Target-Mediated Drug Disposition Pharmacokinetic-Pharmacodynamic Model of Bosentan and Endothelin-1.

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-dependent pharmacokinetics (PK). The aim of this analysis was to develop a PK model of bosentan after i.v. administration including competitive antagonism with ET-1 and to analyze its influence on blood pressure and heart rate with a combined pharmacokinetic/pharmacodynamic (PK/PD) model. METHODS:PK/PD data from 70 young male Caucasian subjects were analyzed after single i.v. administration of 10, 50, 250, 500, and 750 mg of bosentan. Population analyses, simulations, and evaluation were performed using a non-linear mixed-effects modeling approach. RESULTS:The PK of bosentan was best described by a two-compartment, target-mediated drug disposition (TMDD) model. ET-1 plasma and urine profiles were successfully integrated into the bosentan two-compartment, TMDD model encompassing competition for the same receptor. A multiple-peak phenomenon of bosentan plasma concentrations after i.v. administration was best described by a diurnal expression or reappearance of ET receptors on the cell surface. Blood pressure was best described by an E max model; heart rate was modeled as a compensatory effect of changes in blood pressure. CONCLUSION:The developed competitive PK/PD model of bosentan and ET-1 after i.v. administration provides a first step towards understanding the complex PK properties of bosentan and offers a valuable tool for future PK/PD research.

journal_name

Clin Pharmacokinet

authors

Volz AK,Krause A,Haefeli WE,Dingemanse J,Lehr T

doi

10.1007/s40262-017-0534-4

subject

Has Abstract

pub_date

2017-12-01 00:00:00

pages

1499-1511

issue

12

eissn

0312-5963

issn

1179-1926

pii

10.1007/s40262-017-0534-4

journal_volume

56

pub_type

杂志文章
  • Pharmacokinetic and pharmacodynamic properties of metoprolol in patients with impaired renal function.

    abstract::The pharmacokinetics of metoprolol have been studied in a group of patients with varying degrees of renal impairment and in healthy subjects after administration of 20 mg of metoprolol tartrate intravenously and 50 mg orally in a single dose and during steady-state conditions. There were no significant differences in ...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章

    doi:10.2165/00003088-198005020-00004

    authors: Jordö L,Attman PO,Aurell M,Johansson L,Johnsson G,Regårdh CG

    更新日期:1980-03-01 00:00:00

  • Biowaivers for oral immediate-release products: implications of linear pharmacokinetics.

    abstract::Bioequivalence of drug formulations plays an important role in drug development. Recently, the Biopharmaceutical Classification System (BCS) has been implemented for the purpose of waiving bioequivalence studies on the basis of the solubility and gastrointestinal permeability of drug substance. Using the rationale of ...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-200443150-00004

    authors: Faassen F,Vromans H

    更新日期:2004-01-01 00:00:00

  • Pharmacokinetics of cetirizine in tear fluid after a single oral dose.

    abstract:BACKGROUND:Antihistamines (histamine H(1) receptor antagonists) are effective and convenient drugs for the treatment of allergic conjunctivitis. Because of the short duration of action generally observed for drugs administered topically to the eye, the oral route is often preferred. However, the presence of a selective...

    journal_title:Clinical pharmacokinetics

    pub_type: 临床试验,杂志文章

    doi:10.2165/00003088-200241070-00006

    authors: Grumetto L,Cennamo G,Del Prete A,La Rotonda MI,Barbato F

    更新日期:2002-01-01 00:00:00

  • Clinical pharmacokinetics of ticlopidine.

    abstract::Platelets contribute significantly to arterial-occlusive thrombosis, one of the major causes of death and disease throughout the world. Consequently, inhibiting platelet function is a potentially important therapeutic goal. Among agents that inhibit platelet function, ticlopidine shows a wide spectrum of antiplatelet ...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-199426050-00003

    authors: Desager JP

    更新日期:1994-05-01 00:00:00

  • Overview of the Clinical Pharmacology of Ertugliflozin, a Novel Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor.

