Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor.

Abstract:

:Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases plasma low-density lipoprotein cholesterol (LDL-C) by decreasing expression of the LDL receptor on hepatic cells. Evolocumab is a human monoclonal immunoglobulin G2 that binds specifically to human PCSK9 to reduce LDL-C. Evolocumab exhibits nonlinear kinetics as a result of binding to PCSK9. Elimination is predominantly through saturable binding to PCSK9 at lower concentrations and a nonsaturable proteolytic pathway at higher concentrations. The effective half-life of evolocumab is 11-17 days. The pharmacodynamic effects of evolocumab on PCSK9 are rapid, with maximum suppression within 4 h. At steady state, peak reduction of LDL-C occurs approximately 1 week after a subcutaneous dose of 140 mg every 2 weeks (Q2W) and 2 weeks after a subcutaneous dose 420 mg once monthly (QM), and returns towards baseline over the dosing interval. In several clinical studies, these doses of evolocumab reduced LDL-C by approximately 55-75% compared with placebo. Evolocumab also reduced lipoprotein(a) [Lp(a)] levels and improved those of other lipids in clinical studies. No clinically 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.

journal_name

Clin Pharmacokinet

authors

Kasichayanula S,Grover A,Emery MG,Gibbs MA,Somaratne R,Wasserman SM,Gibbs JP

doi

10.1007/s40262-017-0620-7

subject

Has Abstract

pub_date

2018-07-01 00:00:00

pages

769-779

issue

7

eissn

0312-5963

issn

1179-1926

pii

10.1007/s40262-017-0620-7

journal_volume

57

pub_type

杂志文章,评审
  • Clinical pharmacokinetics of drugs used in the treatment of gastrointestinal diseases (Part II).

    abstract::Part I of this article, which appeared in the previous issue of the Journal, covered the following agents: histamine H2-receptor antagonists (cimetidine, ranitidine, famotidine, nizatidine); muscarinic-M1-receptor antagonists (pirenzepine); proton pump inhibitors (omeprazole); site-protective agents (colloidal bismuth...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-199019020-00002

    authors: Lauritsen K,Laursen LS,Rask-Madsen J

    更新日期:1990-08-01 00:00:00

  • Therapeutic drug monitoring of imatinib: Bayesian and alternative methods to predict trough levels.

    abstract:BACKGROUND:The imatinib trough plasma concentration (C(min)) correlates with clinical response in cancer patients. Therapeutic drug monitoring (TDM) of plasma C(min) is therefore suggested. In practice, however, blood sampling for TDM is often not performed at trough. The corresponding measurement is thus only remotely...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章

    doi:10.2165/11596990-000000000-00000

    authors: Gotta V,Widmer N,Montemurro M,Leyvraz S,Haouala A,Decosterd LA,Csajka C,Buclin T

    更新日期:2012-03-01 00:00:00

  • Clinical role of protein binding of quinolones.

    abstract::Protein binding of antibacterials in plasma and tissues has long been considered a component of their pharmacokinetic parameters, playing a potential role in distribution, excretion and therapeutic effectiveness. Since the beginning of the 'antibacterial era', this factor has been extensively analysed for all antibact...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-200241100-00004

    authors: Bergogne-Bérézin E

    更新日期:2002-01-01 00:00:00

  • Continuous infusion of beta-lactam antibiotics.

    abstract::There are considerable laboratory data and information from animal and continuous culture in vitro models to support continuous infusion therapy for penicillins and cephalosporins, but, as yet, the only existing clinical data relate to cephalosporins. Penicillins do not exert concentration-dependent killing in the the...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-199835050-00004

    authors: MacGowan AP,Bowker KE

    更新日期:1998-11-01 00:00:00

  • Pharmacokinetics of orally administered duloxetine in children and adolescents with major depressive disorder.

    abstract:BACKGROUND:Duloxetine, a selective serotonin (5-hydroxytryptamine) and norepinephrine reuptake inhibitor, has been approved since 2004 for the treatment of adults with major depressive disorder (MDD). It is currently not approved for use in pediatric patients (aged <18 years) with MDD. The clinical development program ...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章

    doi:10.1007/s40262-014-0149-y

    authors: Lobo ED,Quinlan T,Prakash A

    更新日期:2014-08-01 00:00:00

  • Cardiovascular Risk Management and Hepatitis C: Combining Drugs.

    abstract::Direct-acting antivirals (DAAs) are known victims (substrate) and perpetrators (cause) of drug-drug interactions (DDIs). These DAAs are used for the treatment of hepatitis C virus (HCV) infections and are highly effective drugs. Drugs used for cardiovascular risk management are frequently used by HCV-infected patients...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.1007/s40262-018-0710-1

    authors: Smolders EJ,Ter Horst PJG,Wolters S,Burger DM

    更新日期:2019-05-01 00:00:00

  • Salivary antipyrine half-life during injectable progestagen contraception.

