Effect of severe renal impairment on pharmacokinetics, safety, and tolerability of lemborexant
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 w...
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| Published in | Pharmacology research & perspectives Vol. 9; no. 2; pp. e00734 - n/a |
|---|---|
| Main Authors | , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
John Wiley & Sons, Inc
01.04.2021
John Wiley and Sons Inc Wiley |
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| Online Access | Get full text |
| ISSN | 2052-1707 2052-1707 |
| DOI | 10.1002/prp2.734 |
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| 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 (Cmax) 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 Cmax, AUC(0‐t), and AUC(0‐inf), respectively. In both groups, the median lemborexant time to Cmax (tmax) was 1 h, and the mean unbound fraction of lemborexant was ~7%. For the M4, M9, and M10 metabolites, Cmax 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; tmax 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.
Lemborexant is a dual orexin receptor antagonist approved for the treatment of adults with insomnia. Lemborexant tmax and Cmax were not altered in subjects with severe renal impairment compared with healthy subjects, but exposure (AUC) was increased approximately 1.5‐fold. Lemborexant has a favorable safety profile and dosing is initiated at 5 mg, which can be increased based on efficacy and tolerability. Thus, these results support the use of lemborexant in subjects with mild to severe renal impairment without dosing adjustment. |
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| AbstractList | 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 (Cmax) 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 Cmax, AUC(0‐t), and AUC(0‐inf), respectively. In both groups, the median lemborexant time to Cmax (tmax) was 1 h, and the mean unbound fraction of lemborexant was ~7%. For the M4, M9, and M10 metabolites, Cmax 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; tmax 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. 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 (Cmax) 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 Cmax, AUC(0‐t), and AUC(0‐inf), respectively. In both groups, the median lemborexant time to Cmax (tmax) was 1 h, and the mean unbound fraction of lemborexant was ~7%. For the M4, M9, and M10 metabolites, Cmax 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; tmax 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. Lemborexant is a dual orexin receptor antagonist approved for the treatment of adults with insomnia. Lemborexant tmax and Cmax were not altered in subjects with severe renal impairment compared with healthy subjects, but exposure (AUC) was increased approximately 1.5‐fold. Lemborexant has a favorable safety profile and dosing is initiated at 5 mg, which can be increased based on efficacy and tolerability. Thus, these results support the use of lemborexant in subjects with mild to severe renal impairment without dosing adjustment. 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 m 2 ; 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. 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. Lemborexant is a dual orexin receptor antagonist approved for the treatment of adults with insomnia. Lemborexant t max and C max were not altered in subjects with severe renal impairment compared with healthy subjects, but exposure (AUC) was increased approximately 1.5‐fold. Lemborexant has a favorable safety profile and dosing is initiated at 5 mg, which can be increased based on efficacy and tolerability. Thus, these results support the use of lemborexant in subjects with mild to severe renal impairment without dosing adjustment. 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 m ; 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 ) was similar, whereas area under the plasma concentration-time curve from zero to time of last quantifiable concentration (AUC ) and AUC from zero to infinity (AUC ) 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 , AUC , and AUC , respectively. In both groups, the median lemborexant time to C (t ) was 1 h, and the mean unbound fraction of lemborexant was ~7%. For the M4, M9, and M10 metabolites, C was reduced ~20% and exposure (AUC and AUC ) was ~1.4- to 1.5-fold higher in subjects with SRI versus healthy subjects; t 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. 