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Population pharmacokinetic analysis to recommend the optimal dose of udenafil in patients with mild and moderate hepatic impairment.

ABSTRACT: AIMS:The aim of this study was to develop a population pharmacokinetic (PK) model of udenafil and its active metabolite, DA-8164, in healthy subjects and patients with hepatic impairment (HI) and to estimate the optimal dosing recommendations for patients with HI. METHODS:An open label, three parallel group, age and weight matched control study was conducted in 18 volunteers, six healthy subjects (n = 6) and patients with mild (Child-Pugh class A, n = 6) and moderate HI (Child-Pugh class B, n = 6). Serial blood samples were collected for up to 72 h after a single administration of udenafil 100 mg. A population PK model was developed using non-linear mixed effects modelling (nonmem, ver. 7.2). The simulated data from the final PK model and original data of healthy subjects were compared to identify the optimal dose for patients with HI. RESULTS:A two compartment model for both udenafil and DA-8164 best described the data. Prothrombin time on metabolic clearance of udenafil to DA-8164 was included in the final model as a covariate. Compared with the AUC(0,tlast ) value after administration of udenafil 100 mg to healthy subjects, the geometric mean ratios (95% confidence interval) after 100 mg and 75 mg udenafil administration were 1.21 (1.10, 1.32) and 0.74 (0.67, 0.81) in patients with mild HI, respectively. Meanwhile, those were 1.55 (1.43, 1.67) and 1.02 (0.92, 1.12) in patients with moderate HI, respectively. CONCLUSIONS:This study suggests that the recommended doses of udenafil are 100 mg and 75 mg in patients with mild and moderate HI, respectively.

SUBMITTER: Kim A

PROVIDER: S-EPMC4972155 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Population pharmacokinetic analysis to recommend the optimal dose of udenafil in patients with mild and moderate hepatic impairment.

Kim Anhye A Lee Jongtae J Shin Donghoon D Jung Yong Jin YJ Bahng Mi Young MY Cho Joo-Youn JY Jang In-Jin IJ

British journal of clinical pharmacology 20160603 2

<h4>Aims</h4>The aim of this study was to develop a population pharmacokinetic (PK) model of udenafil and its active metabolite, DA-8164, in healthy subjects and patients with hepatic impairment (HI) and to estimate the optimal dosing recommendations for patients with HI.<h4>Methods</h4>An open label, three parallel group, age and weight matched control study was conducted in 18 volunteers, six healthy subjects (n = 6) and patients with mild (Child-Pugh class A, n = 6) and moderate HI (Child-Pug ...[more]

PMID: 27084997

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Project description:BackgroundPatients with hepatic impairment receiving antithrombotic agents metabolized primarily through the liver can be at risk for bleeding. Milvexian (BMS-986177/JNJ-70033093) is a small-molecule, active-site inhibitor of activated Factor XI (FXIa). Modulation of FXI may provide systemic anticoagulation without increased risk of clinically significant bleeding.ObjectiveThis open-label study evaluated the effects of mild or moderate hepatic impairment on the pharmacokinetics of milvexian to assess their impact on safety and dosing.MethodsSingle doses of milvexian 60 mg were administered to participants with mild hepatic impairment (n = 9), moderate hepatic impairment (n = 8), and normal hepatic function (n = 9). Healthy participants were matched to participants with hepatic impairment by body weight, age, and sex. Analysis of variance was performed on natural log-transformed milvexian exposure parameters, with hepatic function group as a fixed effect.ResultsSingle doses of milvexian 60 mg were generally well tolerated, with no serious adverse events (AEs), bleeding AEs, or discontinuations due to AEs. Geometric mean ratios (90% confidence interval) for total milvexian maximum observed plasma concentration and area under the plasma concentration-time curve from time zero extrapolated to infinite time were 1.180 (0.735-1.895) and 1.168 (0.725-1.882), respectively, for mild hepatic impairment versus normal hepatic function and 1.140 (0.699-1.857) and 0.996 (0.609-1.628), respectively, for moderate hepatic impairment versus normal hepatic function. Across groups, milvexian exposure-related increases were observed for activated partial thromboplastin time.ConclusionMilvexian was well tolerated in participants with normal, mildly impaired, and moderately impaired hepatic function. Observed pharmacokinetic changes suggest it is unlikely that dose adjustments will be necessary in patients with mild or moderate hepatic impairment. Clinical Trial RegistrationClinicaltrials.gov identifier: NCT02982707.

Dataset Information

Population pharmacokinetic analysis to recommend the optimal dose of udenafil in patients with mild and moderate hepatic impairment.

Publications

Population pharmacokinetic analysis to recommend the optimal dose of udenafil in patients with mild and moderate hepatic impairment.

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