A Mechanistic Pharmacokinetic Approach to the Development of Predictive Models in HIV-malaria co-infection.
Z.H. Zakaria (1), G.L. Woodhall (2), R.K.S Badhan (1)
(1) Aston Pharmacy School, School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK. (2) Aston Brain Centre, School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK.
Objectives: To develop a physiologically-based pharmacokinetic (PBPK) model describing PK relationships between efavirenz and antimalarial.
Methods: In the current project, a stepwise platform was applied to developing a PBPK model to assess the impact of efavirenz on antimalarial PK [1]. Firstly, assessment and optimization of CYP3A4-mediated induction by efavirenz were conducted using kinetic data to drive the model. The model was also populated with relevant pharmacogenetic data. Second, the PBPK model were established for a range of antimalarial compounds, forming a drug-drug interaction (DDI) test-data set. Finally, the developed model was validated and qualified by comparing model-predicted plasma profile with published literature PK data. Simcyp were used to model the data.
Results: Once developed and qualified, our model successfully predicted human plasma drug concentrations of efavirenz and DDI from a limited set of routinely available pre-clinical and in vitro drug-specific parameters. Model also suggested optimal therapeutic doses for treatment with efavirenz in HIV-malaria co-infection patients.
Conclusions: This approach has significant implications for assessing DDI between efavirenz and antimalarial as well as provides an opportunity for exploring the relationship between efavirenz and HIV-malaria co-infection.
References:
[1] Ke, A., et al. (2016). "Towards a Best Practice Approach in PBPK Modeling: Case Example of Developing a Unified Efavirenz Model Accounting for Induction of CYPs 3A4 and 2B6." Cpt Pharmacometrics & Systems Pharmacology 5(7): 367-376.
