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Background: Lopinavir (LPV)/ritonavir (RTV) co-formulation (LPV/r) is a widely used protease inhibitor (PI) based regimen to treat HIV-infection.As with all PIs, the trough concentration (C 12h) is a primary determinant of response, but the optimum exposure remains poorly defined.Objectives:The primary objective was to develop an integrated LPV population pharmacokinetic (PK) model to investigate the influence of α-1-acid glycoprotein (AAG) and link total and free LPV exposure to pharmaeodynarnic (PD) changes in HIV-1 RNA and assess viral dynamic and drug efficacy parameters.Methods:Data from 35 treatment-naive HIV-infected patients initiating therapy with LPV/r 400/100 mg PO BID across two studies were used for model development and simulations using ADAPT.Total LPV (LPVt) and RTV concentrations were measured by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection.Free LPV (LPVf) concentrations were measured using equilibrium dialysis and mass spectrometry.Plasma AAG concentrations were quantified using an enzyme-linked immunosorbent assay (ELISA).The population model was constructed by developing separate models for RTV, LPVt,LPVf, and viral dynamics in sequence, then integrating these submodels to construct the composite final PK-PD model shown in Figure 1.As indicated in Figure 1, LPVt CLt/F depends on the concentration of ritonavir (CRTV), where LPVf concentration (CLPVf) is a function of both LPVt (CLPVt) and AAG.The LPV effect on viral dynamics was modeled by linking LPVf concentrations through transit delay compartments.Results:LPVt typical value of clearance (CLt/F) was 4.73 L/h and distribution volume (Vt/F) was 55.7 L.Clearance (CLf/F) and distibution volume (Vf/F) for LPVf were 596 L/h and 6370 L, respectively.Virion clearance ratewas 0.035 h-1.Simulated LPVt C12h at 90% (EC90) and 95% (EC95) maximum responsewere 316 and 726 ng/mL, respectively.Conclusion:The PK-PD model provides a useful tool to quantitatively describe the relationship between LPV/r exposure and viral response.This comprehensive modeling and simulation approach could be used as a surrogate assessment of antiretrovirals where adequate early phase dose-ranging studies are lacking in order to defme target trough concentrations and possibly refine dosing recommendations.