PII-012 - LEVERAGING COPROPORPHYRIN-I AS AN ENDOGENOUS OATP1B BIOMARKER TO DISENTANGLE THE EFFECTS OF CEDIROGANT IN COMPLEX DRUG-DRUG INTERACTIONS.

R. Kikuchi¹, Y. Qian², M. Badawi¹, J. Savaryn², S. Gannu¹, A. Eldred¹, S. Hao¹, A. Salem², W. Liu¹, M. Mohamed²; ¹AbbVie Inc, ²AbbVie Inc..

Background: Cedirogant is an inverse agonist of retinoic acid-related orphan receptor gamma, thymus (RORγt) that was being developed for treatment of chronic plaque psoriasis. Cedirogant inhibits breast cancer resistance protein (BCRP), organic anion transporting polypeptides (OATP) 1B1/1B3 while inducing cytochrome P450 (CYP) 3A4 in vitro, leading to challenges in evaluating and interpreting clinical drug-drug interactions (DDI). This study aims to utilize coproporphyrin-I (CP-I) as an endogenous OATP1B biomarker for deciphering DDI observed in a clinical study between cedirogant and two statin drugs.

Methods: In an open-label, two-part, Phase 1 study, healthy participants received once-daily (QD) doses of rosuvastatin (BCRP and OATP1B substrate) in Part 1 and atorvastatin (CYP3A, BCRP and OATP1B substrate) in Part 2. Within each part, the statin was administered alone in Period 1, followed by co-administration of the statin with 375 mg QD cedirogant in Period 2. Changes in plasma exposure, as measured by maximum plasma concentration (Cmax) and area under plasma concentration curve over a dosing interval (AUC0-24), of rosuvastatin and atorvastatin due to co-administration with cedirogant were calculated. Changes in CP-I concentration from baseline were assessed in Period 2, Part 2 as well as in a separate multiple ascending dose (MAD) study of cedirogant at the same dose.

Results: Co-administration with cedirogant increased rosuvastatin Cmax and AUC0-24 (90% confidence interval) by 141% (96%, 197%) and 55% (33%, 80%), respectively, while increased atorvastatin Cmax by 40% (22%, 61%) without affecting its AUC0-24. Cedirogant did not notably increase CP-I levels relative to the baseline values (geometric mean ratio within 1.25-fold) in either the statin DDI study or the MAD study, suggesting no relevant effect on OATP1B transporters.

Conclusion: These results indicated that the increased statin exposure observed with cedirogant is likely attributed to inhibition of BCRP rather than OATP1B transporters. This study demonstrated the utility of CP-I to distinguish between different mechanisms in a complex DDI that involves multiple transporters and enzymes.