Abstract
Cytochrome-P-450 (CYP)1A2 has been considered the major enzyme metabolizing riluzole since its approval. However, the inhibitor that was used in the original experiments, α-naphthoflavone, is also a potent inhibitor of CYP1A1. In this work, physiologically based pharmacokinetic (PBPK) modeling investigates the interplay between CYP1A1 and CYP1A2 and the relevance to drug-drug interactions. Following review of clinical and non-clinical data from literature, the relative contributions of CYP1A1, CYP1A2, and UGT1A8/9 to riluzole metabolism were assigned as 60%, 30%, and 10%, respectively. The model was calibrated on single-dose pharmacokinetic (PK) data from healthy subjects. The translational potential of the model was verified by predicting riluzole PK in people with amyotrophic lateral sclerosis, spinal muscular atrophy, advanced age, renal impairment, and hepatic impairment, and when administered with a high-fat meal. The relative contributions of CYP1A1 and CYP1A2 to metabolism were verified through prediction of an observed drug-drug interaction between riluzole and fluvoxamine-a strong CYP1A2 inhibitor and a weak CYP1A1 inhibitor-in children with obsessive-compulsive disorder. Overall, evidence suggests that CYP1A1 is a major enzyme metabolizing riluzole, and that CYP1A2 has similar or lower importance. Only clinically relevant inhibitors of both enzymes may pose a safety concern when administered with riluzole. Strong CYP1A1 inhibitors and strong CYP1A2 inhibitors may be used with caution if they do not significantly modulate the other enzyme. Concomitant use of CYP1A1 inducers may be reconsidered where possible. The enzymatic contributions to riluzole metabolism should be reconsidered after formal drug-drug interaction studies are completed.