C103-07 In Vitro Characterization of Pirfenidone as an Inducer of CYP3A4 and Associated Clinical DDI Implications

Abstract Rationale Pirfenidone (Esbriet®) is an oral antifibrotic treatment for idiopathic pulmonary fibrosis (IPF). In the FIBRONEER™-IPF Phase 3 trial investigating the safety and efficacy of the oral preferential PDE4B inhibitor nerandomilast (JASCAYD®), IPF patients on background pirfenidone therapy had a 50% reduction in nerandomilast plasma concentrations and a lack of efficacy with nerandomilast at a dose of 9 mg BID. Lower plasma concentrations were also reported for two other investigational compounds in IPF, fezagepras (PBI-4050) and ziritaxestat, in Phase 2 and 3 trials, respectively, in patients on background pirfenidone. It was hypothesized that concomitantly administered pirfenidone caused a pharmacokinetic drug-drug interaction (DDI) through a mechanism not indicated in its prescribing information. Methods As the major pathway of nerandomilast metabolism occurs via oxidation by cytochrome P450 3A4 (CYP3A4), the potential for pirfenidone to induce CYP3A4 was assessed in vitro in primary human hepatocytes, in accordance with the current ICH M12 DDI regulatory guideline. Hepatocytes from three individual donors were incubated with pirfenidone at concentrations up to 5 mM for 48 h, and CYP3A4 gene expression and enzyme activity was measured. In vitro CYP3A induction parameters (EC50 and Emax) were derived and equations outlined in the ICH M12 DDI guideline were applied to estimate the potential in vivo impact of co-administered pirfenidone on the plasma exposure of nerandomilast. Results Pirfenidone induced CYP3A4 mRNA expression and enzyme activity in vitro to similar levels as the reference inducer, rifampicin, in all three hepatocyte donors. Using the derived induction parameters and equations described in the ICH M12 DDI guideline, pirfenidone was predicted to be an in vivo inducer of CYP3A4 at plasma exposure levels correlating with therapeutic doses. Additionally, coadministered pirfenidone was predicted to decrease nerandomilast plasma exposure by approximately 50-70% in vivo. Conclusions Based on this in vitro study, pirfenidone is an inducer of CYP3A. Therefore, pirfenidone is likely an in vivo inducer of CYP3A4, which may result in clinical DDIs with coadministered drugs that are metabolized by CYP3A4. As such an interaction is not described in the prescribing information for pirfenidone, this induction effect could lead to an unanticipated reduction in plasma exposure and efficacy of concomitant medications in IPF patients taking pirfenidone. The observed decreased plasma concentration and efficacy of nerandomilast in IPF patients on background pirfenidone therapy can likely be explained by induction of CYP3A4 precipitated by pirfenidone; however, this needs to be confirmed in a dedicated clinical DDI trial. This abstract is funded by: Boehringer Ingelheim