated with statins. CONCLUSIONS: Despite observed changes in lovastatin bioavailability in the pharmacokinetic drug interaction study, exenatide did not negatively affect long-term lipid profiles or statin dosage in patients with concurrent statin therapy. Thus, co-administration of exenatide does not require adjustment in statin dosage.

Exenatide: effect of injection time on postprandial glucose in patients with Type 2 diabetes.

AIMS: Exenatide is an incretin mimetic whose effect on glycaemic control in patients with Type 2 diabetes is currently under investigation. This study assessed the effect of injection time relative to a standardized meal on postprandial pharmacodynamics of exenatide in patients with Type 2 diabetes. METHODS: Eighteen patients participated in this single-centre, open-label, placebo-controlled, randomized, six-way crossover study. Patients received subcutaneous injections of either placebo (-15 min) or 10 microg of exenatide at -60, -15, 0, +30 or +60 min relative to a standardized breakfast meal on six consecutive days. Serial blood samples were assayed for plasma glucose and insulin concentrations. RESULTS: For all exenatide treatments, incremental postprandial glucose area under the postprandial plasma glucose curve from zero to 6 h (AUC0-6 h) was significantly reduced compared with placebo. When exenatide was administered before (-60, -15 min) or with the meal (0 min), peak postprandial glucose concentrations were significantly decreased (P < 0.0001 for all treatments) compared with placebo. Post-meal exenatide administration (+30, P < 0.05; +60 min, P = 0.21) resulted in smaller peak glucose reductions and in some patients transient low plasma glucose concentrations were reported. Peak plasma insulin concentrations in the pre-meal treatments were significantly lower than placebo (P < 0.05 for all treatments), while post-meal dosing groups exhibited a trend towards higher insulin peaks compared with placebo. The most common adverse events related to exenatide were headache, nausea, dyspepsia and vomiting, and were generally of mild-to-moderate intensity. CONCLUSIONS: In this study, all exenatide treatments demonstrated reductions in postprandial plasma glucose excursions compared with placebo. Pre-meal and with meal administration of exenatide produced greater reduction of postprandial glucose excursions compared with post-meal administration. These data support flexible dosing of exenatide at any time within 60 min before a meal.

The intestinal uptake of phenol from micellar systems does not conform to the aqueous transfer model.

PURPOSE: To evaluate the aqueous transfer model as the mechanism for the micelle-mediated uptake of phenol in the rat in situ intestinal perfusion model. METHODS: Phenol in isotonic HEPES buffer was perfused through the jejunal segment at two flow rates and at various concentrations. Phenol was then dispersed in two, distinct mixed micelle systems composed of sodium taurocholate and phosphatidylcholine at 10 mM:2.5 mM (10:2.5 system) and at 10 mM: 10 mM (10:10 system) and its uptake studied in each case. Equilibrium dialysis was done to determine the aqueous fraction of phenol in each system. RESULTS: The P(eff) of phenol in isotonic HEPES buffer at a low flow rate (n = 6) was 1.7 +/- 0.4 x 10(-4) cm/s and at a high flow rate (n = 13) was 1.8 +/- 0.5 x 10(-4) cm/s. The P(eff) for the 10:2.5 system at the high flow rate (n = 3) was 1.5 +/- 0.4 x 10(-4) cm/s and at the low flow rate (n = 3) was 1.4 +/- 0.3 x 10(-4) cm/s. Uptake was membrane rate-limited in both the non-micellar and 10:2.5 systems. P(eff) at a high flow rate (n = 3) in the 10:10 system was 1.3 +/- 0.1 x 10(-4) cm/s. Equilibrium dialysis (n = 4) revealed free fractions of 0.60 +/- 0.05 and 0.50 +/- 0.03 for the 10:2.5 and 10:10 systems. CONCLUSIONS: The uptake of micellized phenol did not follow the aqueous transfer model of uptake.