Can a monthly exenatide extended release regimen provide a therapeutic and cost benefit?

Exenatide is used to treat type 2 diabetes mellitus. The current regimen is a 2 mg extended release (ER) weekly injection. The aim of our study was to prove the efficacy of exenatide ER if administered once-monthly. The proposed monthly dose was based on an Excel simulation using pharmacokinetic parameters extracted using Plot Digitizer® (version 2.6.8) from Cirincione et al. (2017), as well as accounting for the exenatide ER formulation characteristics, in vivo and in vitro exenatide stability. A PBPK model of exenatide molecule was developed using (Simcyp® version 19) based on data from in vitro and clinical PK studies. The model was used to confirm the Excel simulation findings of the effectiveness of exenatide ER monthly in maintaining the plasma level above the minimum effective concentration (MEC). Our simulation from Excel and Simcyp® showed that the drug plasma levels of the once monthly ER dose maintained a steady state concentration (Css ) above the MEC. The simulated Excel plasma level ranged from Cmin to Cmax of 60-130ng/L, respectively. The exenatide compound was successfully modeled and used to predict the Css of the ER monthly dose. The Simcyp® simulated Css of the ER was 117 ng/L. A monthly exenatide ER dose provides a plasma level within the therapeutic range. This new proposed dose has a significant pharmacoeconomic benefit and could well improve patient adherence.

Preparation and evaluation of lactic acid acylated exenatide and its long-acting preparation.

Exenatide (EX), a glucagon-like peptide-1 receptor agonist, is used to treat diabetes mellitus. However, its short half-life necessitates frequent administration and fluctuations in its plasma concentration may cause adverse effects. Previously, we developed glycolic acid acylated EX, which showed a good glucose-lowering effect. However, the release of lactic acid (LA) acylated exenatide (LA-EX) as an acylated adduct in EX microspheres has not been studied. Here, we investigated the biological properties of LA-EX. Additionally, LA-EX-loaded microspheres were formulated by an emulsion-solvent evaporation method and their in vitro characteristics, in vivo pharmacokinetic properties, and antidiabetic activities were evaluated. Pharmacokinetic studies revealed that the t1/2 of LA-EX (5.95 h) was 2.3-fold longer than that of EX. The antidiabetic activities of LA-EX in db/db mice were similar to those of EX. LA-EX release from microspheres was fairly well-sustained compared to that of EX microspheres. Additionally, LA-EX-loaded microspheres were more effective in lowering nonfasting blood glucose concentrations than EX microspheres. These findings suggest that LA-EX have the same efficacy as EX and that encapsulating LA-EX into microspheres can achieve better efficacy for the long-term type 2 diabetes mellitus treatment.

An Albumin Sandwich Enhances in Vivo Circulation and Stability of Metabolically Labile Peptides.

The effectiveness of numerous molecular drugs is hampered by their poor pharmacokinetics. Different from previous approaches with limited effectiveness, most recently, emerging high-affinity albumin binding moieties (ABMs) for in vivo hitchhiking of endogenous albumin opens up an avenue to chaperone small molecules for long-acting therapeutics. Although several FDA-approved fatty acids have shown prolonged residence and therapeutic effect, an easily synthesized, water-soluble, and high-efficiency ABM with versatile drug loading ability is urgently needed to improve the therapeutic efficacy of short-lived constructs. We herein identified an ideal bivalent Evans blue derivative, denoted as N(tEB)2, as a smart ABM-delivery platform to chaperone short-lived molecules, through both computational modeling screening and efficient synthetic schemes. The optimal N(tEB)2 could reversibly link two molecules of albumin through its two binding heads with a preferable spacer, resulting in significantly extended circulation half-life of a preloaded cargo and water-soluble. Notably, this in situ dimerization of albumin was able to sandwich peptide therapeutics to protect them from proteolysis. As an application, we conjugated N(tEB)2 with exendin-4 for long-acting glucose control in a diabetic mouse model, and it was superior to both previously tested NtEB-exendin-4 (Abextide) and the newly FDA-approved semaglutide, which has been arguably the best commercial weekly formula so far. Hence, this novel albumin binder has excellent clinical potential for next-generation biomimetic drug delivery systems.

