Rimegepant 75 mg in Subjects With Hepatic Impairment: Results of a Phase 1, Open-Label, Single-Dose, Parallel-Group Study

by Selleckchem | May 10 2023

Rimegepant is a small-molecule calcitonin gene-related peptide receptor antagonist (gepant) with demonstrated efficacy and safety in the acute and preventive treatment of migraine. Here, we report the pharmacokinetics and safety of a single 75-mg oral dose of rimegepant in subjects with severe, moderate, or mild hepatic impairment and matched healthy subjects from an open-label, single-dose, 4-group phase 1 study. Thirty-six subjects aged 41-71 years were enrolled, including 6 each with severe, moderate, or mild hepatic impairment and 18 healthy subjects. All subjects completed the study. A <20% increase in total and unbound pharmacokinetics was observed in subjects with mild hepatic impairment and ≤65% increase with moderate hepatic impairment versus matched healthy controls. Total and unbound systemic exposure increased 2.0- and 3.9-fold in the severe hepatic impairment group. In subjects with severe hepatic impairment, geometric mean ratios (severe impairment/controls) for total concentrations were 202.2% for area under the plasma concentration-time curve from time 0 to the last quantifiable concentration, 202.2% for area under the plasma concentration-time curve from time 0 to infinity, and 189.1% for maximum observed plasma concentration. Corresponding geometric mean ratios using unbound concentrations were 388.8% and 388.7%, respectively. Three (8.3%) subjects reported 4 treatment-emergent adverse events. Rimegepant is not recommended for use in adults with severe hepatic impairment.

Comments：

The study reports the pharmacokinetics and safety of a single 75-mg oral dose of rimegepant in subjects with severe, moderate, or mild hepatic impairment and matched healthy subjects. A total of 36 subjects aged 41-71 years were enrolled, including 6 each with severe, moderate, or mild hepatic impairment and 18 healthy subjects. The study found that a <20% increase in total and unbound pharmacokinetics was observed in subjects with mild hepatic impairment, and ≤65% increase with moderate hepatic impairment versus matched healthy controls. However, in subjects with severe hepatic impairment, the total and unbound systemic exposure increased 2.0- and 3.9-fold, respectively, compared to healthy controls.

The geometric mean ratios (severe impairment/controls) for total concentrations were 202.2% for area under the plasma concentration-time curve from time 0 to the last quantifiable concentration, 202.2% for area under the plasma concentration-time curve from time 0 to infinity, and 189.1% for maximum observed plasma concentration. The corresponding geometric mean ratios using unbound concentrations were 388.8% and 388.7%, respectively.

Overall, rimegepant was well-tolerated, with only three (8.3%) subjects reporting four treatment-emergent adverse events. However, the study concludes that rimegepant is not recommended for use in adults with severe hepatic impairment based on the observed increase in systemic exposure in this population.