title: Effect of renal impairment on the pharmacokinetics, efficacy, and safety of albiglutide.
abstract: BACKGROUND
  Chronic kidney disease is frequently present in patients with type 2 diabetes mellitus (T2DM). New therapeutic options in this patient subpopulation are needed.
  
  
  OBJECTIVE
  Assess the effect of renal impairment on the pharmacokinetics (PK), efficacy, and safety of albiglutide in single- and multiple-dose studies.
  
  
  METHODS
  Pharmacokinetics, safety, and efficacy of once weekly albiglutide in patients with T2DM was assessed from a single-dose (30 mg), nonrandomized, open-label study (N = 41) including subjects with normal and varying degrees of renal impairment, including hemodialysis, and a pooled analysis of 4 phase 3, randomized, double-blind (1 open-label), active or placebo-controlled multiple-dose studies. The pooled analysis of the latter 4 studies (N = 1113) was part of the population PK analysis, which included subjects with normal and varying degrees of renal impairment (mild, moderate, severe) treated with albiglutide (30 to 50 mg) to primary end points of 26 to 52 weeks.
  
  
  RESULTS
  Single-dose PK showed area-under-the-curve ratios (and 90% CIs) of 1.32 (0.96-1.80), 1.39 (1.03-1.89), and 0.99 (0.63-1.57) for the moderate, severe, and hemodialysis groups, respectively, relative to the normal group. Results indicate that modest increases in plasma concentration of albiglutide were observed with the severity of renal impairment. There was a trend for more glycemic lowering as the estimated glomerular filtration rate decreased. The severe group had a higher frequency of gastrointestinal (eg, diarrhea, constipation, nausea, and vomiting) and hypoglycemic (with background sulfonylurea use) events compared with patients with mild or moderate renal impairment.
  
  
  CONCLUSIONS
  The PK, efficacy, and safety data indicate that albiglutide has a favorable benefit/risk ratio in patients with T2DM and varying degrees of renal impairment, and the need for a dose adjustment is not suggested. Experience in patients with more severe renal impairment is very limited, so the recommendation is to use albiglutide carefully in this population.
  
  
  BACKGROUND
  (ClinicalTrials.gov):NCT00938158, NCT00849017, NCT00838916, NCT00839527, NCT0198539.
authors.affiliation: Senior Director, Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, NC. Malcolm.a.young@gsk.com.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Young
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Wald
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Matthews
authors.forename: Fred
authors.initials: F
authors.lastname: Yang
authors.forename: Rickey R
authors.initials: RR
authors.lastname: Reinhardt
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001794:Blood Pressure; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000453:epidemiology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005919:Glomerular Filtration Rate; D052216:Glucagon-Like Peptide 1 / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006442:Glycated Hemoglobin; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D007676:Kidney Failure, Chronic / Q000453:epidemiology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D016032:Randomized Controlled Trials as Topic; D012720:Severity of Illness Index
chemical_list: D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; C534611:rGLP-1 protein