1. Immune Activation Mediated Change in Alpha-1-Acid Glycoprotein: Impact on Total and Free Lopinavir Plasma Exposure.
- Author
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Ofotokun, Ighovwerha, Lennox, Jeffrey L., Eaton, Molly E., Ritchie, James C., Easley, Kirk A., Masalovich, Svetlana E., Long, Mary C., and Acosta, Edward P.
- Subjects
LOPINAVIR-ritonavir ,DATA analysis software ,REPEATED measures design ,RESEARCH funding ,REGRESSION analysis ,LONGITUDINAL method ,IMMUNE system ,HIV-positive persons ,HIGH performance liquid chromatography ,GLYCOPROTEINS ,ENZYME-linked immunosorbent assay ,CONFIDENCE intervals ,BLOOD testing ,BIOLOGICAL assay ,ANALYSIS of variance ,ANALYSIS of covariance - 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 log10 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 (AUC12_total) and maximum concentration (Cmax_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 AUC12_total and Cmax_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. [ABSTRACT FROM PUBLISHER]
- Published
- 2011
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