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Effect of renal impairment on the pharmacokinetics of prucalopride: a single- dose open-label Phase I study.

ABSTRACT: To evaluate the pharmacokinetics of prucalopride in individuals with renal impairment (RI).This open-label Phase I study (ClinicalTrials.gov identifier: NCT01674192) enrolled men and women aged 18-75 years who were classified by renal function: normal renal function (creatinine clearance ? 80 mL/min/1.73 m²), mild RI (50-79 mL/min/1.73 m²), moderate RI (25-49 mL/min/1.73 m²), and severe RI (? 24 mL/min/1.73 m²). All received a single oral dose of prucalopride 2 mg.Thirty-four individuals (normal renal function: 10; mild RI: 8; moderate RI: 7; severe RI: 9) received prucalopride. In all groups, maximum plasma concentration was reached within 2-4 hours. There was no significant difference in exposure (area under the plasma concentration-time curve from time zero to infinity) between participants with mild RI and those with normal renal function. However, area under the plasma concentration-time curve from time zero to infinity values were 1.5- and 2.3-fold higher (P = 0.002 and P < 0.001) in patients with moderate RI and severe RI, respectively, than in those with normal renal function. The proportion of total body clearance accounted for by renal clearance was significantly reduced in those with RI.Clinically meaningful reductions in renal clearance were seen in participants with severe RI, which supports a decrease from the standard dose of prucalopride 2 mg daily to 1 mg daily in these individuals.

SUBMITTER: Smith WB

PROVIDER: S-EPMC3529624 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Effect of renal impairment on the pharmacokinetics of prucalopride: a single- dose open-label Phase I study.

Smith William B WB Mannaert Erik E Verhaeghe Tom T Kerstens René R Vandeplassche Lieve L Van de Velde Vera V

Drug design, development and therapy 20121218

<h4>Objective</h4>To evaluate the pharmacokinetics of prucalopride in individuals with renal impairment (RI).<h4>Methods</h4>This open-label Phase I study (ClinicalTrials.gov identifier: NCT01674192) enrolled men and women aged 18-75 years who were classified by renal function: normal renal function (creatinine clearance ≥ 80 mL/min/1.73 m²), mild RI (50-79 mL/min/1.73 m²), moderate RI (25-49 mL/min/1.73 m²), and severe RI (≤ 24 mL/min/1.73 m²). All received a single oral dose of prucalopride 2 ...[more]

PMID: 23269861

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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 impairment on the pharmacokinetics of prucalopride: a single- dose open-label Phase I study.

Publications

Effect of renal impairment on the pharmacokinetics of prucalopride: a single- dose open-label Phase I study.

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