Abstract:
:Ertugliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), is approved in the US, EU, and other regions for the treatment of adults with type 2 diabetes mellitus (T2DM). This review summarizes the ertugliflozin pharmacokinetic (PK) and pharmacodynamic data obtained during phase I clinical development, which supported the registration and labeling of this drug. The PK of ertugliflozin was similar in healthy subjects and patients with T2DM. Oral absorption was rapid, with time to peak plasma concentrations (Tmax) occurring at 1 h (fasted) and 2 h (fed) postdose. The terminal phase half-life ranged from 11 to 18 h and steady-state concentrations were achieved by 6 days after initiating once-daily dosing. Ertugliflozin exposure increased in a dose-proportional manner over the tested dose range of 0.5-300 mg. Ertugliflozin is categorized as a Biopharmaceutical Classification System Class I drug with an absolute bioavailability of ~ 100% under fasted conditions. Administration of the ertugliflozin 15 mg commercial tablet with food resulted in no meaningful effect on ertugliflozin area under the plasma concentration-time curve (AUC), but decreased peak concentrations (Cmax) by 29%. The effect on Cmax is not clinically relevant and ertugliflozin can be administered without regard to food. Mild, moderate, and severe renal impairment were associated with a ≤ 70% increase in ertugliflozin exposure relative to subjects with normal renal function, and no dose adjustment in renal impairment patients is needed based on PK results. Consistent with the mechanism of action of SGLT2 inhibitors, 24-h urinary glucose excretion decreased with worsening renal function. In subjects with moderate hepatic impairment, a decrease in AUC (13%) relative to subjects with normal hepatic function was observed and not considered clinically relevant. Concomitant administration of metformin, sitagliptin, glimepiride, or simvastatin with ertugliflozin did not have clinically meaningful effects on the PK of ertugliflozin or the coadministered medications. Coadministration of rifampin decreased ertugliflozin AUC and Cmax by 39% and 15%, respectively, and is not expected to affect efficacy in a clinically meaningful manner. This comprehensive evaluation supports administration to patients with T2DM without regard to prandial status and with no dose adjustments for coadministration with commonly prescribed drugs, or in patients with renal impairment or mild-to-moderate hepatic impairment based on ertugliflozin PK.
journal_name
Clin Pharmacokinetjournal_title
Clinical pharmacokineticsauthors
Fediuk DJ,Nucci G,Dawra VK,Cutler DL,Amin NB,Terra SG,Boyd RA,Krishna R,Sahasrabudhe Vdoi
10.1007/s40262-020-00875-1subject
Has Abstractpub_date
2020-08-01 00:00:00pages
949-965issue
8eissn
0312-5963issn
1179-1926pii
10.1007/s40262-020-00875-1journal_volume
59pub_type
杂志文章,评审abstract:BACKGROUND:Olaparib is a first-in-class potent oral poly(ADP-ribose) polymerase inhibitor. OBJECTIVES:The aims of this analysis were to establish an integrated population pharmacokinetic (PK) model of olaparib in patients with solid tumors and to bridge the PK of olaparib between capsule and tablet formulations. METH...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,meta分析
doi:10.1007/s40262-018-0714-x
更新日期:2019-05-01 00:00:00
abstract:BACKGROUND:Entecavir is an orally administered guanosine nucleoside analog with activity against hepatitis B virus (HBV) polymerase, which is approved for the treatment of chronic hepatitis B (CHB) infection in adults and children ≥2 years old (USA and EU). OBJECTIVE:To develop simplified entecavir dosing recommendati...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-016-0420-5
更新日期:2016-12-01 00:00:00
abstract:BACKGROUND AND OBJECTIVE:Clearance is an important pharmacokinetic concept for scaling dosage, understanding the risks of drug-drug interactions and environmental risk assessment in children. Accurate clearance scaling to children requires prior knowledge of adult clearance mechanisms and the age-dependence of physiolo...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-200645070-00004
更新日期:2006-01-01 00:00:00
abstract::Interleukins and tumour necrosis factor (TNF) are a complex group of proteins and glycoproteins able to exert pleiotropic effects with respect to a number of different target cells. In physiological conditions, they are induced and released in basal amounts only in restricted microenvironments where they have paracrin...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199121040-00004
更新日期:1991-10-01 00:00:00
abstract:BACKGROUND AND OBJECTIVE:Buprenorphine has been shown to be effective in treating infants with neonatal opioid withdrawal syndrome. However, an evidence-based buprenorphine dosing strategy has not been established in the treatment of neonatal opioid withdrawal syndrome because of a lack of exposure-response data. The a...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-020-00939-2
更新日期:2020-09-17 00:00:00
abstract::A change in drug clearance with age is considered an important factor in determining the high prevalence of adverse drug reactions associated with prescribing medications for the elderly. Despite this, no general principles have been available to guide drug administration in the elderly, although a substantial body of...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-199834050-00003
更新日期:1998-05-01 00:00:00
