Physiologically based pharmacokinetic modeling of aldehyde oxidase drug-drug interactions mediated by erlotinib

Abstract

The propensity for aldehyde oxidase (AO) substrates to be implicated in drug-drug interactions (DDI) has remained largely uninterrogated due to the lack of a precipitant drug which elicits potent inhibition of AO in vivo. Recently, we characterized the epidermal growth factor receptor inhibitor erlotinib as a clinical AO inhibitor and proposed, through mechanistic metabolism studies and static modeling, that AO inhibition was responsible for its observed DDI with the investigational drug OSI-930. However, as erlotinib also inhibits the organic anion transporting polypeptide 2B1 transporter in the liver and gut at clinically relevant concentrations, the potential contribution of transporter-mediated interactions to the observed clinical DDI with OSI-930 remained unclear. In this follow-up study, uptake studies in organic anion transporting polypeptide 2B1-transfected human embryonic kidney 293 cells confirmed that OSI-930 is not a substrate for this transporter. Physiologically based pharmacokinetic (PBPK) models for erlotinib and OSI-930, which incorporated competitive and time-dependent AO inhibition and an AO-mediated metabolism component, respectively, were iteratively developed, refined and verified using published clinical data. Our physiologically based pharmacokinetic model successfully recapitulated the in vivo AO-mediated DDI between erlotinib and OSI-930 occurring after multiple erlotinib doses, with predicted/observed C_max and area under the curve ratios ranging from 0.84 to 1.06. Additional simulations were also conducted to investigate untested clinical DDI scenarios between erlotinib and other known AO substrates-O6-benzylguanine, zaleplon, ziprasidone, and zoniporide. These prospective simulations suggested a considerable DDI risk (ie, area under the curve ratio > 3-fold) for high fraction metabolized by AO (f_m,AO) compounds codosed with clinical doses of erlotinib, thereby warranting further clinical investigation. SIGNIFICANCE STATEMENT: The contribution of OATP2B1 and AO inhibition to the observed erlotinib-OSI-930 DDI was investigated using in vitro experiments and PBPK modeling. Our study revealed that the DDI is due to inhibition of AO-mediated clearance of OSI-930 by erlotinib. Additionally, our erlotinib model also predicts clinically significant DDIs would occur when dosing erlotinib with high f_m,AO AO substrates. These findings highlight the need to consider AO inhibition in DDI risk assessments and may help inform future drug development and regulatory strategies.

Keywords: Aldehyde oxidase; Drug-drug interaction; Erlotinib; Organic anion transporting polypeptide; Physiologically-based pharmacokinetic modeling.