Clinical Assessment of the Drug–Drug Interaction Potential of Omaveloxolone in Healthy Adult Participants

The Journal of Clinical Pharmacology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 7, 2025

Omaveloxolone is approved in the United States and European Union for treatment of patients with Friedreich ataxia aged ≥16 years. It mainly metabolized by cytochrome P450 (CYP) 3A4 vitro. Two drug-drug interaction studies (NCT04008186 NCT05909644) were performed to evaluate (1) effect drug-metabolizing enzymes (DMEs) drug transporter (DT) modulators on pharmacokinetics omaveloxolone (2) DME DT substrates. Additionally, safety coadministering these drugs was assessed. Coadministration strong CYP3A4 inhibitor itraconazole significantly increased maximum plasma concentration (Cmax) area under concentration-time curve from time 0 extrapolated infinity (AUC0-∞) approximately 3- 4-fold, respectively. Conversely, coadministration moderate inducer efavirenz decreased Cmax AUC0-∞ 38.0% 48.5%, exposure also following verapamil, a P-glycoprotein (P-gp) inhibitor, but it unaffected CYP2C8 gemfibrozil. reduced systemic substrates CYP3A4, CYP2C8, breast cancer resistance protein, organic anion transporting polypeptide 1B1 had no those P-gp cation 1. well tolerated when administered alone combination or These findings support concomitant medication precautions dosing recommendations coadministered inducer, as certain CYP450 transporters.

Язык: Английский

Effect of a Supratherapeutic Dose of Omaveloxolone on the Corrected QT Interval in Healthy Participants: A Randomized, Double‐Blind, Placebo‐ and Active‐Controlled, Three‐Way Crossover Study

Clinical and Translational Science, Год журнала: 2025, Номер 18(2)

Опубликована: Фев. 1, 2025

ABSTRACT Omaveloxolone is approved for the treatment of Friedreich ataxia (FA) in patients aged ≥ 16 years at a dose 150 mg once daily. This double‐blind, randomized, placebo‐ and active‐controlled, three‐way crossover, thorough corrected QT interval (QTc) study (NCT05927649) evaluated effect supratherapeutic omaveloxolone exposure on QTc to exclude clinically significant prolongation (defined as > 10 ms). Healthy adults were randomized one six sequences three single oral doses (omaveloxolone 450 mg, placebo, or moxifloxacin 400 [open‐label positive control]) administered with an FDA high‐fat meal. Serial pharmacokinetic blood sampling time‐matched electrocardiogram assessments performed. The primary endpoint was placebo‐corrected change from baseline QTcF (ΔΔQTcF) following administration. Secondary endpoints included parameters its major plasma metabolites (M17 M22) safety. All 30 enrolled participants completed study. mean C max 319 ng/mL this (4.5‐fold steady‐state [71.5 ng/mL] dose). intervals < ms, changes ms all timepoints doses. upper limit 90% CIs ΔΔQTcF administration timepoints. At omaveloxolone, M17, M22, alone combined, limits model‐predicted ms. No safety concerns identified. Supratherapeutic that covers worst‐case clinical did not cause generally well tolerated.

Язык: Английский

Beneficial Effect of Dimethyl Fumarate Drug Repositioning in a Mouse Model of TDP-43-Dependent Frontotemporal Dementia

Antioxidants, Год журнала: 2024, Номер 13(9), С. 1072 - 1072

Опубликована: Сен. 2, 2024

Frontotemporal dementia (FTD) causes progressive neurodegeneration in the frontal and temporal lobes, leading to behavioral, cognitive, language impairments. With no effective treatment available, exploring new therapeutic approaches is critical. Recent research highlights transcription factor Nuclear Factor erythroid-derived 2-like 2 (NRF2) as vital limiting neurodegeneration, with its activation shown mitigate FTD-related processes like inflammation. Dimethyl fumarate (DMF), an NRF2 activator, has demonstrated neuroprotective effects a TAU-dependent FTD mouse model, reducing This suggests DMF repositioning potential for treatment. Until now, trial had been conducted analyze effect of on TDP-43-dependent FTD. In this study, we aimed determine efficacy TDP-43-related model that exhibits early cognitive impairment. Mice received oral every other day from presymptomatic symptomatic stages. By post-natal (PND) 60, improvement function already evident, becoming even more pronounced by PND90. enhancement correlates neuroprotection observed dentate gyrus reduction astrogliosis stratum lacunosum-moleculare zone. At prefrontal cortex (PFC) level, also observed, accompanied astrogliosis. Collectively, our results suggest application patients

Язык: Английский