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 (Cmax ) 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 Cmax , AUC(0-t) , and AUC(0-inf) , respectively. In both groups, the median lemborexant time to Cmax (tmax ) was 1 h, and the mean unbound fraction of lemborexant was ~7%. For the M4, M9, and M10 metabolites, Cmax 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; tmax 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.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 (Cmax ) 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 Cmax , AUC(0-t) , and AUC(0-inf) , respectively. In both groups, the median lemborexant time to Cmax (tmax ) was 1 h, and the mean unbound fraction of lemborexant was ~7%. For the M4, M9, and M10 metabolites, Cmax 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; tmax 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. 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 (Cmax) 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 Cmax, AUC(0‐t), and AUC(0‐inf), respectively. In both groups, the median lemborexant time to Cmax (tmax) was 1 h, and the mean unbound fraction of lemborexant was ~7%. For the M4, M9, and M10 metabolites, Cmax 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; tmax 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. |
| Author | Dayal, Satish Filippov, Gleb Landry, Ishani Reyderman, Larisa Moline, Margaret Hall, Nancy Aluri, Jagadeesh |
| AuthorAffiliation | 1 Eisai Inc. Woodcliff Lake NJ USA 2 Eisai Ltd. Hatfield United Kingdom |
| AuthorAffiliation_xml | – name: 2 Eisai Ltd. Hatfield United Kingdom – name: 1 Eisai Inc. Woodcliff Lake NJ USA |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33689224$$D View this record in MEDLINE/PubMed |
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| CitedBy_id | crossref_primary_10_1016_j_sleepx_2023_100070 crossref_primary_10_7759_cureus_71049 crossref_primary_10_1177_02698811221080459 crossref_primary_10_1007_s11920_022_01357_w |
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| Notes | Funding information This study was financially supported by Eisai Inc., Woodcliff Lake, New Jersey, USA. Eisai Inc. is the owner and manufacturer of lemborexant. The investigators retained full independence in the conduct of this research. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 |
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| PublicationYear | 2021 |
| Publisher | John Wiley & Sons, Inc John Wiley and Sons Inc Wiley |
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| References | 2021; 49 2013; 15 2021; 10 2019; 42 2017; 26 2019; 2 2021 2020; 60 2017; 13 2019 2019; 49 2020; 16 2018 2020; 43 2008; 4 2014; 85 2014; 103 2006; 145 2016; 46 2014; 20 2018; 46 2019; 176 e_1_2_13_13_1 e_1_2_13_25_1 e_1_2_13_14_1 e_1_2_13_24_1 e_1_2_13_15_1 e_1_2_13_16_1 e_1_2_13_21_1 e_1_2_13_10_1 e_1_2_13_20_1 e_1_2_13_11_1 e_1_2_13_12_1 e_1_2_13_22_1 e_1_2_13_9_1 e_1_2_13_8_1 Anderson LH (e_1_2_13_3_1) 2014; 20 e_1_2_13_6_1 (e_1_2_13_7_1) 2019 e_1_2_13_5_1 e_1_2_13_4_1 e_1_2_13_2_1 e_1_2_13_17_1 e_1_2_13_18_1 Alexander SPH (e_1_2_13_23_1) 2019; 176 e_1_2_13_19_1 |
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| Snippet | 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... 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... |
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| SubjectTerms | Adolescent Adult Aged Area Under Curve Body mass index Chromatography chronic kidney disease clinical pharmacology Drug dosages drug safety Female Glomerular Filtration Rate - physiology Glycoproteins Half-Life Humans Insomnia lemborexant Male Metabolism Metabolites Middle Aged Orexin Receptor Antagonists - administration & dosage Orexin Receptor Antagonists - adverse effects Orexin Receptor Antagonists - pharmacokinetics Original Pharmacokinetics Pharmacology phase 1 Plasma Proteins Pyridines - administration & dosage Pyridines - adverse effects Pyridines - pharmacokinetics Pyrimidines - administration & dosage Pyrimidines - adverse effects Pyrimidines - pharmacokinetics Renal Elimination - physiology renal impairment Renal Insufficiency - diagnosis Renal Insufficiency - metabolism Renal Insufficiency - physiopathology Severity of Illness Index Sleep Sleep Initiation and Maintenance Disorders - drug therapy Urine Young Adult |
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| Title | Effect of severe renal impairment on pharmacokinetics, safety, and tolerability of lemborexant |
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