WCK 4873 (Nafithromycin): Assessment of in vitro Human CYP Inhibitory Potential of a Novel Lactone-ketolide

Background: Macrolide and ketolide class of community antibacterials are generally associated with CYP inhibitory activity leading to undesirable drug-drug interaction potential. In the present study, we investigated in vitro human CYP inhibitory potential of WCK 4873, solithromycin, telithromycin, and cethromycin.

Methods:

CYP inhibitory potential for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5was assessed using pooled human liver microsomes (HLM) and isoform specific probe substrates by LC-MS/MS method. The time dependent inhibition (TDI) and metabolism dependent inhibition (MDI) of CYP3A4/5 by all test compounds were assessed by IC₅₀ shift approach employing midazolam (MDZ) and testosterone (TST) as substrates. Multiple concentrations of test ketolides along with reference inhibitors were pre-incubated (0 and 30 min) with HLM in presence and absence NADPH.

Results:

WCK 4873 did not show inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6 (IC₅₀>300 µM) and was a weak inhibitor of CYP3A4/5 activity with substrate dependent IC₅₀ values of 83.8 µM, 70.2 µM and > 300 µM using midazolam (MDZ), nifedipine and TST as substrates, respectively. Contrastingly, employing these substrates, IC₅₀ range for solithromycin, telithromycin and cethromycin were 1.2-6 µM, 19.4-103 µM and 14.9-45.7 µM, respectively. Unlike WCK 4873, solithromycin and telithromycin showed significant CYP2D6 inhibition potential (IC₅₀: 224, 95 and 39 µM, respectively). For CYP3A4/5, no IC₅₀ shift for WCK 4873 was observed employing MDZ and testosterone as substrates indicating absence of MDI potential. However, a higher MDI potential was observed for telithromycin, cethromycin and solithromycin (IC₅₀ shift: 2, 5 and 11 and 11, 22 and 49 times, respectively for the two substrates).

Conclusion:

Unlike most macrolides and ketolides, WCK 4873 was found to be non inhibitor of all key human CYP isoforms even at significantly higher concentrations. For WCK 4873, no TDI and MDI potential was noted indicating that even the metabolites of WCK 4873 do not have potential to cause CYP3A4/5 inhibition. Cumulatively, the results suggest a lower potential of clinical drug-drug interaction for WCK 4873 (Nafithromycin).