Physiologically based pharmacokinetic (PBPK) modelling and simulation based integrative approach to assess natural product-drug interactions – effect of glycyrrhetinic acid on quetiapine

Case reports of adverse event and loss of efficacy in individuals are the primary source of natural product drug interactions (NPDIs). Given the fundamental constraints, there is clear need for prospective and systematic study as foolproof methodology to understand NPDIs. Although human trials are confirmatory, an integrative physiologically-based pharmacokinetic (PBPK) modelling approach can be considered, despite challenges associated with NP data availability, variability and complexity.To explore the applicability of this approach, glycyrrhizin (GL) and its active metabolite glycyrrhetinic acid (GA) were identified as an NP with numerous pharmacological benefits and a potential likelihood of concomitant administration with narrow therapeutic antipsychotic drug quetiapine. Numerous serious case reports of quetiapine toxicity in combination with NPs support the proposed hypothesis.Simcyp^® simulator was used to develop and validate quetiapine PBPK model followed by its utilisation for the evaluation of NPDI risk. PBPK modelling data indicated ∼ three-fold increase in quetiapine area under the curve (AUC) and peak plasma concentration (C_max) in the presence of GA, signifying moderate increase in exposure which implies the need for further clinical assessment. This study successfully demonstrated the translation of <i>in vitro</i> information into helpful risk predictions for <i>in vivo</i> NPDIs by PBPK modelling.