    abstract::Antipyrine pharmacokinetics were studied in 6 healthy women before and 2, 8 and 12 weeks after administering the injectable progestagen (progestin), norethisterone (norethindrone) enanthate 200mg intramuscularly. Additionally, antipyrine kinetics in 5 women who had previously used the injectable contraceptive for 8 to...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章

    doi:10.2165/00003088-198611020-00007

    authors: Joshi JV,Gupta KC,Hazari KT,Gokral J,Pohujani S,Satoskar R

    更新日期:1986-03-01 00:00:00

  • Older Age is Associated with Higher Dolutegravir Exposure in Plasma and Cerebrospinal Fluid of People Living with HIV.

    abstract:BACKGROUND:People living with human immunodeficiency virus are ageing under combination antiretroviral treatments but data on drug exposure in serum and cerebrospinal fluid are limited. Dolutegravir is a widely used second-generation integrase strand transfer inhibitor: conflicting data suggest that neuropsychiatric si...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章

    doi:10.1007/s40262-020-00916-9

    authors: Calcagno A,Moltó J,Borghetti A,Gervasoni C,Milesi M,Valle M,Avataneo V,Alcantarini C,Pla-Junca F,Trunfio M,D'Avolio A,Di Giambenedetto S,Cattaneo D,Di Perri G,Bonora S

    更新日期:2021-01-01 00:00:00

  • A Mechanism-Based Population Pharmacokinetic Analysis Assessing the Feasibility of Efavirenz Dose Reduction to 400 mg in Pregnant Women.

    abstract:BACKGROUND:Reducing the dose of efavirenz can improve safety, reduce costs, and increase access for patients with HIV infection. According to the World Health Organization, a similar dosing strategy for all patient populations is desirable for universal roll-out; however, it remains unknown whether the 400 mg daily dos...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章

    doi:10.1007/s40262-018-0642-9

    authors: Schalkwijk S,Ter Heine R,Colbers AC,Huitema ADR,Denti P,Dooley KE,Capparelli E,Best BM,Cressey TR,Greupink R,Russel FGM,Mirochnick M,Burger DM

    更新日期:2018-11-01 00:00:00

  • Dosage adjustment from simple nortriptyline spot level predictor tests in depressed patients.

    abstract::20 routine patients with endogenous depression were investigated in a kinetic and 4 week treatment study. Steady-state plasma nortriptyline concentrations above 200 microgram/L were associated with a highly significant poorer therapeutic outcome. The correlations between the 24, 48 and 72 hour concentrations and stead...

    journal_title:Clinical pharmacokinetics

    pub_type: 临床试验,杂志文章

    doi:10.2165/00003088-197904020-00005

    authors: Montgomery SA,McAuley R,Montgomery DB,Braithwaite RA,Dawling S

    更新日期:1979-03-01 00:00:00

  • Pharmacokinetics and blood pressure effects of felodipine in elderly hypertensive patients. A comparison with young healthy subjects.

    abstract::The pharmacokinetics and antihypertensive effects of felodipine, a new dihydropyridine calcium channel blocker, were studied in elderly hypertensive patients, 67 to 79 years of age and in young healthy subjects, 20 to 34 years of age following oral administration of 5 mg twice daily to steady-state. A single intraveno...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章

    doi:10.2165/00003088-198814060-00004

    authors: Landahl S,Edgar B,Gabrielsson M,Larsson M,Lernfelt B,Lundborg P,Regårdh CG

    更新日期:1988-06-01 00:00:00

  • Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus.

    abstract:BACKGROUND:Lorazepam is one of the preferred agents used for intravenous treatment of status epilepticus (SE). We combined data from two pediatric clinical trials to characterize the population pharmacokinetics of intravenous lorazepam in infants and children aged 3 months to 17 years with active SE or a history of SE....

    journal_title:Clinical pharmacokinetics

    pub_type: 临床试验,杂志文章,多中心研究,随机对照试验

    doi:10.1007/s40262-016-0486-0

    authors: Gonzalez D,Chamberlain JM,Guptill JT,Cohen-Wolkowiez M,Harper B,Zhao J,Capparelli EV,Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee.