abstract::The safety profile of any pharmacological agent is defined on the basis of its toxicity, tolerability and potential for pharmacokinetic and/or pharmacodynamic interactions with other compounds, which may belong to the same or to a different pharmacological class. Drug-drug interactions are important in clinical practi...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199835020-00003
更新日期:1998-08-01 00:00:00
abstract::Rational pharmacotherapy is dependent upon an understanding of the clinical pharmacokinetic and pharmacodynamic properties of the drugs employed. Although the available data on drug biodisposition and action in the neonate have increased considerably in the last few years, pharmacokinetic-pharmacodynamic interactions ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-198814040-00001
更新日期:1988-04-01 00:00:00
abstract::A pharmacokinetic study of alpha 1-antitrypsin (ATT) was performed in 2 groups of homozygous PiZ-deficient patients (treated and untreated) and 1 group of healthy volunteers. The distribution of the 131I-labelled protein corresponds to a 3-compartment model. The intravenously administered protein diffused quickly to t...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-199223020-00007
更新日期:1992-08-01 00:00:00
abstract:OBJECTIVE:To analyse the influence of covariates on the apparent clearance (CL) of tacrolimus in paediatric liver transplant recipients being converted from cyclosporin to tacrolimus. DESIGN:Retrospective modelling study. PATIENTS AND PARTICIPANTS:18 children, 13 girls and 5 boys, aged 4 months to 16 years (median 9....
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-200140010-00005
更新日期:2001-01-01 00:00:00
abstract::The disposition of simeprevir (SMV) in humans is characterised by cytochrome P450 3A4 metabolism and hepatic uptake by organic anion transporting polypeptide 1B1/3 (OATP1B1/3). This study was designed to investigate SMV plasma and liver exposure upon oral administration in subjects infected with hepatitis C virus (HCV...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-016-0476-2
更新日期:2017-07-01 00:00:00
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
更新日期:1980-07-01 00:00:00
abstract:BACKGROUND:A population pharmacokinetic (PK) protein-binding model was developed to (1) predict free mycophenolic acid (fMPA) based on total MPA (tMPA) concentrations in renal transplant patients, to establish the therapeutic range of fMPA through pharmacokinetic-pharmacodynamic studies; and (2) provide a guideline for...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-017-0603-8
更新日期:2018-07-01 00:00:00
abstract:BACKGROUND AND OBJECTIVE:To assess the influence of hepatitis C virus (HCV) co-infection and the extent of liver fibrosis on lopinavir/ritonavir pharmacokinetics in HIV-infected patients without liver function impairment. METHODS:Cross-sectional, comparative study enrolling HIV-infected adults receiving lopinavir/rito...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-200746010-00005
更新日期:2007-01-01 00:00:00
abstract::In the drug therapy of cardiac emergencies, it is necessary to rapidly achieve therapeutic drug concentrations and adjust drug dose as the patient's clinical status changes. Cardiac dysfunction is often present and may alter drug pharmacokinetics. Circulatory failure causes sympathetically mediated vasoconstriction in...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-198409040-00001
更新日期:1984-07-01 00:00:00
abstract::There is a considerable range in the dose of many drugs that is required to produce a given pharmacological effect in an individual patient. This individual variation in dose requirement is sometimes reflected in the wide scatter in the steady state plasma concentration that follows the same oral dose of a drug given ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-197702010-00004
更新日期:1977-01-01 00:00:00
abstract::Rapid drug delivery (arterial "boli') and high drug concentrations occur with nicotine inhaled in smoke. These are believed to be key elements in producing addiction to cigarettes. Preparations which reduce the rate of delivery and/or concentration of nicotine have been introduced as treatments for smoking cessation. ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199631010-00005
更新日期:1996-07-01 00:00:00
abstract::Dosage adjustments can be difficult and time-consuming, especially for the non-specialist. The objective of this investigation was to obtain shortcut formulae to calculate dosage adjustments for (i) a drug obeying linear pharmacokinetics (i.e. first order) and given orally, by a continuous infusion or by an intermitte...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/11313460-000000000-00000
更新日期:2009-01-01 00:00:00
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
更新日期:1993-01-01 00:00:00
abstract:BACKGROUND AND OBJECTIVE:Elagolix is an oral, non-peptide, gonadotropin-releasing hormone receptor antagonist. It is approved for the treatment of moderate-to-severe pain associated with endometriosis and is being investigated for the treatment of heavy menstrual bleeding associated with uterine fibroids. Use of low-do...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-020-00921-y
更新日期:2021-01-01 00:00:00
abstract:OBJECTIVE:To assess the differences between patients with hepatic insufficiency and healthy subjects with regard to the pharmacokinetics, cardiac safety and overall safety of ebastine and its active metabolite carebastine. DESIGN:Open-label parallel-group study. PARTICIPANTS:24 patients with varying degrees of hepati...
