darapladib and Renal-Insufficiency

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.. 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.. 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.. 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.

Topics: Adolescent; Adult; Aged; Benzaldehydes; Female; Humans; Male; Middle Aged; Oximes; Phospholipase A2 Inhibitors; Renal Insufficiency; Young Adult

High-potency statins reduce cardiovascular events after acute coronary syndromes but remain underused in clinical practice. We examined predictors of nonuse of high-potency statins after acute coronary syndromes.. The Stabilization of pLaques usIng Darapladib-Thrombolysis in Myocardial Infarction (SOLID-TIMI 52) trial enrolled patients after an acute coronary syndrome in 36 countries between 2009 and 2011. Statin use was strongly encouraged throughout the trial, and statin potency was at the discretion of the treating physician. A high-potency statin was defined as ≥40 mg atorvastatin, ≥20 mg rosuvastatin, or 80 mg simvastatin daily. Predictors of nonuse of high-potency statins were examined using logistic regression. Of the patients included (n=12 446), 11 850 (95.2%) were treated with a statin at baseline after acute coronary syndrome (median 14 days), but only 5212 (41.9%) were on a high-potency statin. Selected patient factors associated with nonuse of high-potency statins included age ≥75 years (odds ratio 1.39, 95% CI 1.24-1.56), female sex (odds ratio 1.11, 95% CI 1.02-1.22), renal dysfunction (odds ratio 1.17, 95% CI 1.03-1.32), and heart failure during hospital admission (odds ratio 1.43, 95% CI 1.27-1.62). At 3 months after baseline, only 49% of patients had low-density lipoprotein cholesterol <70 mg/dL. Among the 5490 patients (59%) who were not on a high-potency statin at 3 months, lower low-density lipoprotein cholesterol was a predictor of nonuse of a high-potency statin after a median of 2.3 years (odds ratio 1.15 for 10 mg/dL decrease, 95% CI 1.11-1.19).. Despite the widespread use of statins after acute coronary syndromes, most patients are not treated with high-potency statins early and late after the event, including patients at the highest risk of recurrent cardiovascular events.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01000727.

Topics: Acute Coronary Syndrome; Age Factors; Aged; Angina, Unstable; Atorvastatin; Benzaldehydes; Female; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Oximes; Phospholipase A2 Inhibitors; Practice Patterns, Physicians'; Randomized Controlled Trials as Topic; Renal Insufficiency; Rosuvastatin Calcium; Secondary Prevention; Sex Factors; Simvastatin