studies showed that while liraglutide could be metabolized by DPP-4 and NEP in a manner similar to GLP-1, its degradation was much slower [69], possibly due to the steric hindrance provided by fatty-acid-bound albumin

studies showed that while liraglutide could be metabolized by DPP-4 and NEP in a manner similar to GLP-1, its degradation was much slower [69], possibly due to the steric hindrance provided by fatty-acid-bound albumin. patient usability and ultimately, the commercial success of GLP-1 RA products. We also anticipate future GLP-1 RA development trends. Since comparable drug delivery strategies are also applied for developing other therapeutic peptides, we expect this case study of GLP-1 RAs will provide generalizable concepts for the rational design of therapeutic peptides products with extended duration of action. resulting in a half-life of only 2 minutes [17, 18]. GLP-RA developers have applied various half-life extending strategies and some of them have successfully resulted in FDA-approved diabetes products (Table 1). Simple sequential modification enhances DPP-4 resistance and improves GLP-1 receptor activation potency. This strategy led to the twice-daily and once-daily products, Byetta? and Adlyxin?, respectively. Sequence modification to enhance DPP-4 resistance combined with covalent attachment of a fatty acid leads to slower absorption and mediates albumin binding in plasma, a strategy employed in the development of the once-daily and once-weekly brokers, Victoza? and Ozempic?, respectively. More complicated molecular modifications that led to the approval of once-weekly products include fusing either recombinant human serum albumin (Tanzeum?) or an antibody fragment crystallizable (Fc) moiety (Trulicity?) to a GLP-1 analog. Other GLP-1 modifications have also been tested, including GLP-1 RA altered either with a recombinant peptide polymer XTEN? (VRS-859) or polyethylene glycol (LY2428757). Both molecules progressed into clinic trials, leading to the possibility of once-monthly and once-weekly products, but the development of these molecules appears to have been halted. Controlled release GLP-RA products have Rabbit Polyclonal to NKX28 also been developed including the FDA-approved once-weekly poly(lactide-co-glycolide) microspheres (Bydureon?) and a once-yearly titanium implant (ITCA 650) which is currently under review by the FDA. Table 1. Overview of GLP-1 RAs on the market for type 2 diabetes treatment. studies exhibited that exendin-4 has a slightly higher potency than native GLP-1 [46], attributable to their high similarity of AI-10-49 key N-terminal residues. Compared to native GLP-1, exendin-4 is usually more resistant to cleavage by DPP-4 due to a Gly to Ala substitution at the second position [47]. Furthermore, the Leu29-Ser39 segment of exendin-4 can form a tertiary AI-10-49 fold, or Trp cage, which conformationally shields residues 21-39, protecting these sites from being cleaved by NEP 24.11 [48, 49]. The AI-10-49 enzyme resistance results in a distinct metabolic pathway of exendin-4. Studies reported that exendin-4 is mainly degraded on kidney membranes and eliminated via glomerular filtration [50, 51]. In comparison, native GLP-1 is usually eliminated by both the kidneys and liver while also subject to metabolism in peripheral tissues. Exenatide, a synthetic version of exendin-4, was the first GLP-1 RA to be approved by the FDA under the brand name of Byetta? (Table 1). In 2009 2009, Byetta? was approved as a stand-alone therapy for type 2 diabetes by the FDA [19]. Byetta? is supplied in multi-dose prefilled pens consisting of 250 g/ml synthetic exenatide answer in pH 4.5 acetate buffer with mannitol (tonicity-adjusting agent) and metacresol (preservative). It can be stored at 2-8C for 3 years before use, and stored at room heat below 25 C for 30 days after first use (Table 2) [19]. Byetta? is usually administered as a twice daily (BID) subcutaneous injection before each main meal (Table 1). Patients begin with a 5 g dose for one month, followed by titration up to 10 g [19]. Pharmacokinetic parameters of exenatide are summarized in Table 3. Peak plasma concentration is usually achieved about 2 hours post administration. The product half-life is usually 2.4 hours, which allows for twice-daily administration, and is a large improvement over endogenous GLP-1 [19]. Animal studies have shown that exenatide is mainly cleared by renal filtration. Table 2. Formulations and storage conditions for GLP-1 RA products studies found that lixisenatide has four times greater affinity for the GLP-1 receptor than native GLP-1 and exenatide [52]. Adlyxin? is usually administered once daily at 10 C 20 g per day (Table 1). The pharmacokinetic profile of lixisenatide is similar to that of exenatide with a characteristic kidney elimination and Tmax of 2 hours post administration. The apparent volume of distribution is usually 100 L, with approximately 55% of lixisenatide bound to plasma proteins in circulation (Table 3) [25]. The half-life of lixisenatide is usually 2.6 hours, which is similar to that of exenatide [25]; however, unlike exenatide, lixisenatide is usually indicated as a once-daily injection. This is partly due to lixisenatides better ability to slow gastric emptying, yielding a better.