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Effect of renal function on the pharmacokinetics of fimasartan: a single-dose, open-label, Phase I study.

ABSTRACT: Fimasartan is a novel angiotensin II receptor blocker. Fimasartan is mainly eliminated via biliary excretion, and its urinary elimination is less than 3%.Based on guidance from the United States Food and Drug Administration, a reduced pharmacokinetic (PK) study was conducted to evaluate the effect of renal function on the PK of fimasartan in patients with renal impairment and healthy volunteers.A single centre, single-dose, open-label, healthy volunteer controlled trial was conducted in patients with renal impairment (RI) (estimated glomerular filtration rate lower than 30 mL/min/1.73 m(2)) and age-, weight- and sex-matched healthy volunteers (estimated glomerular filtration rate higher than 90 mL/min/1.73 m(2)). All participants received a single oral dose of fimasartan 120 mg, after which serial blood sampling for PK evaluation was conducted. Noncompartmental PK analysis of fimasartan was performed. A mixed-effects model approach was used to identify significant covariates and PK parameters.Sixteen subjects were enrolled (8 healthy volunteers and 8 RI patients). The maximum plasma concentrations and areas under the plasma concentration curves of the RI patients were higher than those of the healthy volunteers, with geometric mean ratios of 1.87 and 1.73, respectively. The relative bioavailability of fimasartan from the population PK analysis was 77% higher in the RI patients than in the healthy volunteers.The increased drug exposure of fimasartan in RI patients was explained by the increased relative bioavailability. This result can be explained from our knowledge concerning alterations in PK related to renal function.

SUBMITTER: Kim S

PROVIDER: S-EPMC4199969 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Effect of renal function on the pharmacokinetics of fimasartan: a single-dose, open-label, Phase I study.

Kim Seokuee S Lee Jongtae J Shin Donghoon D Lim Kyoung Soo KS Kim Yon Su YS Jang In-Jin IJ Yu Kyung-Sang KS

Drug design, development and therapy 20141006

<h4>Background</h4>Fimasartan is a novel angiotensin II receptor blocker. Fimasartan is mainly eliminated via biliary excretion, and its urinary elimination is less than 3%.<h4>Objective</h4>Based on guidance from the United States Food and Drug Administration, a reduced pharmacokinetic (PK) study was conducted to evaluate the effect of renal function on the PK of fimasartan in patients with renal impairment and healthy volunteers.<h4>Methods</h4>A single centre, single-dose, open-label, healthy ...[more]

PMID: 25336916

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Project description:IntroductionAs patients who receive cannabidiol (CBD) may have co-existing renal morbidities, it is important to understand whether dose adjustments are necessary to mitigate the risk of exposure-related toxicity. This study was conducted to evaluate the pharmacokinetics, safety, and tolerability of CBD in patients with renal impairment.MethodsThe pharmacokinetics and safety of a single oral 200 mg dose of a plant-derived pharmaceutical formulation of highly purified CBD in oral solution (Epidiolex® in the USA; 100 mg/mL) were assessed in subjects with mild, moderate, or severe renal impairment (n = 8/group) relative to matched subjects with normal renal function (n = 8). Blood samples were collected until 48 h post-dose and evaluated by liquid chromatography with tandem mass spectrometry. Analysis of variance was used to compare primary pharmacokinetic parameters (maximum measured plasma concentration [Cmax], oral clearance of drug from plasma [CL/F], renal clearance [CLR], area under the plasma concentration-time curve [AUC] from time zero to last measurable concentration [AUCt], and AUC from time zero to infinity [AUC∞]); descriptive analysis was used for secondary pharmacokinetic parameters (time to Cmax [tmax], terminal [elimination] half-life [t½], cumulative amount excreted from time zero to the last quantifiable sample [Aelast], and fraction of the systemically available drug excreted into the urine [fe]).ResultsNo statistically significant differences were observed in Cmax, AUCt, AUC∞, or tmax values between subjects with mild, moderate, or severe renal impairment and subjects with normal renal function for CBD or its major metabolites, 7-carboxy-CBD (7-COOH-CBD) and 7-hydroxy-CBD (7-OH-CBD), and minor metabolite, 6-hydroxy-CBD (6-OH-CBD); geometric mean ratio for Cmax values ranged from 0.68 to 1.35. No differences were observed for other secondary parameters (Aelast and fe). CBD, 7-COOH-CBD, 7-OH-CBD, and 6-OH-CBD were highly protein bound (> 90%); binding was similar in all subject groups. Urine analysis for CBD recorded no appreciable amount, and thus no urinary pharmacokinetic parameters could be derived. Adverse events (AEs) affected two subjects; all five AEs were mild in severity and resolved during the trial. There were no serious AEs or discontinuations due to AEs. Laboratory, physical examination, vital sign, and 12-lead electrocardiogram findings were not clinically significant.ConclusionRenal impairment had no effect on the metabolism of CBD after a single oral 200 mg dose. CBD was generally well tolerated in subjects with varying degrees of renal function.RegistrationEuropean Union Clinical Trials Register (EudraCT) no. 2015-002122-39.

Dataset Information

Effect of renal function on the pharmacokinetics of fimasartan: a single-dose, open-label, Phase I study.

Publications

Effect of renal function on the pharmacokinetics of fimasartan: a single-dose, open-label, Phase I study.

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