title: Immune activation mediated change in alpha-1-acid glycoprotein: impact on total and free lopinavir plasma exposure.
abstract: BACKGROUND
  Immune mediated changes in circulating α-1-acid glycoprotein (AAG), a type 1 acute phase protein, which binds protease inhibitors (PI), may alter protein binding and contribute to PI's pharmacokinetic (PK) variability.
  
  
  METHODS
  In a prospective, 2-phase intensive PK study on antiretroviral naive human immunodeficiency virus (HIV)-infected subjects treated with a lopinavir-/ritonavir-based regimen, steady state PK sampling and AAG assays were performed at weeks 2 and 16 of treatment.
  
  
  RESULTS
  Median entry age was 43 years (n = 16). Median plasma log(10) HIV-1 RNA, CD4 T-cell counts, and AAG were 5.16 copies/mL, 28 cells/µL, and 143 mg/dL, respectively.The total lopinavir area under the concentration time curve (AUC(12_total)) and maximum concentration (C(max_total)) changed linearly with AAG at mean rates of 16±7 mg*hr/L (slope ± SE); P = .04, and 1.6 ± 0.6 mg/L, P = .02, per 100 mg/dL increase in AAG levels, respectively (n = 15).A 29% drop in AAG levels between week 2 and week 16 was associated with 14% (geometric mean ratio [GMR] = 0.86; 90% confidence interval [CI] = 0.74-0.98) and 13% (GMR = 0.87; 90% CI = 0.79-0.95) reduction in AUC(12_total) and C(max_total), respectively. Neither free lopinavir PK parameters nor antiviral activity (HIV-1 RNA average AUC minus baseline) was affected by change in plasma AAG.
  
  
  CONCLUSIONS
  Changes in plasma AAG levels alter total lopinavir concentrations, but not the free lopinavir exposure or antiviral activity. This observation may have implications in therapeutic drug monitoring.
authors.affiliation: Division of Infectious Disease, Department of Medicine, Emory University School of Medicine, 49 Jesse Hill Jr Drive, Atlanta, GA 30303, USA. iofotok@emory.edu
authors.forename: Ighovwerha
authors.initials: I
authors.lastname: Ofotokun
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Lennox
authors.forename: Molly E
authors.initials: ME
authors.lastname: Eaton
authors.forename: James C
authors.initials: JC
authors.lastname: Ritchie
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Easley
authors.forename: Svetlana E
authors.initials: SE
authors.lastname: Masalovich
authors.forename: Mary C
authors.initials: MC
authors.lastname: Long
authors.forename: Edward P
authors.initials: EP
authors.lastname: Acosta
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D006678:HIV; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D061466:Lopinavir / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009961:Orosomucoid / Q000276:immunology* / Q000378:metabolism; D011446:Prospective Studies; D011485:Protein Binding; D012367:RNA, Viral / Q000097:blood; D019438:Ritonavir / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D009961:Orosomucoid; D012367:RNA, Viral; D061466:Lopinavir; D019438:Ritonavir