title: Integrated population pharmacokinetic/viral dynamic modelling of lopinavir/ritonavir in HIV-1 treatment-naïve patients.
abstract: 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 (VLPVt/F) was 55.7 L. The clearance (CLLPVf/F) and distribution volume (Vf/F) for LPVf were 596 L/h and 6,370 L, respectively. The virion clearance rate was 0.0350 h(-1). The simulated LPVLPVt C trough 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.
authors: Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors: Kun
authors: K
authors: Wang
authors: David Z
authors: DZ
authors: D'Argenio
authors: Edward P
authors: EP
authors: Acosta
authors: Anandi N
authors: AN
authors: Sheth
authors: Cecile
authors: C
authors: Delille
authors: Jeffrey L
authors: JL
authors: Lennox
authors: Corenna
authors: C
authors: Kerstner-Wood
authors: Ighovwerha
authors: I
authors: Ofotokun
mesh_terms: D000328:Adult; D000465:Algorithms; D004338:Drug Combinations; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D061466:Lopinavir / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009961:Orosomucoid / Q000378:metabolism; D011153:Population; D019438:Ritonavir / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019562:Viral Load
chemical_list: D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D009961:Orosomucoid; D061466:Lopinavir; D019438:Ritonavir