The Influence of Hepatic and Renal Impairment on the Pharmacokinetics of a Treatment for Herpes Zoster, Amenamevir (ASP2151): Phase 1, Open-Label, Single-Dose, Parallel-Group Studies

Abstract

IntroductionAmenamevir (ASP2151) is a nonnucleoside human herpesvirus helicase-primase inhibitor that was approved in Japan for the treatment of herpes zoster (shingles) in 2017. This article reports the results of two clinical trials that investigated the effects of renal and hepatic impairment on the pharmacokinetics of amenamevir.MethodsThese studies were phase 1, open-label, single-dose (oral 400 mg), parallel-group studies evaluating the pharmacokinetics, safety, and tolerability of amenamevir in healthy participants and participants with moderate hepatic impairment and mild, moderate, and severe renal impairment.ResultsIn the hepatic impairment study, the pharmacokinetic profile of amenamevir in participants with moderate hepatic impairment was generally similar to that of participants with normal hepatic function. In the renal impairment study, the area under the amenamevir concentration versus time curve from the time of dosing up to the time of the last sample with extrapolation to infinity of the terminal phase was increased by 78.1% in participants with severe renal impairment. There was a positive relationship between creatinine clearance and oral and renal clearance for amenamevir in the renal impairment study. In both studies, amenamevir was safe and well tolerated.ConclusionThe findings of the hepatic impairment study indicate that no dosing adjustment is required in patients with moderate hepatic impairment. In the renal impairment study, systemic amenamevir exposure was increased by renal impairment. However, it is unlikely that renal impairment will have a significant effect on the safety of amenamevir given that in previous pharmacokinetic and safety studies in healthy individuals amenamevir was safe and well tolerated after a single dose (5–2400 mg, fasted condition) and repeated doses for 7 days (300 or 600 mg, fed condition), and the amount of amenamevir exposure in the renal impairment study was covered by those studies. These findings suggest that amenamevir does not require dosage reduction in accordance with the creatinine clearanceFundingAstellas Pharma.

Pharmacokinetics and Dialyzability of a Single Oral Dose of Amenamevir, an Anti-Herpes Drug, in Hemodialysis Patients

“…The C max of amenamevir in hemodialysis patients (1585 ng/mL) was similar to that in healthy adults (1612 ng/mL). The AUC inf of amenamevir in hemodialysis patients (38,120 ng h/mL) was slightly higher than that reported in non-dialysis patients with severe renal impairment (30,621 ng h/mL), and approximately double that of healthy adults (16,886 ng h/mL) [6]. The t 1/2 of amenamevir was slightly longer in patients with mild (8.4 h), moderate (9.5 h) and severe (9.8 h) renal impairment compared with that in participants with normal renal function (8.1 h) [6].…”

“…The AUC inf of amenamevir in hemodialysis patients (38,120 ng h/mL) was slightly higher than that reported in non-dialysis patients with severe renal impairment (30,621 ng h/mL), and approximately double that of healthy adults (16,886 ng h/mL) [6]. The t 1/2 of amenamevir was slightly longer in patients with mild (8.4 h), moderate (9.5 h) and severe (9.8 h) renal impairment compared with that in participants with normal renal function (8.1 h) [6]. The median t 1/2pre , t 1/2HD , and t 1/2post of amenamevir in this study were 14.7, 15.2, and 12.4 h, respectively, suggesting that t 1/2 is prolonged in proportion to the extent renal function impairment.…”

“…The median t 1/2pre , t 1/2HD , and t 1/2post of amenamevir in this study were 14.7, 15.2, and 12.4 h, respectively, suggesting that t 1/2 is prolonged in proportion to the extent renal function impairment. Hemodialysis had a greater effect on the disposition of R5 than amenamevir as was also shown in non-dialysis patients with CKD [6]. The AUC and C max of R5 in hemodialysis patients were respectively almost triple and double those reported in participants with normal renal function [6].…”

“…In patients with chronic kidney disease (CKD), the clearance of amenamevir decreased depending on the severity of renal failure [6]. However, even in non-dialysis patients with severe renal impairment, systemic exposure was found to be 1.78 times higher than that of healthy adults, and amenamevir was safe and well tolerated in these patients [6]. Therefore, the package insert of amenamevir does not require dose reduction in relation to the degree of renal impairment [7].…”

Absorption, Distribution, Metabolism, and Excretion of the Novel Helicase-Primase Inhibitor, Amenamevir (ASP2151), in Rodents

“…Allometric scaling results also revealed the similarity in pharmacokinetics between rodents and humans. While elimination by metabolism is often associated with plasma concentration changes in patients with impaired hepatic function, such changes were not observed with amenamevir [ 27 ]. Metabolism-mediated drug–drug interaction of amenamevir was reported by our group [ 28 ] and is described in the package insert in Japan [ 29 ] to facilitate proper use.…”