Unexpected interaction between CYP3A4 and BI 11634: is BI 11634 interacting with CYP3A4 similar to nifedipine?

Abstract

These data indicated that BI 11634 may interact with CYP3A4 similar to nifedipine. CYP3A4 substrates have been categorized into three subgroups, including a stand-alone subgroup for dihydropyridine calcium channel blockers such as nifedipine and felodipine. In addition, this study emphasizes the importance of using rCYP in conjunction with approaches relying on inhibition when conducting CYP450 reaction phenotyping studies, as one single method may generate misleading results. The specificity of quinidine as a CYP2D6 inhibitor is questionable as it can also significantly inhibit CYP3A4-mediated metabolism of some compounds.

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions—an Industry Perspective

“…Scenarios include high protein concentration resulting in high nonspecific binding of inhibitor resulting in ,90% inhibition of the intended P450-this underestimates f m of intended P450; use of excessive inhibitor concentration resulting in substantial cross-reactivity, which leads to overestimation of f m of intended P450; high substrate/ NME concentration . .K m , resulting in (12) overwhelming the inhibitory effect of reversible inhibitors and underestimating f m of intended P450; 3) the lack of absolute specificity of the probe substrate and/or inhibitor for P450; 4) potential difference in P450 binding site for the probe substrate and the NME, where the NME may interact with the P450 at a binding site, different from that of the probe substrate (Mathur et al, 2013). Large discrepancies in f m values obtained from chemical inhibition and rhCYP scaling methods, often result in considerable differences in the magnitude of the predicted victim DDI liability for a NME and warrant a systematic look into factors discussed above Correlation analysis is another method that has been assessed for the P450 isoforms (and infrequent cases of UGT; Kamdem et al, 2010); however, review of current industry practices among the working group member companies did not advocate this to be a method of choice for phenotyping of drug candidates, especially when there is discrepancy in the f m values from RAF/ISEF and chemical inhibitor methods.…”