Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A

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Over the past decade, drug‐drug interactions (DDIs) mediated via drug transporters, including organic anion‐transporting polypeptides (OATPs), MDR1 P‐glycoprotein (P‐gp), and breast cancer resistance protein (BCRP), have been increasingly recognized for their associations with several clinically important DDIs.1 However, understanding the roles of drug transporters and their involvement in DDIs is merely emerging. The lack of specific substrates and inhibitors has been a major impediment to mechanistically informing the relative contribution of individual transporters to clinical DDIs necessitating the conduct of dedicated clinical studies with multiple substrates.2 Furthermore, drug transporters are known for their functional redundancy and the existence of compensatory mechanisms and substrate‐specific modulation hampers the extrapolation of in vitro to in vivo data.2 Moreover, the complexity related to dependency of in vitro model systems and methodologies used across laboratories further confounds the situation.2 Consequently, quantitative extrapolation of in vitro data to in vivo situations is usually associated with much uncertainty requiring confirmation with clinical DDI trials.
Given the aforementioned reasons, there is a need for a more efficient clinical DDI study design to allow simultaneous assessment of a perpetrator's risk potential on multiple substrate probes with different transporter selectivity profiles. To date, unlike cytochrome P450 (CYP)s, there are no data demonstrating the utility of a cocktail approach to simultaneously assess DDIs mediated via drug transporters.4 In recent studies,6 a four‐component transporter cocktail consisting of digoxin (P‐gp), rosuvastatin (OATP and BCRP), metformin (organic cation transporter, multidrug and toxin extrusion transporters), and furosemide (organic anion transporter (OAT)) have been proposed based on in vitro assessment and clinical pharmacokinetic studies, but no clinical DDI study with transporter inhibitors has been performed to confirm the validity of the proposed probe cocktail.
In this investigation, we aimed to establish an in vivo clinical tool, using a microdose cocktail approach, to simultaneously assess a perpetrator's impact on the most common drug metabolizing enzyme, CYP3A, and major transporters OATP1B, BCRP, and P‐gp. The cocktail consisted of midazolam (a specific and sensitive probe for CYP3A), dabigatran etexilate (DABE; a selective and sensitive probe for gut P‐gp),8 pitavastatin (a relatively selective probe for OATP1B), rosuvastatin (a substrate of BCRP, OATP, and P‐gp), and atorvastatin (a substrate of OATP, BCRP, P‐gp, and CYP3A).9 The validity of the proposed probe substrates was assessed using three well‐characterized inhibitors with different transporter/enzyme profiles based on clinical DDIs reported at therapeutic doses, namely rifampin, itraconazole, and clarithromycin.11 We also explored the impact of rifampin on bilirubin, a potential endogenous biomarker for OATP1B.14 Additionally, comparative in vitro inhibitory effects of the three inhibitors on major transporters were performed to enable in vivo data interpretations and in vitro‐in vivo transporter relationship investigations.
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