    更新日期:2017-08-01 00:00:00

  • Drug kinetics in childbirth.

    abstract::Drugs from a wide range of pharmacological classes are commonly given to women in childbirth, either for a maternal effect or a fetal/neonatal effect. A number of striking physiological and biochemical changes occur during labour and delivery that might alter drug kinetics. The rate of drug absorption from the gastroi...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-198005040-00003

    authors: Nation RL

    更新日期:1980-07-01 00:00:00

  • Drug disposition in cystic fibrosis.

    abstract::There are many pathological changes in patients with cystic fibrosis (CF) which can lead to alterations in drug disposition. Although, in patients with CF, the extent of drug absorption varies widely and the rate of absorption is slower, bioavailability is not altered. Plasma protein binding for the majority of drugs ...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-199835040-00004

    authors: Rey E,Tréluyer JM,Pons G

    更新日期:1998-10-01 00:00:00

  • Pharmacokinetics of deferiprone in patients with β-thalassaemia: impact of splenectomy and iron status.

    abstract:BACKGROUND AND OBJECTIVE:Iron-rich transfusions and/or a compensatory increase in iron absorption ultimately result in iron loading in patients with β-thalassaemia. Hence, without iron chelation, iron accumulates relentlessly. Deferiprone has been shown to be capable of reducing the iron burden in patients with β-thala...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章

    doi:10.2165/11536630-000000000-00000

    authors: Limenta LM,Jirasomprasert T,Jittangprasert P,Wilairat P,Yamanont P,Chantharaksri U,Fucharoen S,Morales NP

    更新日期:2011-01-01 00:00:00

  • Pharmacokinetics of metformin in girls aged 9 years.

    abstract:BACKGROUND AND OBJECTIVE:Metformin is a biguanide used in the treatment of type 2 diabetes mellitus. In girls with a low birth weight, and early-normal and rapidly progressive puberty, metformin therapy is capable of modifying this outcome, prolonging pubertal growth, increasing height gain, delaying the age at menarch...

    journal_title:Clinical pharmacokinetics

    pub_type: 临床试验,杂志文章

    doi:10.2165/11593970-000000000-00000

    authors: Sánchez-Infantes D,Díaz M,López-Bermejo A,Marcos MV,de Zegher F,Ibáñez L

    更新日期:2011-11-01 00:00:00

  • Pharmacokinetics of anticancer drugs in children.

    abstract::Interpatient pharmacokinetic variability normally observed in adults is often of even greater magnitude in paediatric patients because of age-related maturation of physiological processes responsible for drug disposition. Several antineoplastic agents have shown age-related changes, including alterations in volume of ...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-198712030-00002

    authors: Crom WR,Glynn-Barnhart AM,Rodman JH,Teresi ME,Kavanagh RE,Christensen ML,Relling MV,Evans WE

    更新日期:1987-03-01 00:00:00

  • Rethinking the Application of Pemetrexed for Patients with Renal Impairment: A Pharmacokinetic Analysis.

    abstract:BACKGROUND:Pemetrexed is used for the treatment for non-small cell lung cancer and mesothelioma. Patients with renal impairment are withheld treatment with this drug as it is unknown what dose is well tolerated in this population. OBJECTIVE:The purpose of our study was to investigate the pharmacokinetics (PK) of pemet...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章

    doi:10.1007/s40262-020-00972-1

    authors: de Rouw N,Boosman RJ,Huitema ADR,Hilbrands LB,Svensson EM,Derijks HJ,van den Heuvel MM,Burger DM,Ter Heine R

    更新日期:2021-01-09 00:00:00

  • Comparative serum prednisone and prednisolone concentrations following administration to patients with chronic active liver disease.

    abstract::Following administration of equivalent oral doses (30mg) of either prednisone or prednisolone to 5 patients with chronic active liver disease who had failed to respond to therapy, 5 patients with chronic active liver disease in remission induced by prednisone, and 7 healthy volunteers, corticosteroid concentrations we...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章

    doi:10.2165/00003088-198207050-00005

    authors: Uribe M,Summerskill WH,Go VL

    更新日期:1982-09-01 00:00:00

  • Dosing in children: a critical review of the pharmacokinetic allometric scaling and modelling approaches in paediatric drug development and clinical settings.

    abstract::It should be recognized that children are not small adults, hence dosing in children should not be a 'small adult dose'. A mean population dose in all age groups is just an average dose and not necessarily the best or the correct dose for a given patient. The dose of a drug varies from patient to patient and individua...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.1007/s40262-014-0134-5

    authors: Mahmood I

    更新日期:2014-04-01 00:00:00

  • Population pharmacokinetics of olmesartan following oral administration of its prodrug, olmesartan medoxomil: in healthy volunteers and hypertensive patients.

    abstract:BACKGROUND:Olmesartan medoxomil (CS-866) is a new orally active angiotensin II receptor antagonist that is highly selective for the AT1 receptor subtype. OBJECTIVE:To develop a population pharmacokinetic model for olmesartan (RNH-6270), the active metabolite of olmesartan medoxomil, in healthy volunteers and hypertens...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,meta分析

    doi:10.2165/00003088-200544120-00011

    authors: Yoshihara K,Gao Y,Shiga H,Wada DR,Hisaoka M

    更新日期:2005-01-01 00:00:00

  • Author's Reply to Reith: "Morbidly Obese Patients Exhibit Increased CYP2E1-Mediated Oxidation of Acetaminophen".