Long-term oral administration of Exendin-4 to control type 2 diabetes in a rat model.

Exendin-4 is a glucagon-like peptide-1 (GLP-1) receptor agonist and potent insulinotropic agent for type 2 diabetes patients; however, its therapeutic utility is limited due to the frequent injections required. Long-acting agonists reduce the number of injections, but they can compromise potency. In this study, chondroitin sulfate-g-glycocholic acid-coated and Exendin-4 (Ex-4)-loaded liposomes (EL-CSG) were prepared for oral administration of Ex-4. The Ex-4 loading efficiency was 77% and the loading content in the nanoparticles was 1 wt-%. In rat models, a single oral dose (200 µg/kg) of EL-CSG showed a relative oral bioavailability of 19.5%, compared with subcutaneous administration (20 µg/kg), and sustained pharmacokinetics for up to 72 h. The overall long-term pharmacodynamic effects, assessed by hemoglobin A1c (HbA1c), body weight, and blood lipid concentrations, of daily oral EL-CSG (300 µg/kg) for four weeks were equivalent to or better than daily subcutaneous injections of free Ex-4 solution (20 µg/kg).

Exenatide effects on gastric emptying rate and the glucose rate of appearance in plasma: A quantitative assessment using an integrative systems pharmacology model.

This study aimed to quantify the effect of the immediate release (IR) of exenatide, a short-acting glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA), on gastric emptying rate (GER) and the glucose rate of appearance (GluRA), and evaluate the influence of drug characteristics and food-related factors on postprandial plasma glucose (PPG) stabilization under GLP-1RA treatment. A quantitative systems pharmacology (QSP) approach was used, and the proposed model was based on data from published sources including: (1) GLP-1 and exenatide plasma concentration-time profiles; (2) GER estimates under placebo, GLP-1 or exenatide IR dosing; and (3) GluRA measurements upon food intake. According to the model's predictions, the recommended twice-daily 5- and 10-µg exenatide IR treatment is associated with GluRA flattening after morning and evening meals (48%-49%), whereas the midday GluRA peak is affected to a lesser degree (5%-30%) due to lower plasma drug concentrations. This effect was dose-dependent and influenced by food carbohydrate content, but not by the lag time between exenatide injection and meal ingestion. Hence, GER inhibition by exenatide IR represents an important additional mechanism of its effect on PPG.

Replacement of the C-terminal Trp-cage of exendin-4 with a fatty acid improves therapeutic utility.

Exendin-4, a 39 amino acid peptide isolated from the saliva of the Gila monster, plays an important role in regulating glucose homeostasis, and is used clinically for the treatment of type 2 diabetes. Exendin-4 shares 53% sequence identity with the incretin hormone glucagon-like peptide 1 (GLP-1) but, unlike GLP-1, is highly resistant to proteolytic enzymes such as dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidase 24.11 (NEP 24.11). Herein, we focused on the structure and function of the C-terminal Trp-cage of exendin-4, and suggest that it may be structurally required for resistance to proteolysis by NEP 24.11. Using a series of substitutions and truncations of the C-terminal Trp-cage, we found that residues 1-33, including the N-terminal and helical regions of wild-type (WT) exendin-4, is the minimum motif required for both high peptidase resistance and potent activity toward the GLP-1 receptor comparable to WT exendin-4. To improve the therapeutic utility of C-terminally truncated exendin-4, we incorporated various fatty acids into exendin-4(1-33) in which Ser33 was substituted with Lys for acylation. Exendin-4(1-32)K-capric acid exhibited the most well balanced activity, with much improved therapeutic utility for regulating blood glucose and body weight relative to WT exendin-4.