    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 developm...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.1007/s40262-020-00875-1

    authors: Fediuk DJ,Nucci G,Dawra VK,Cutler DL,Amin NB,Terra SG,Boyd RA,Krishna R,Sahasrabudhe V

    更新日期:2020-08-01 00:00:00

  • Clinical pharmacokinetics of metformin.

    abstract::Metformin is widely used for the treatment of type 2 diabetes mellitus. It is a biguanide developed from galegine, a guanidine derivative found in Galega officinalis (French lilac). Chemically, it is a hydrophilic base which exists at physiological pH as the cationic species (>99.9%). Consequently, its passive diffusi...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/11534750-000000000-00000

    authors: Graham GG,Punt J,Arora M,Day RO,Doogue MP,Duong JK,Furlong TJ,Greenfield JR,Greenup LC,Kirkpatrick CM,Ray JE,Timmins P,Williams KM

    更新日期:2011-02-01 00:00:00

  • Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer's disease.

    abstract::With the aging population and its rapidly increasing prevalence, dementia has become an important public health concern in developed and developing countries. To date, the pharmacological treatment is symptomatic and based on the observed neurotransmitter disturbances. The four most commonly used drugs are donepezil, ...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.1007/s40262-013-0038-9

    authors: Noetzli M,Eap CB

    更新日期:2013-04-01 00:00:00

  • Crushed Versus Integral Tablets of Ticagrelor in ST-Segment Elevation Myocardial Infarction Patients: A Randomized Pharmacokinetic/Pharmacodynamic Study.

    abstract:OBJECTIVE:The objective of this study was to assess the pharmacokinetic and pharmacodynamic behavior of ticagrelor administered either as crushed (in the semi-upright sitting position) or as integral (in the supine position) tablets in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percu...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,随机对照试验

    doi:10.1007/s40262-015-0320-0

    authors: Alexopoulos D,Barampoutis N,Gkizas V,Vogiatzi C,Tsigkas G,Koutsogiannis N,Davlouros P,Hahalis G,Nylander S,Parodi G,Xanthopoulou I

    更新日期:2016-03-01 00:00:00

  • Dose linearity of lacidipine pharmacokinetics after single and repeated oral doses in healthy volunteers.

    abstract:OBJECTIVE:To assess the dose proportionality of lacidipine after single and repeated oral doses, and to obtain new information on the pharmacokinetics of the compound since improvement of the plasma assay method. DESIGN:Open, randomised, four-way cross-over trial. PARTICIPANTS:24 healthy male and female volunteers, a...

    journal_title:Clinical pharmacokinetics

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.2165/00003088-200342010-00004

    authors: Da Ros L,Squassante L,Milleri S

    更新日期:2003-01-01 00:00:00

  • Covariance analysis of laboratory variance in steady-state serum phenytoin concentrations.

    abstract::Inpatients (n = 57) on long term prophylaxis with 2 oral phenytoin preparations were followed up via monthly checks of serum drug concentrations. Duplicate serum aliquots were submitted to 2 laboratories, and covariance analysis was used to estimate laboratory error. The laboratory-associated variance of examinations ...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章

    doi:10.2165/00003088-199120040-00007

    authors: Costeff H,Groswasser Z,Soroker N,van Belle G

    更新日期:1991-04-01 00:00:00

  • Physiologic Indirect Response Modeling to Describe Buprenorphine Pharmacodynamics in Newborns Treated for Neonatal Opioid Withdrawal Syndrome.

    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

    authors: Mizuno T,McPhail BT,Kamatkar S,Wexelblatt S,Ward L,Christians U,Akinbi HT,Vinks AA

    更新日期:2020-09-17 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

  • 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

  • Predicting Drug Extraction in the Human Gut Wall: Assessing Contributions from Drug Metabolizing Enzymes and Transporter Proteins using Preclinical Models.

    abstract::Intestinal metabolism can limit oral bioavailability of drugs and increase the risk of drug interactions. It is therefore important to be able to predict and quantify it in drug discovery and early development. In recent years, a plethora of models-in vivo, in situ and in vitro-have been discussed in the literature. T...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.1007/s40262-015-0351-6

    authors: Peters SA,Jones CR,Ungell AL,Hatley OJ

    更新日期:2016-06-01 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

  • Drugs and Diseases Interacting with Cigarette Smoking in US Prescription Drug Labelling.

    abstract::The US Food and Drug Administration (FDA) draft guidance for industry on drug interaction studies recommends, but does not mandate, that both cigarette smokers and non-smokers can be used to study drug metabolism in clinical trials, and that important results related to smoking should be included in drug labelling to ...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.1007/s40262-015-0246-6

    authors: Li H,Shi Q

    更新日期:2015-05-01 00:00:00

  • Pharmacokinetic optimisation of asthma treatment.

