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.

Figure 1

Longitudinal change in mean serum α-1-acid glycoprotein (AAG) (A), and mean C-reactive protein (B), in 16 antiretroviral naïve HIV-infected patients treated with a lopinavir-/ritonavir-based regime. Vertical bars = 95% confidence intervals (CIs).

Figure 2

Longitudinal change by period in mean total and mean free lopinavir concentration time profiles in 15 antiretroviral naive HIV-infected patients treated with a lopinavir-/ritonavir-based regime. Vertical bars = 95% confidence intervals (CIs).

Figure 3

(A) Estimated mean linear increase in total lopinavir area under the concentration time curve (AUC₁₂) by serum α-1-acid glycoprotein (AAG)using data from periods 1 and 2 (P = .04 when comparing the estimated AUC₁₂ slope to zero). (B) No statistically significant linear relationship when free lopinavir AUC₁₂ was regressed on serum AAG (P = .76). (C) Estimated mean linear increase in total lopinavir C_max by serum AAG (P = .02). (D) No statistically significant linear relationship when free lopinavir C_max was regressed on serum AAG (P = .89).

Figure 4

No significant linear relationship was identified between the total and free lopinavir pharmacokinetic (PK) parameters, nor between serum α-1-acid glycoprotein (AAG) regressed on HIV-1 RNA average AUC minus baseline (AAUCMB).