The effect of severe renal impairment on the pharmacokinetics, safety and tolerability of mitiperstat

Aims: Mitiperstat is a novel, highly potent myeloperoxidase inhibitor being evaluated in patients with cardio-metabolic disease (phase 2). These patients often have impaired renal function, which may affect mitiperstat pharmacokinetics. This study assessed mitiperstat pharmacokinetics, safety and tolerability in participants with severe renal impairment and normal renal function, to inform inclusion of participants with estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m(2) in phase 3. Methods: Participants with severe renal impairment (eGFR >= 15 and <30 mL/min/1.73 m(2)) who were not on dialysis (n = 10) and group-matched controls (eGFR >= 90 mL/min/1.73 m(2); n = 10) received a single mitiperstat 2.5 mg oral tablet. Blood samples were collected at intervals for 2 weeks and urine samples for 24 h post-dose. Results: Total apparent mitiperstat clearance was 10.83 L/h in the severe renal impairment cohort and 25.62 L/h in the control cohort. The area under the plasma concentration-time curve was 2.37-fold higher (90% confidence interval [CI]: 1.79, 3.12) in the severe renal impairment cohort than in the control cohort, with longer elimination half-life and similar maximum concentration. Non-renal clearance was similar between the cohorts. Conclusions: Mitiperstat apparent clearance was approximately twofold lower in individuals with severe renal impairment than in those with normal renal function. Lower clearance was driven by reduced renal clearance; non-renal clearance was similar. Mitiperstat was generally well tolerated by participants with severe renal impairment and normal renal function. These findings, together with efficacy and safety/tolerability data from phase 2b, will guide the dosing regimen for phase 3.