Monitoring Free Concentrations of Protease Inhibitors

Antiretroviral drugs used in treating patients with AIDS demonstrate wide variations in serum protein bindings. Protease inhibitors with the exception of indinavir are strongly protein bound (>90%) mainly to a1 acid glycoprotein. Efavirenz, a non-nucleoside reverse transcriptase inhibitor, is more than 99% bound to serum protein (mainly albumin). The pharmacological effect of antiretroviral drugs is dependent upon the unbound concentration of drugs capable of entering cells that harbor human immunodeficiency virus (HIV) (32). Protein binding of indinavir varied between 54 and 70% in eight men with a mean protein binding of 61%. However, the variability of protein binding was concentration-dependent (33). Although determination of indinavir concentrations in saliva using HPLC is useful in determining compliance of patients with indinavir therapy, salivary concentrations of indinavir do not correlate with unbound concentration of indinavir in plasma if saliva collection was stimulated, but correlate well with unbound concentration in plasma if saliva collection was not stimulated (34).

The mean free plasma-unbound amprenavir concentration was 8.6% (range 4.420%) in one study. Moreover, lopinavir was able to displace amprenavir from protein binding in vitro, but another strongly protein-bound protease inhibitor ritonavir had no effect (35). Boffito et al. studied lopinavir protein binding in vivo through a 12-h dosing interval and measured free lopinavir concentrations using HPLC-MS/MS. The mean unbound lopinavir concentration was 0.92% when measured using ultrafiltration but 1.32% using equilibrium dialysis. The unbound percentage of lopinavir was also found to be higher after 2 h than at baseline (36). However, therapeutic drug monitoring of free concentrations of antiretroviral drugs are at this point in the preliminary stage, and more studies are needed with a larger patient base as well as clinical correlations to establish guidelines for monitoring the free drug concentration of antiretroviral drugs.

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