The pharmacokinetics and safety of darapladib in subjects with severe renal impairment

• Published in: British journal of clinical pharmacology Vol. 80; no. 4; pp. 654 - 661
• Main Authors: He Magee, Mindy, Shaddinger, Bonnie, Collins, David, Siddiqi, Shabana, Soffer, Joseph
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Ltd 01.10.2015
• Subjects: Adolescent; Adult; Aged; atherosclerosis; Benzaldehydes - adverse effects; Benzaldehydes - blood; Benzaldehydes - pharmacokinetics; darapladib; Female; Humans; Male; Middle Aged; Oximes - adverse effects; Oximes - blood; Oximes - pharmacokinetics; Pharmacokinetics; phospholipase A2; Phospholipase A2 Inhibitors - adverse effects; Phospholipase A2 Inhibitors - blood; Phospholipase A2 Inhibitors - pharmacokinetics; renal impairment; Renal Insufficiency - metabolism; Young Adult; atherosclerosis; pharmacokinetics; darapladib; phospholipase A2; renal impairment
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.12661

Aim Darapladib is a potent and reversible orally active inhibitor of lipoprotein‐associated phospholipase A2 (Lp‐PLA2). The aim of the study was to assess the effects of severe renal impairment on the pharmacokinetics and safety/tolerability of darapladib compared with normal renal function. Methods This was an open label, parallel group study of darapladib following 10 day once daily 160 mg oral dosing in subjects with normal (n = 8) and severe renal impairment (estimated glomerular filtration rate <30 ml min–1 1.73 m–2, n = 8). Plasma concentrations of total and unbound darapladib as well as total darapladib metabolites were determined in samples obtained over 24 h on day 10. Results Plasma concentrations of total and unbound darapladib as well as all three metabolites were higher in subjects with severe renal impairment. Area under the plasma concentration vs. time curve between time zero and 24 h (AUC(0,24 h) and maximum plasma concentration (Cmax) of total darapladib in severely renally impaired subjects were 52% and 59% higher than those in the matched healthy subjects, respectively. Similar results were found with the darapladib metabolites. Darapladib was highly plasma protein bound with 0.047% and 0.034% unbound circulating in plasma in severely renally impaired and healthy subjects, respectively. Unbound plasma darapladib exposures were more than two‐fold higher in severely renally impaired subjects than in healthy controls. Adverse events (AE) were reported in 38% of healthy subjects and 75% of severely renally impaired subjects, most of which were mild or moderate in intensity. Conclusions The results of this study showed that darapladib exposure was increased in subjects with severe renal impairment compared with healthy controls. However, darapladib was generally well tolerated in both groups.