Effect of Renal or Hepatic Impairment on the Pharmacokinetics of Mirabegron
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Background and Objectives
Mirabegron, a selective β3-adrenoceptor agonist for the treatment of overactive bladder (OAB), is eliminated by renal and metabolic routes. The potential influence of renal or hepatic impairment on the pharmacokinetics of mirabegron was evaluated.
Two separate open-label, single-dose, parallel-group studies were conducted. Male and female subjects (n = 8 per group) were categorized according to their baseline renal function (mild, moderate, severe or no impairment as determined by estimated glomerular filtration rate [eGFR] using the abbreviated modification of diet in renal disease formula) or hepatic function (mild, moderate or no impairment as determined by the Child-Pugh classification). All subjects received a single oral 100 mg dose of mirabegron. Non-compartmental pharmacokinetic parameters were determined from plasma and urine concentration-time data of mirabegron and metabolites.
Compared with healthy subjects who were similar overall in terms of age, sex and body mass index (BMI), the geometric mean area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC∞) for mirabegron was 31, 66 and 118 % higher in subjects with mild, moderate and severe renal impairment, respectively. Peak plasma concentrations (Cmax) increased 6, 23 and 92 %, respectively, in subjects with mild, moderate and severe renal impairment. Renal clearance but not apparent total body clearance of mirabegron correlated well with renal function. Compared with healthy subjects matched for age, sex and BMI, mirabegron AUC∞ values were 19 and 65 % higher in subjects with mild and moderate hepatic impairment, respectively. Mirabegron Cmax was 9 and 175 % higher, respectively, compared with matched healthy subjects. No clear relationship was evident between pharmacokinetic parameters and Child-Pugh scores. Protein binding was approximately 71 % in healthy subjects and was not altered to a clinically significant extent in subjects with renal or hepatic impairment. No consistent changes in mirabegron elimination half-life were observed in subjects with renal or hepatic impairment. There was high pharmacokinetic variability and significant overlap in exposures between subjects with renal or hepatic impairment and healthy subjects.
Mirabegron AUC∞ and Cmax increased 118 and 92 %, respectively, in subjects with severe renal impairment, and 65 and 175 %, respectively, in subjects with moderate hepatic impairment. Pharmacokinetic changes observed in subjects with mild or moderate renal impairment or mild hepatic impairment are of small magnitude and likely to be without clinical importance.
KeywordsRenal Impairment Hepatic Impairment Severe Renal Impairment Mirabegron Moderate Hepatic Impairment
These studies were supported financially by Astellas. Astellas was responsible for the design and overall management of the studies, and the collection, analysis and interpretation of data. James Dickinson, Michaelene Lewand, Taiji Sawamoto, Walter Krauwinkel, Marloes Schaddelee, James Keirns, Selina Moy, John Meijer, Donna Kowalski and Marcel van Gelderen are employees of Astellas. Virginie Kerbusch (PharmAspire Consulting) participated in the analysis and interpretation of the data and writing of the reports and drafted the manuscript, funded by Astellas. Richard Morton (external consultant statistician) performed the statistical analysis of the hepatic impairment study, which was funded by Astellas. Kenneth Lasseter, Dennis Riff and Viera Kupčová were the principal investigators for the studies and have no conflicts of interest to declare. All authors listed were involved in critical review and revision of the manuscript, and all provided final approval of the content.
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