Pharmacokinetics and Safety After a Single Dose of Imarikiren in Subjects with Renal or Hepatic Impairment

• Published in: Clinical drug investigation 2018-11, Vol.38 (11), p.1041-1051
• Main Authors: Shimasaki, Yukio, Sakaki, Masashi, Itou, Minoru, Kobayashi, Tokurou, Aso, Masako, Kagawa, Tomoya, Saiki, Takuya, Matsuno, Kumi, Sano, Yuhei, Shimizu, Kohei, Kuroda, Shingo, Koumura, Emiko
• Format: Article
• Language: English
• Subjects: Adult; Aged; Area Under Curve; Benzimidazoles - administration & dosage; Benzimidazoles - adverse effects; Benzimidazoles - pharmacokinetics; Bioavailability; Cardiovascular Agents - administration & dosage; Cardiovascular Agents - adverse effects; Cardiovascular Agents - pharmacokinetics; Clinical medicine; Data analysis; Drug dosages; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacokinetics; Enzymes; FDA approval; Female; Glycoproteins; Hemodialysis; Humans; Hypertension; Internal Medicine; Kidney - drug effects; Kidney - metabolism; Kidney diseases; Kidney Failure, Chronic - drug therapy; Kidney Failure, Chronic - metabolism; Liver Diseases - drug therapy; Liver Diseases - metabolism; Male; Medicine; Medicine & Public Health; Metabolism; Metabolites; Middle Aged; Morpholines - administration & dosage; Morpholines - adverse effects; Morpholines - pharmacokinetics; Nephrology; Original Research Article; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Piperidines - administration & dosage; Piperidines - adverse effects; Piperidines - pharmacokinetics; Renal Dialysis - trends; Studies; Urine
• ISSN: 1173-2563; 1179-1918
• DOI: 10.1007/s40261-018-0695-4

Background and Objective Imarikiren hydrochloride (TAK-272; SCO-272) is a novel direct renin inhibitor. The objective of this study was to determine the effects of renal impairment (RI) or hepatic impairment (HI) on the pharmacokinetics and safety of imarikiren. Methods This phase I, open-label, parallel-group comparative study evaluated the pharmacokinetics and safety of a single 40 mg oral dose of imarikiren in RI [mild, moderate, severe, or end-stage renal disease (ESRD), and on hemodialysis] or HI (mild or moderate) subjects compared with subjects with normal renal or hepatic function. Results Following administration of a single 40 mg oral imarikiren dose, the geometric mean imarikiren area under the plasma concentration–time curve from time zero to infinity (AUC ∞ ) and maximum observed plasma concentration ( C max ) in subjects with mild, moderate, and severe RI (including non-hemodialysis and ESRD), and hemodialysis subjects compared with normal renal function subjects were approximately 0.5-, 1.2-, 2.7-, and 1.8-fold, respectively, for AUC ∞ ; and approximately 0.6-, 0.8-, 2.1-, and 1.4-fold, respectively, for C max . The mean fraction of excretion of imarikiren in dialysate was ~ 3% during the 4 h dialysis period. The geometric mean imarikiren AUC ∞ and C max in mild and moderate HI subjects compared with normal hepatic function subjects were approximately 1.0- and 1.4-fold, respectively, for AUC ∞ , and approximately 0.9- and 1.3-fold, respectively, for C max . No deaths or serious adverse events were observed; all adverse events were mild or moderate in intensity. Conclusions RI and HI are associated with limited changes in imarikiren pharmacokinetics. Imarikiren was safe and well-tolerated, regardless of the severity of RI or HI. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT02367872.