Effect of severe renal impairment on pharmacokinetics, safety, and tolerability of lemborexant.

ABSTRACT: The primary aim of this study was to examine the effect of severe renal impairment (SRI) on the pharmacokinetics of lemborexant, a dual orexin receptor antagonist indicated for the treatment of insomnia. A phase 1 multicenter, single-dose, open-label, parallel-group study was conducted in subjects with SRI not requiring dialysis (estimated glomerular filtration rate 15-29 ml/min/1.73 m² ; n = 8) compared with demographically matched healthy subjects with normal renal function (n = 8). Plasma levels of lemborexant and its metabolites were measured over 240 h following a single oral 10-mg dose administered in the morning. Relative to subjects with normal renal function, lemborexant maximum plasma concentration (C_max ) was similar, whereas area under the plasma concentration-time curve from zero to time of last quantifiable concentration (AUC_{(0- t )} ) and AUC from zero to infinity (AUC_(0-inf) ) were about 1.5-fold higher in subjects with SRI. The geometric mean ratios (90% confidence interval) were 104.8 (77.4-142.0), 150.5 (113.2-200.3), and 149.8 (113.1-198.6) for C_max , AUC_{(0- t )} , and AUC_(0-inf) , respectively. In both groups, the median lemborexant time to C_max (t_max ) was 1 h, and the mean unbound fraction of lemborexant was ~7%. For the M4, M9, and M10 metabolites, C_max was reduced ~20% and exposure (AUC_{(0- t )} and AUC_(0-inf) ) was ~1.4- to 1.5-fold higher in subjects with SRI versus healthy subjects; t_max was delayed ~1.5-2 h for M4 and M10. All treatment-emergent adverse events were mild or moderate. Lemborexant pharmacokinetics were not sufficiently altered to warrant a dose adjustment for subjects with renal impairment.

SUBMITTER: Landry I 

PROVIDER: S-EPMC7945683 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature