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Background: LPV and RTV are both highly bound to plasma proteins (98—99%), including albumin andα;1- acid glycoprotein. However, the attenuation of LPV in vitro potency by addition of 50% human serum (HS) (mean 8.6-fold) is less than that of RTV (ca. 20-fold). Since disease states may affect the plasma composition and in vitro experiments need to be conducted with diluted plasma, there is a concern of clinical relevancy for data obtained using uninfected or diluted plasma.
Methods: The free fractions of LPV and RTV determined in several media were compared: healthy volunteers’ plasma with spiked drugs, steady-state plasma from healthy or HIV-infected subjects dosed with LPV/RTV or RTV, and in a medium similar to that employed to conduct in vitro antiviral activity experiments (50% human serum + 40% RPMI medium 1640 + 10% fetal calf serum). Binding was also determined for RTV in HIV- infected subjects with normal, mild and moderately impaired hepatic functions.
Results: For LPV (in the presence of RTV) and RTV, the free fractions were similar among all the samples analyzed. In healthy volunteers taking LPV/RTV for 2 weeks, the binding ranged from 98.8 to 99.2% (2.1 to 12.6mg/mL). In HIV-infected subjects taking LPV/RTV for 3 weeks, the binding ranged from 98.4 to 99.1% (1.4 to 12.4mg/mL). In 40% RPMI medium 1640 + 10% fetal calf serum + 50% human serum, the binding ranged from 98.8—99.4% for LPV and 99.2—99.4% for RTV, with both drugs ranging from 0.1—10mg/mL. Furthermore, RTV mean free fractions were similar, being 1.49, 1.25, and 1.66%, respectively, for HIV-infected subjects with normal, mild or moderately impaired hepatic functions.
Conclusions: The free fractions of LPV and RTV were similar in samples containing 60% or more plasma proteins. HIV infection does not significantly alter the binding of LPV and RTV. The difference in attenuation of antiviral activity by plasma proteins between LPV and RTV is probably due to differences in dynamics of equilibrium between drugs and proteins.
Authors
1 Abbott Laboratories, Abbott Park, IL; 2 Amgen Inc, Thousand Oaks, CA; 3 Covance Laboratories, Madison, WI
© 2001 Medical Advocates
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