Encapsulation of exenatide in poly-(D,L-lactide-co-glycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes

Abstract

Exenatide once-weekly (EQW [2 mg s.c.]) is under development as monotherapy as an adjunct to diet and exercise or as a combination therapy with an oral antidiabetes drug(s) in adults with type 2 diabetes. This long-acting formulation contains the active ingredient of the original exenatide twice-daily (EBID) formulation encapsulated in 0.06-mm-diameter microspheres of medical-grade poly-(D,L-lactide-co-glycolide) (PLG). After mechanical suspension and subcutaneous injection by the patient, EQW microspheres hydrate in situ and adhere to one another to form an amalgam. A small amount of loosely bound surface exenatide, typically less than 1%, releases in the first few hours, whereas drug located in deeper interstices diffuses out more slowly (time to maximum, ~2 weeks). Fully encapsulated exenatide (i.e., drug initially inaccessible to diffusion) releases over a still longer period (time to maximum, ~7 weeks) as the PLG matrix hydrolyzes into lactic acid and glycolic acid, which are subsequently eliminated as carbon dioxide and water. For EQW, plasma exenatide concentrations reach the therapeutic range by 2 weeks and steady state by 6-7 weeks. This gradual approach to steady state seems to improve tolerability, as nausea is less frequent with EQW than EBID. EQW administrations may be associated with palpable skin nodules that generally resolve without further medical intervention. In comparative trials, EQW improved hemoglobin A1c more than EBID, sitagliptin, pioglitazone, or insulin glargine and reduced fasting plasma glucose more than EBID. Weight loss due to EQW or EBID was similar. EQW is the first glucose-lowering agent that is administered once weekly.

FIG. 1.

Basics of poly-(d,l-lactide-co-glycolide) microspheres. (a) Spontaneous hydrolysis of poly-(d,l-lactide-co-glycolide) polymers. (b) Exenatide once-weekly microspheres exhibiting (left) a typical pinched raisin shape and (right) dense surface layer. (c) Mechanism of drug release from poly-(d,l-lactide-co-glycolide) microspheres.

FIG. 2.

Control of initial release: (a and b) effect of drug particle size and (c) total load (drug+excipients) on release.

FIG. 3.

Control of diffusion/erosion: (a) effect of lactide:glycolide ratio and (b) polymer molecular size on in vitro release.

FIG. 4.

Examples of subcutaneous nodules observed after exenatide once-weekly injection in patients with type 2 diabetes.

FIG. 5.

Pharmacokinetics of exenatide once-weekly (QW), shown in plasma exenatide concentrations following a single dose of exenatide twice-daily (BID) (n=39) and multiple doses of exenatide QW (n=31). Shading represents exenatide blood level predictions for 2-mg (top boundary) and 0.8-mg (bottom boundary) weekly repeating exenatide QW administrations with the use of superpositioning of single-dose data. The vertical dashed line shows the end of the exenatide QW dosing period in the trial. The horizontal line is the minimally effective level of exenatide demonstrated to reduce fasting plasma glucose concentrations. Modified from Fineman et al. and reproduced with permission from Adis, a Wolters Kluwer business (© Adis Data Information BV 2011. All rights reserved).

FIG. 6.

Glucose control mediated by exenatide once-weekly (EQW). (a) Change from baseline in hemoglobin A1c (HbA1c) in the placebo-controlled trial (Kim et al.) and DURATION-1, -2, and -3.^,, (b) Change from baseline in fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) in DURATION-1. EBID, exenatide twice-daily; Glar, insulin glargine; Pio, pioglitazone; Sita, sitagliptin. *P<0.05 versus comparators.