Efflux Transporter‐Mediated Interactions With Atorvastatin—Interesting Findings With Multiple Substrates: Istradefylline, Verapamil, and Rifampicin

Istradefylline, currently under development for a potential treatment of Parkinson disease, is an interesting compound from a clinical pharmacology perspective because it can be classified as a dual inhibitor of cytochrome P450 3A4 and P-glycoprotein.1 The dynamics of the dual interplay in the modulation of CYP3A4/efflux transporters (ie, P-glycoprotein and others) has been documented extensively.2,3 In an interesting study, Rao et al1 evaluated the pharmacokinetic disposition of atorvastatin following a single-dose administration in healthy participants who had reached steady-state levels of istradefylline after repeated dosing. Although the interaction liability, if any, on the pharmacokinetic disposition parameters of istradefylline by the coadministered atorvastatin was not evaluated, the reported data on atorvastatin suggested a potential drug-drug interaction when the 2 agents were coadministered.1 Interestingly, the data supported the likely role of the transporter system (presumably P-glycoprotein inhibition) rather than CYP3A4 inhibition of atorvastatin by the steady-state levels of istradefylline, as evidenced by the metabolite data (ortho- and para-hydroxyl atorvastatin), which showed minimal to no changes in the exposure data.1 In summary, the exposure of atorvastatin increased by over 50% in this study, with no alterations in the elimination kinetics of atorvastatin, suggesting that bioavailability of atorvastatin was altered upon coadministration with istradefylline.1 A few recently reported pharmacokinetic investigations are discussed in this note so that the interplay between CYP3A4/efflux transporter systems (P-glycoprotein) can be better appreciated.4–7 In totality, these data aim to provide better perspectives of the drug-drug interactions observed with atorvastatin, an important agent for treating cardiovascular risk factors, which may depend on the type of interacting substrate (verapamil, rifampicin, sildenafil, and/or istradefylline). Choi et al4 evaluated the potential drug-drug interaction between atorvastatin and verapamil following a single-dose administration of the 2 agents in healthy human volunteers. Here again, the CYP3A4/P-glycoprotein dual interplay exhibited by both atorvastatin and verapamil made this clinical study very interesting from both a mechanistic perspective and a clinical pharmacology point of view.4 As the study evaluated the pharmacokinetics of verapamil and its active metabolite, norverapamil, it was unknown if verapamil/norverapamil would have perhaps altered the pharmacokinetic disposition of atorvastatin and/or its key metabolites.4 However, literature data confirmed that verapamil altered the pharmacokinetics of simvastatin likely by the CYP3A4 inhibitory pathway exhibited by verapamil.8 Interestingly, following a mere single-dose administration, atorvastatin increased the exposure of verapamil by greater than 40%, suggesting that CYP3A4 isozyme and/or P-glycoprotein inhibition are likely culprits for the observed increase in verapamil's exposure.4 However, CYP3A4's inhibitory role of atorvastatin was readily discounted because the exposure of norverapamil (formation mediated by CYP3A4 isozyme) remained unaltered between verapamil given alone versus verapamil + atorvastatin combined treatment.4 Another recent work of Lau et al5 showed how another substrate that has the potential for dual CYP3A4/efflux transporter interplay such as rifampicin has the potential to alter the pharmacokinetics of atorvastatin at a single-dose administration itself. In this study, the hepatic uptake of atorvastatin was blocked by the effective inhibition of the organic anion transporter pathway (OAT1B1) by rifampicin after a single-dose administration, which resulted in a significant increase in the exposure levels of atorvastatin.5 Previously, rifampicin has been shown to produce the blockade of the OAT1B1 pathway, thereby significantly inhibiting the hepatic uptake of bosentan.6 Another totally different substrate, sildenafil, has also been shown to inhibit the hepatic uptake of bosentan, which resulted in an almost 50% increase in the exposure of bosentan upon coadministration.7 However, because rifampicin is an inducer of CYP3A4 isozyme, it has been documented that upon repeated dosing of rifampicin, the atorvastatin exposure levels were drastically decreased.9 Therefore, these data suggest that within the dual interplay, there is a delicate balance between the 2 systems, as evidenced by single-dose and steady-state drug interaction profiles between rifampicin and atorvastatin.4,9 In addition to P-glycoprotein's involvement in the efflux phenomenon that controls bioavailability, the hepatic uptake transporter may also play an important role in efficacy as well as in clearance mechanisms of atorvastatin.10 In view of the data summarized in this report, it would be interesting to pinpoint the nature of interaction(s) that occur between istradefylline and atorvastatin (additional transporter(s) outside of P-glycoprotein involved in the postulated interaction). Although the multiplicities of the transporters' involvement are known, it would be good to ask if istradefylline participates in the blockade of the organic anion transporter system and, if so, the possible consequences of such interaction(s). It should be noted that rifampicin, through its inhibitory influence on the organic ion transporter system, also participates in the blockade of biliary excretion of ezetemibe and its glucuronides, resulting in higher systemic exposure of these agents.11 Because drug-drug interaction studies are the cornerstone of any sound clinical pharmacology strategy, it is important that such studies are designed, executed, and interpreted to guide drug development process. It is my opinion that drug-drug interaction studies involving the dual interplay of the CYP3A4/efflux transporter system (P-glycoprotein and/or others) could be interpreted better when conducted at steady-state levels of both agents to mimic chronic clinical conditions. In addition, the measurements of pharmacokinetic parameters of both interacting agents and applicable metabolites would rationalize the decision-making process for any dose adjustment requirement(s) of one or both agents that are being evaluated.