The effect of hepatic or renal impairment on the pharmacokinetics of edivoxetine, a selective norepinephrine transporter reuptake inhibitor

Abstract

PurposeTo assess the impact of hepatic or renal impairment on the pharmacokinetics (PK) of edivoxetine.MethodsTwo separate multi-center, open-label studies with males and females were conducted. Subjects were categorized according to their hepatic function, determined by the Child–Pugh classification, or renal function, determined by creatinine clearance using the Cockcroft–Gault equation. Subjects received a single dose of 18 mg in the hepatic impairment study or 6 mg in the renal impairment study. Noncompartmental PK parameters were computed from the edivoxetine plasma concentration–time data.ResultsIn the hepatic study, the geometric least squares mean (GLSM) and 90 % confidence interval (CI) of the ratio [impaired : normal] of area under the concentration versus time curve from time zero to infinity (AUC0-∞; h × ng/mL) was 1.24 (0.93, 1.64) in the mild, 1.60 (1.21, 2.12) in the moderate, and 1.70 (1.28, 2.24) in the severe group. In the renal impairment study, the GLSM (90 % CI) of the ratio [impaired : normal] of AUC0-∞ was 1.13 (0.73, 1.73) in mild, 1.90 (1.28, 2.82) in moderate, 1.55 (0.94, 2.55) in severe, and 1.03 (0.66, 1.59) in ESRD groups. Overall, the GLSM of the ratio [impaired : normal] of Cmax was slightly less than or approximately 1 across the hepatic and renal impairment groups. Across both studies, there were no clinically significant changes in vital signs and laboratory values, the adverse events were mild in severity and mostly related to nervous system and gastrointestinal disorder-related events.ConclusionsPK changes in subjects with hepatic or renal impairment were of small magnitude and did not appear to impact overall subject tolerability. Daily dosing of edivoxetine in a larger population of impaired subjects, including those with dual impairment, would aid in establishing edivoxetine tolerability and PK in a clinical practice scenario.

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“…Following a single dose oral administration of edivoxetine, renal or hepatic impairment patients did not appear to influence overall subject tolerability. 198 Preparation of edivoxetine started from the cyclocondensation between 2-(benzylamino)ethanol ( 141) and 2-chloroacrylonitrile (142) Blonanserin (AD-5423, 150) is a relatively selective antagonist of serotonin 5-HT 2A and dopamine D 2 receptors, resulting in a novel oral atypical antipsychotic drug (APD) indicated for the treatment of schizophrenia in adults (Figure 16). 200 Blonanserin was developed and launched by Dainippon Sumitomo Pharma and approved in Japan (2008) and Korea (2009).…”

“…The absorption of edivoxetine was rapid with an average time to reach maximum plasma concentration ( C max ) of 2 h. Edivoxetine is extensively metabolized, predominantly via the cytochrome P450 (CYP) enzyme CYP2D6 and CYP3A4. Following a single dose oral administration of edivoxetine, renal or hepatic impairment patients did not appear to influence overall subject tolerability …”