Effect of Renal and Hepatic Impairment on the Pharmacokinetics of Pritelivir and Its Metabolites

• Published in: Clinical pharmacology in drug development Vol. 13; no. 11; pp. 1198 - 1211
• Main Authors: Erb‐Zohar, Katharina, Bonsmann, Susanne, Pausch, Jörg, Sumner, Melanie, Birkmann, Alexander, Zimmermann, Holger, Halabi, Atef, Kropeit, Dirk
• Format: Journal Article
• Language: English
• Published: United States 01.11.2024
• Subjects: Administration, Oral; Adult; Aged; Area Under Curve; Female; hepatic impairment; Humans; Liver Diseases - metabolism; Male; Middle Aged; nonnucleoside helicase‐primase inhibitor; pharmacokinetics; pritelivir; Protein Binding; renal impairment; Renal Insufficiency - metabolism; Severity of Illness Index; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - blood; Sulfonamides - pharmacokinetics; Young Adult; hepatic impairment; pharmacokinetics; pritelivir; nonnucleoside helicase‐primase inhibitor; renal impairment
• ISSN: 2160-763X; 2160-7648
• DOI: 10.1002/cpdd.1469

Two trials were performed to evaluate the effect of renal and hepatic impairment on the pharmacokinetics of pritelivir and its metabolites. The renal impairment trial included subjects with mild, moderate, and severe impairment, while the hepatic impairment trial included subjects with moderate impairment. Both trials recruited a matched control group of healthy subjects. Following a single oral dose of 100 mg of pritelivir, mild and moderate renal impairment and moderate hepatic impairment did not have a clinically relevant effect on the pharmacokinetics of pritelivir. In subjects with severe renal impairment, pritelivir exposure (area under the plasma concentration‐time curve from time 0 to infinity (AUC0‐inf) was 57% higher compared with controls. Pritelivir plasma protein binding was similar in subjects and controls with renal impairment, while the free fraction was higher in subjects with moderate hepatic impairment, increasing unbound pritelivir exposure by 23%. For the metabolites pyridinyl phenyl acetic acid (PPA), amino thiazole sulfonamide (ATS), and PPA‐acyl glucuronide, generally higher exposure was observed with increasing degree of renal impairment (ie, moderate to severe), but not with mild impairment. A modest effect of moderate hepatic impairment was observed for PPA and ATS. Pritelivir was safe and well tolerated in healthy subjects and subjects with renal or hepatic impairment.