Background: Lopinavir (LPV)/ritonavir (RTV) co-formulation (LPV/RTV) is a widely used protease inhibitor (PI)-based regimen to treat HIV-infection. As with all PIs, the trough concentration (C trough) is a primary determinant of response, but the optimum exposure remains poorly defined. The primary objective was to develop an integrated LPV population pharmacokinetic model to investigate the influence of α-1-acid glycoprotein and link total and free LPV exposure to pharmacodynamic changes in HIV-1 RNA and assess viral dynamic and drug efficacy parameters. Methods: Data from 35 treatment-naïve HIV-infected patients initiating therapy with LPV/RTV 400/100 mg orally twice daily 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 with ultraviolet (UV) detection. Free LPV (LPVf) concentrations were measured using equilibrium dialysis and mass spectrometry. Results: The LPVt typical value of clearance ( CLLPVt/F) was 4.73 L/h and the distribution volume (V LPVt) was 55.7 L. The clearance ( CL LPVt/F) and distribution volume (V fF) for LPVf were 596 L/h and 6,370 L, respectively. The virion clearance rate was 0.0350 h-1. The simulated LPVLPVttrough values at 90 % (EC90) and 95 % (EC95) of the maximum response were 316 and 726 ng/mL, respectively. Conclusions: The pharmacokinetic-pharmacodynamic model provides a useful tool to quantitatively describe the relationship between LPV/RTV exposure and viral response. This comprehensive modelling and simulation approach could be used as a surrogate assessment of antiretroviral (ARV) activity where adequate early-phase dose-ranging studies are lacking in order to define target trough concentrations and possibly refine dosing recommendations. © 2013 Springer International Publishing Switzerland.