- Poster presentation
- Open Access
Modelling the change in lopinavir apparent oral clearance over time following cessation of lopinavir/ritonavir: data from the TAIL study
© Dickinson et al; licensee BioMed Central Ltd. 2008
- Published: 10 November 2008
- Absorption Model
- Objective Function Value
- Apparent Oral Clearance
- Minimal Objective Function
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 . 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.
Parameter estimates and standard errors.
IIV CL0 (%)
Residual error – proportional (%)
Residual error – additive (mg/L)
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.