Review of P‐gp Inhibition Data in Recently Approved New Drug Applications: Utility of the Proposed [I₁]/IC₅₀ and [I₂]/IC₅₀ Criteria in the P‐gp Decision Tree

Solitary Inhibition of the Breast Cancer Resistance Protein Efflux Transporter Results in a Clinically Significant Drug-Drug Interaction with Rosuvastatin by Causing up to a 2-Fold Increase in Statin Exposure

“…where K i = absolute inhibition constant (equating to IC 50 if the probe [S] , ,,, K m in the inhibition assay and assuming competitive inhibition, based on the Cheng-Prusoff equation; Cheng and Prusoff, 1973) and [I] = maximum enterocyte concentration (I gut max ; as described by Agarwal et al, 2013). Additionally, the predicted change in rosuvastatin AUC based upon inhibition of OATP1B1 (ƒ e = 0.38) was also determined using K i values derived from either the aforementioned in vitro OATP1B1 inhibition assay (at 0.3, 1, 3, 10, 30, and 100 mM; using LC-MS/MS as the analytical endpoint) or the literature, in context with the unbound maximum hepatic inlet concentration as [I], to understand the contribution (if any) of OATP1B1 inhibition toward the overall magnitude of exposure change observed clinically through DDI.…”

“…4 mM) are inhibitors, R-value extrapolations indicate their potential for DDI as unlikely (,1.25), and lopinavir is not an inhibitor (De Bruyn et al, 2011Takeuchi et al, 2011;Vildhede et al, 2014). Finally, inhibition of sodium/taurocholate cotransporting peptide (NTCP) can be ruled out as a contributory factor since 1) despite being an NTCP inhibitor in vitro (K i = 25 mM; Dong et al, 2013), ezetimibe is not expected to cause a DDI via this mechanism in vivo (R = 1.00); 2) lopinavir does not inhibit NTCP (Vildhede et al, 2014); and 3) although it is unknown whether the ), and Q ent is the enterocyte blood flow (300 ml/min [ 18 l/h; Agarwal et al, 2013); I inlet max u , maximum unbound liver inlet concentration, calculated as f u  [(C max total ) + (F a  k a  dose/Q h )], where F a is the fraction absorbed (as default taken to be 1.0), k a is the absorption rate constant (as default taken to be 0.1 min 21 ), and Q h is hepatic blood flow (1500 ml/min); K i , absolute inhibition constant (assuming competitive inhibition; equates to IC 50 in these assays as probe substrate concentration used is , ,,, K m ); MW, molecular weight [taken from the drug label accessed via Pharmapendium database (http://www.pharmapendium.com)]; NA, not applicable.…”

“…However, such an approach likely overpredicts the impact due to BCRP inhibition (particularly for those DDIs where the increase in observed AUC is ,2-fold) because of high [I 2 ] values, which may not reflect true concentrations once intestinal solubility is accounted for. An alternative parameter, maximum inhibitor concentration in the enterocyte [I gut max ], may be a more accurate representation of intestinal concentration as it is independent of solubility (Agarwal et al, 2013) (see Table 3 for equation). Consequently, in this study, we explored the use of [I gut max ] in the adapted Rowland-Matin equation, alongside a BCRP f e = 0.5, to establish whether taking into account varying degrees of intestinal BCRP inhibition (rather than assuming 100% inhibition) resulted in more accurate predictions of clinical exposure.…”

Application of Receiver Operating Characteristic Analysis to Refine the Prediction of Potential Digoxin Drug Interactions

“…If no alteration in transport is observed with increasing concentrations of the NCE then the NCE is not likely to interact with digoxin and no further studies are needed. Agarwal et al (2012) assembled a data set of 11 compounds approved between 2003 and 2010. The authors observed that the decision criteria in the current FDA guidance was highly accurate in predicting the TP (100%, 5 of 5) and FN (0%, 0 of 5), with TN at 67% (4 of 6) and FP at 33% (2 of 6) in this small data set.…”

Association between statin use and ischemic stroke or major hemorrhage in patients taking dabigatran for atrial fibrillation

“…Emerging evidence from in vitro studies suggests that statins administered in their lactone forms (i.e., simvastatin and lovastatin) are potent inhibitors of Pglycoprotein and carboxylesterase enzyme activity, whereas other statins are not. [7][8][9][10] Because hypothetical intestinal concentrations of simvastatin and lovastatin likely exceed those required to inhibit intestinal P-glycoprotein, 11 coadministration with dabigatran etexilate could increase the absorption of dabigatran and the resultant risk of hemorrhage. Conversely, inhibition of the carboxy-able adjustment, use of simvastatin or lova statin was not associated with an increased risk of stroke (adjusted odds ratio [OR] 1.33, 95% confidence interval [CI] 0.88 to 2.01).…”