    abstract:: ...

    journal_title:Clinical pharmacokinetics

    pub_type: 评论,信件

    doi:10.1007/s40262-018-0665-2

    authors: van Rongen A,Välitalo PAJ,Knibbe CAJ

    更新日期:2018-07-01 00:00:00

  • Etodolac clinical pharmacokinetics.

    abstract::Etodolac is a chiral nonsteroidal anti-inflammatory drug (NSAID) that is marked as the racemate. Currently, the drug is available in several countries for the treatment of arthritis and the alleviation of pain. Etodolac possesses several unique disposition features mainly due to its stereoselective pharmacokinetics. I...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-199426040-00003

    authors: Brocks DR,Jamali F

    更新日期:1994-04-01 00:00:00

  • Blockade of the High-Affinity Interleukin-2 Receptors with Daclizumab High-Yield Process: Pharmacokinetic/Pharmacodynamic Analysis of Single- and Multiple-Dose Phase I Trials.

    abstract:BACKGROUND AND OBJECTIVE:Daclizumab high-yield process (DAC HYP) is a humanized monoclonal antibody that selectively blocks the α-subunit (CD25) of the high-affinity interleukin-2 receptors, and has shown robust efficacy as a treatment for multiple sclerosis (MS). This work quantitatively characterized the relationship...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,随机对照试验

    doi:10.1007/s40262-015-0305-z

    authors: Minocha M,Tran JQ,Sheridan JP,Othman AA

    更新日期:2016-01-01 00:00:00

  • Clinical pharmacokinetics of fluconazole.

    abstract::Fluconazole was recently developed for the treatment of superficial and systemic fungal infections. Triazole groups and insertion of 2 fluoride atoms increase the polarity and hydrosolubility of the drug, allowing it to be used in a parenteral form. Bioassay methods using Candida pseudotropicalis as a test organism we...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-199324010-00002

    authors: Debruyne D,Ryckelynck JP

    更新日期:1993-01-01 00:00:00

  • Clarithromycin clinical pharmacokinetics.

    abstract::Clarithromycin is a semisynthetic macrolide antibiotic, structurally related to erythromycin. It has a more favourable pharmacokinetic profile than erythromycin, thus allowing twice-daily administration and possibly increasing compliance among outpatients. Clarithromycin is well absorbed from the gastrointestinal trac...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-199325030-00003

    authors: Fraschini F,Scaglione F,Demartini G

    更新日期:1993-09-01 00:00:00

  • Clinical pharmacokinetics of the newer intravenous anaesthetic agents.

    abstract::In the last 15 years the role of opioids in anaesthesia management has undergone dramatic change. Initially used as premedicants, or adjuvants to inhalation anaesthetic agents or as analgesics for postoperative pain relief, narcotics have now evolved into primary anaesthetic agents, primarily because of their ability ...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-198611010-00002

    authors: Davis PJ,Cook DR

    更新日期:1986-01-01 00:00:00

  • Formation of active metabolites of psychotropic drugs. An updated review of their significance.

    abstract::Most of the currently available psychotropic drugs form 1 or more active metabolites during in vivo biotransformation in humans and/or animals. In some cases these metabolites are rapidly conjugated and excreted, but in others they attain blood and/or brain concentrations within the same range as, or even higher than,...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-199018060-00002

    authors: Caccia S,Garattini S

    更新日期:1990-06-01 00:00:00

  • The pharmacokinetics of zileuton in healthy young and elderly volunteers.

    abstract::The effects of age and gender on the single and multiple dose pharmacokinetics of zileuton have been examined in a phase I nonblinded study. A total of 27 healthy volunteers were evaluable, 9 in the young group (age range 20 to 40 years; 5 males and 4 females) and 18 in the elderly group (range 65 to 81 years; 9 males...

    journal_title:Clinical pharmacokinetics

    pub_type: 临床试验,杂志文章

    doi:10.2165/00003088-199500292-00007

    authors: Braeckman RA,Granneman GR,Locke CS,Machinist JM,Cavannaugh JH,Awni WM

    更新日期:1995-01-01 00:00:00

  • Random-effects linear modeling and sample size tables for two special crossover designs of average bioequivalence studies: the four-period, two-sequence, two-formulation and six-period, three-sequence, three-formulation designs.

    abstract::Due to concern and debate in the epilepsy medical community and to the current interest of the US Food and Drug Administration (FDA) in revising approaches to the approval of generic drugs, the FDA is currently supporting ongoing bioequivalence studies of antiepileptic drugs, the EQUIGEN studies. During the design of ...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章

    doi:10.1007/s40262-013-0103-4

    authors: Diaz FJ,Berg MJ,Krebill R,Welty T,Gidal BE,Alloway R,Privitera M

    更新日期:2013-12-01 00:00:00