Skip to main content
  • Poster presentation
  • Open access
  • Published:

Modelling the change in lopinavir apparent oral clearance over time following cessation of lopinavir/ritonavir: data from the TAIL study

Purpose of the study

The TAIL study determined plasma concentrations of lopinavir/ritonavir (LPV/RTV) over 72 hours following cessation of LPV/RTV (400/100 mg twice daily) in healthy volunteers. There was a rapid decline in LPV concentrations as RTV diminished over time [1]. Here we have determined a model to quantify the changes in LPV apparent oral clearance (CL/F) in relation to RTV concentrations.


Plasma LPV and RTV concentrations were determined by HPLC-MS/MS. Initially, non-linear mixed effects modelling was applied (NONMEM vs. VI) to LPV and RTV data separately using first-order conditional estimation with interaction. Secondly, individual predicted RTV pharmacokinetic (PK) parameters were fed into a model to determine LPV PK parameters assuming competitive inhibition by RTV. Model fit was assessed by statistical and graphical methods. A decrease in minimal objective function value (OFV) of 3.84 points corresponded to a statistically significant difference between hierarchical models.

Summary of results

Sixteen healthy volunteers (six female) were included. A one-compartment model with zero-order absorption was used to generate RTV parameters. Initially, a one-compartment first-order absorption model was used for LPV in the combined model; however, under-prediction of concentrations in the early absorption phase and over-prediction in parts of the elimination phase occurred. A one-compartment zero-order absorption model for LPV improved the fit (OFV -157.934) and was parameterised by LPV clearance in the absence of inhibitor (CL0), apparent volume of distribution (V/F), CL/F and RTV inhibition constant (Ki) with inter-individual variability (IIV) included on CL0 and V/F. Residual error was described by a combined additive-proportional model. A first-pass model produced similar estimations. Parameter estimates and time-dependent changes in LPV CL/F are shown (Table 1; Figure 1, respectively). Larger changes in LPV CL/F were observed from approximately 10 hours post-dose compared to 0.5–8 hours post-dose (3.04–63.83 vs. 0.40–12.99 L/h).

Table 1 Parameter estimates and standard errors.
Figure 1
figure 1

Time-dependent changes in LPV CL/F following drug cessation.


A model assuming competitive inhibition of LPV by RTV combined with zero-order kinetics best described the time-dependent changes in LPV CL/F following drug cessation. Given the complexity of the LPV-RTV interaction, potentially more complex models should be explored.


  1. Boffito M, et al: AIDS. 2008

    Google Scholar 

Download references

Author information

Authors and Affiliations


Rights and permissions

Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

Dickinson, L., Boffito, M., Else, L. et al. Modelling the change in lopinavir apparent oral clearance over time following cessation of lopinavir/ritonavir: data from the TAIL study. JIAS 11 (Suppl 1), P241 (2008).

Download citation

  • Published:

  • DOI: