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Immune Activation Mediated Change in Alpha‐1‐Acid Glycoprotein: Impact on Total and Free Lopinavir Plasma Exposure
Author(s) -
Ofotokun Ighovwerha,
Lennox Jeffrey L.,
Eaton Molly E.,
Ritchie James C.,
Easley Kirk A.,
Masalovich Svetlana E.,
Long Mary C.,
Acosta Edward P.
Publication year - 2011
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010385118
Subject(s) - lopinavir , lopinavir/ritonavir , ritonavir , pharmacokinetics , area under the curve , chemistry , medicine , pharmacology , viral load , endocrinology , immunology , human immunodeficiency virus (hiv) , antiretroviral therapy
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.