Novel oral PORCN inhibitor does not alter the PK of nintedanib, an approved therapy for idiopathic pulmonary fibrosis

AZD5055 is a novel oral inhibitor of the enzyme porcupine, being investigated for IPF. AZD5055 is an inhibitor of the transporter permeability glycoprotein (P-gp) in vitro. Applying regulatory guidance basic models flagged a risk of drug-drug interaction (DDI) with P-gp substrate drugs in the intestine following oral dosing. Nintedanib is an approved oral therapy, widely used in IPF patients, and a known P-gp substrate with a narrow therapeutic index. The main objective was to identify and quantify a potential clinical pharmacokinetic DDI between AZD5055 and nintedanib at therapeutically relevant doses. In an open three-way cross-over study (<ext-link>NCT05644600</ext-link>), using single doses in a fasted state, 18 healthy volunteers received nintedanib alone or nintedanib + AZD5055 (35 mg) or nintedanib + AZD5055 (10 mg) in a randomized order, separated by a 3-day wash-out. The nintedanib dose was 100 mg. We measured nintedanib and AZD5055 plasma concentrations up to 48 hours after dose and computed the area under the concentration–time curve (AUC) and maximum concentration (Cmax). Adjusted geometric mean ratios (with/without 35 mg AZD5055) were 102% and 111% for nintedanib AUC and Cmax, respectively. For both parameters, the 90% confidence intervals included 100%, suggesting similar exposure for administration alone and when co-administered. A similar effect on nintedanib PK was seen for the 10 mg AZD5055 dose. The AZD5055 PK profile was as observed in previous clinical studies. Both treatments were well tolerated. These data indicate there is no relevant pharmacokinetic DDI between AZD5055 and nintedanib, when co-administered in healthy volunteers.