journal_title:Clinical pharmacokinetics
pub_type: 临床试验,杂志文章
doi:10.2165/00003088-200443020-00004
更新日期:2004-01-01 00:00:00
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
更新日期:1979-03-01 00:00:00
abstract:OBJECTIVE:The aims of this study were to (1) determine whether opportunistically collected data can be used to develop physiologically based pharmacokinetic (PBPK) models in pediatric patients; and (2) characterize age-related maturational changes in drug disposition for the renally eliminated and hepatically metaboliz...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-018-00733-1
更新日期:2019-07-01 00:00:00
abstract::The pharmacokinetic effect of extracorporeal elimination can be evaluated from the extracorporeal elimination rate constant, from the amount of drug removed, and from extracorporeal clearance. To compare the validity of these approaches in clinical practice, the effect of multiple plasma exchanges on the steady-state ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-198510060-00004
更新日期:1985-11-01 00:00:00
abstract::Few of the articles published on antibiotics and pregnancy are concerned with pharmacokinetics. It is particularly difficult to evaluate possible alterations in pharmacokinetic parameters that may be due to pregnancy. Most data available have been obtained in connection with abortion or delivery. Such data may not be ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-197904040-00003
更新日期:1979-07-01 00:00:00
abstract::Buspirone is an anxiolytic drug given at a dosage of 15 mg/day. The mechanism of action of the drug is not well characterised, but it may exert its effect by acting on the dopaminergic system in the central nervous system or by binding to serotonin (5-hydroxytryptamine) receptors. Following a oral dose of buspirone 20...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199936040-00003
更新日期:1999-04-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Bosentan is a competitive antagonist on endothelin receptor A and B (ETA and ETB), displacing the endogenous binding partner endothelin-1 (ET-1) from its binding sites. After administration of escalating single doses of 10-750 mg as an intravenous (i.v.) infusion, bosentan showed dose-dependen...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-017-0534-4
更新日期:2017-12-01 00:00:00
abstract::The steady-state plasma concentrations of antipsychotic drugs show large interpatient variations but remain relatively stable from day to day in each individual patient. Monitoring of antipsychotic drug concentrations in plasma might be of value provided the patients are treated with only 1 antipsychotic drug. Some st...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-198611010-00003
更新日期:1986-01-01 00:00:00
abstract::Cyclosporin is a powerful immunosuppressive drug used in transplantation medicine and to treat autoimmune diseases. It is a lipophilic molecule, with its bioavailability dependent on food, bile and other interacting factors. Cyclosporin is extensively metabolised in the liver by the cytochrome P450 3A system, which is...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199324060-00004
更新日期:1993-06-01 00:00:00
abstract::The half-life and metabolic clearance rate (MCR) of antipyrine and phenytoin were determined in 14 young (mean age: 28.8 +/- 8.3 (SD) years] and in 14 elderly [mean age: 83.5 +/- 7.1 (SD) years] subjects and correlated with liver volume, which was determined by ultrasonic scanning, to see if an age-dependent differenc...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-198106050-00005
更新日期:1981-09-01 00:00:00