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  • Open Access

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

  • 1,
  • 2,
  • 3,
  • 2,
  • 3,
  • 2 and
  • 4
Journal of the International AIDS Society200811 (Suppl 1) :P241

https://doi.org/10.1186/1758-2652-11-S1-P241

  • Published:

Keywords

  • Absorption Model
  • Lopinavir
  • Objective Function Value
  • Apparent Oral Clearance
  • Minimal Objective Function

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.

Methods

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.

Parameter

Estimate

Standard Error

CL0 (L/h)

53.2

8.09

Ki (mg/L)

0.0442

0.0102

V/F (L)

124

8.90

IIV CL0 (%)

16.2

9.69

IIV V/F

12.8

8.67

Residual error – proportional (%)

28.8

12.6

Residual error – additive (mg/L)

0.0117

0.00849

Figure 1
Figure 1

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

Conclusion

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.

Authors’ Affiliations

(1)
NIHR National Biomedical Research Centre, Royal Liverpool & Broadgreen University Hospital Trust, Liverpool, UK
(2)
St Stephen's Centre, Chelsea & Westminster Foundation Trust, London, UK
(3)
Department of Pharmacology & Therapeuticsm University of Liverpool, Liverpool, UK
(4)
School of Pharmacy & Pharmaceutical Sciences, University of Manchester, Manchester, UK

References

  1. Boffito M, et al: AIDS. 2008Google Scholar

Copyright

© Dickinson et al; licensee BioMed Central Ltd. 2008

This article is published under license to BioMed Central Ltd.

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