Understanding Inter-individual Variability in the Drug Interaction of a Highly Extracted CYP1A2 Substrate Tizanidine: Application of a Permeability-limited Multi-compartment Liver Model in a Population Based PBPK Framework

Tizanidine, a centrally acting skeletal muscle relaxant, is predominantly metabolised by CYP1A2 and undergoes extensive hepatic first-pass metabolism following oral administration. As a highly extracted drug, the systemic exposure to tizanidine exhibits considerable inter-individual variability and is altered substantially when co-administered with CYP1A2 inhibitors or inducers. The aim of the current study was to compare the performance of a permeability-limited multi-compartment liver (PerMCL) model, which operates as an approximation of the dispersion model (DM), and the well-stirred model (WSM) for predicting tizanidine DDIs. Physiologically-based pharmacokinetic (PBPK) models were developed for tizanidine, incorporating the PerMCL model and the WSM, respectively, to simulate the interaction of tizanidine with a range of CYP1A2 inhibitors and inducers. While the WSM showed a tendency to under-predict the fold change of tizanidine AUC (AUC ratio) in the presence of perpetrators, the use of PerMCL model increased precision (absolute average-fold error: 1.32 - 1.42 versus 1.58) and decreased bias (average-fold error: 0.97 - 1.25 versus 0.63) for the predictions of mean AUC ratios as compared to the WSM. The PerMCL model captured the observed range of individual AUC ratios of tizanidine as well as the correlation between individual AUC ratios and CYP1A2 activities without interactions, whereas the WSM was not able to capture these. The results demonstrate the advantage of using the PerMCL model over the WSM in predicting the magnitude and inter-individual variability of DDIs for a highly extracted sensitive substrate tizanidine. This study demonstrates the advantages of the permeability-limited multi-compartment liver (PerMCL) model, which operates as an approximation of the dispersion model (DM), in mitigating the tendency of the well-stirred model (WSM) to under-predict the magnitude and variability of DDIs of a highly extracted CYP1A2 substrate tizanidine when it is administered with CYP1A2 inhibitors or inducers. The PBPK modelling approach described herein is valuable to the understanding of drug interactions of highly extracted substrates and the source of its inter-individual variability.