Drs. meaningful differences in pharmacodynamic effects on LDL-C were observed in adult subjects regardless of mild/moderate hepatic impairment, renal impairment or renal failure, body weight, race, sex, or age. No clinically meaningful differences were observed for the pharmacodynamic effects of evolocumab on LDL-C between patients who received evolocumab alone or in combination with a statin, resulting in additional lowering of LDL-C when evolocumab was combined with a statin. No dose adjustment is necessary based on patient-specific factors or concomitant medication use. Electronic supplementary material The online version of this article (10.1007/s40262-017-0620-7) contains supplementary material, which is available to authorized users. Key Points S-Gboxin Evolocumab, a human monoclonal immunoglobulin that binds specifically to human proprotein convertase subtilisin/kexin type 9 (PCSK9) on hepatic cells to reduce low-density lipoprotein cholesterol (LDL-C), exhibits nonlinear kinetics and a half-life of 11C17?days.Maximal suppression of PCSK9 occurs within 4?h, and peak reduction of LDL-C, ranging from 55 to 75%, occurs approximately 1C2?weeks after a dose of evolocumab.Patient-specific factors do not have a clinically meaningful effect on the S-Gboxin pharmacodynamic effects of evolocumab; thus, no dose adjustment is necessary based on patient-specific factors or concomitant medication use. Open in a separate window Introduction Cardiovascular disease is S-Gboxin the leading cause of death and disability globally [1, 2]. Dyslipidemia is a major, common, and modifiable risk factor for cardiovascular disease [1, 2]. Randomized clinical studies aimed at lowering low-density lipoprotein cholesterol (LDL-C) show a consistent relationship between LDL-C reduction and cardiovascular risk reduction [3], particularly for treatments that act through the LDL-C receptor (LDLR) [4]. The relationship between lower LDL-C and reduction of major cardiovascular events extends to the lowest limit of LDL-C tested, with no evidence of attenuation of cardiovascular benefits at very low levels of LDL-C [4]. Statins, the first-line treatment for primary hyperlipidemia and mixed dyslipidemia, reduce both LDL-C (30C40% with standard doses [5]) and cardiovascular events [3, 4]. However, in clinical practice, approximately one in four patients with hyperlipidemia, including one in six low-risk patients and one in three high-risk patients, continues to have elevated LDL-C and does not achieve traditional treatment goals with statin therapy [6]. Less than 50% of patients are adherent to statin therapy at 1?year [7]. Some of the nonadherence in clinical practice is attributable to statin intolerance, most commonly because of myopathy, which can lead to either lower doses or complete discontinuation of statin therapy [8]. Few established medical treatment options significantly reduce cardiovascular events among patients who require additional LDL-C lowering after an adequate trial of statin therapy. Among patients with a history of acute coronary syndromes, adding a second lipid-lowering therapy (ezetimibe) to a statin lowered mean LDL-C to 53.7?mg/dl compared with 69.5?mg/dl with a statin alone (a relative LDL-C reduction of 23%), and the combination significantly reduced the incidence of cardiovascular outcomes compared with a statin alone [9]. An enhanced understanding of the regulation of LDL-C led to the development of targeted therapy to lower LDL-C via novel mechanisms. Recycling of the LDLR to the surface of normal hepatic cells regulates plasma LDL-C [10, 11]. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that decreases expression of LDLRs on hepatic cells, leading to increased plasma LDL-C (Fig.?1) [12, 13]. Human genetic studies identified gain-of-function mutations in the gene that Rabbit polyclonal to Src.This gene is highly similar to the v-src gene of Rous sarcoma virus.This proto-oncogene may play a role in the regulation of embryonic development and cell growth.The protein encoded by this gene is a tyrosine-protein kinase whose activity can be inhibited by phosphorylation by c-SRC kinase.Mutations in this gene could be involved in the malignant progression of colon cancer.Two transcript variants encoding the same protein have been found for this gene. are associated with elevated serum LDL-C levels and premature coronary heart disease and also identified other loss-of-function mutations in the gene that are associated with low serum LDL-C levels [14C17]. Open in a separate window Fig.?1 Mechanism of action: PCSK9 inhibition with evolocumab increases LDL-R and decreases serum concentrations of LDL-C [10, 12, 13, 33, 52C55]. a The liver is responsible.