title: 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.
authors.affiliation: Medical Development, Amylin Pharmaceuticals, Inc., San Diego, California 92121, USA. marybeth.deyoung@amylin.com
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: DeYoung
authors.forename: Leigh
authors.initials: L
authors.lastname: MacConell
authors.forename: Viren
authors.initials: V
authors.lastname: Sarin
authors.forename: Michael
authors.initials: M
authors.lastname: Trautmann
authors.forename: Paul
authors.initials: P
authors.lastname: Herbert
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000187:drug effects; D002214:Capsules; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D000077270:Exenatide; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007279:Injections, Subcutaneous; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting / Q000008:administration & dosage / Q000009:adverse effects; D019344:Lactic Acid / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000077205:Pioglitazone; D011100:Polyglycolic Acid / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects; D000068900:Sitagliptin Phosphate; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects; D014688:Venoms / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D001786:Blood Glucose; D002214:Capsules; D000077270:Exenatide; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting; D019344:Lactic Acid; D010455:Peptides; D000077205:Pioglitazone; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011719:Pyrazines; D000068900:Sitagliptin Phosphate; D045162:Thiazolidinediones; D014230:Triazoles; D014688:Venoms; C517652:hemoglobin A1c protein, human