    abstract::Asthma is generally managed with bronchodilator therapy and/or anti-inflammatory drugs. Guidelines now advocate selection of drugs and pharmaceutical formulations (long-acting vs short-acting, inhaled vs systemic) on the basis of disease severity. Theophylline has a narrow therapeutic margin. Clearance is highly varia...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-199426050-00006

    authors: Taburet AM,Schmit B

    更新日期:1994-05-01 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

  • A guide to rational dosing of monoclonal antibodies.

    abstract:BACKGROUND AND OBJECTIVE:Dosing of therapeutic monoclonal antibodies (mAbs) is often based on body size, with the perception that body size-based dosing would reduce inter-subject variability in drug exposure. However, most mAbs are target specific with a relatively large therapeutic window and generally a small contri...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章

    doi:10.2165/11596370-000000000-00000

    authors: Bai S,Jorga K,Xin Y,Jin D,Zheng Y,Damico-Beyer LA,Gupta M,Tang M,Allison DE,Lu D,Zhang Y,Joshi A,Dresser MJ

    更新日期:2012-02-01 00:00:00

  • Clinical pharmacokinetics of dorzolamide.

    abstract::Dorzolamide is a carbonic anhydrase inhibitor for topical ophthalmic application. It is used in the treatment of glaucoma to lower the intraocular pressure. After absorption via the cornea and stroma, it inhibits carbonic anhydrase in the ciliary process, which leads to a reduction of aqueous humour production and the...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-200241030-00004

    authors: Martens-Lobenhoffer J,Banditt P

    更新日期:2002-01-01 00:00:00

  • Clinical pharmacokinetics and kinetic-dynamic relationships of dilevalol and labetalol.

    abstract::Dilevalol and labetalol are examples of a growing number of new beta-blockers which combine nonselective beta-adrenoceptor antagonism with vasodilator activity. Dilevalol is one of the 4 stereoisomers of labetalol, and is estimated to form approximately 25% of the racemic drug. Labetalol itself is an alpha 1-antagonis...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-199121020-00002

    authors: Donnelly R,Macphee GJ

    更新日期:1991-08-01 00:00:00

  • Individualising gentamicin dosage regimens. A comparative review of selected models, data fitting methods and monitoring strategies.

    abstract::The various components required for individualising clinical drug dosage regimens are reviewed, including a study of 3 types of fitting procedures, 2 types of gentamicin pharmacokinetic model and the utility of D-optimal times for obtaining serum gentamicin concentrations. The combination of the current Bayesian fitti...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-199121060-00006

    authors: Jelliffe RW,Iglesias T,Hurst AK,Foo KA,Rodriguez J

    更新日期:1991-12-01 00:00:00

  • Omeprazole drug interaction studies.

    abstract::This review examines the literature on drug interactions with omeprazole. Different mechanisms have been proposed as potential causes for such interactions. First, the absorption of some drugs might be altered due to the decreased intragastric acidity resulting from omeprazole treatment. There was no effect of omepraz...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-199121030-00004

    authors: Andersson T

    更新日期:1991-09-01 00:00:00

  • Patient-controlled analgesic therapy, Part III: pharmacokinetics and analgesic plasma concentrations of ketobemidone.

    abstract::The effects of anaesthesia and surgery on the pharmacokinetics of ketobemidone were studied in 12 patients. Plasma ketobemidone concentrations were assayed with a mass-fragmentographic method. The peroperative Vd(area) was 5.9 +/- 2.6L/kg and the terminal half-life was 3.9 +/- 1.7 h. In the postoperative period Vd(are...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章

    doi:10.2165/00003088-198207030-00005

    authors: Tamsen A,Bondesson U,Dahlström B,Hartvig P

    更新日期:1982-05-01 00:00:00

  • Pharmacokinetic drug interactions of commonly used anticancer drugs.

    abstract::With the use of combination chemotherapy as well as a wide range of symptomatic therapies (e.g. analgesics and antiemetics) for the treatment of patients with cancer, the field of oncology practises polypharmacy to an extreme degree. The risk for a drug interaction under these conditions is high, and the pharmacologic...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-198611030-00004

    authors: Balis FM

    更新日期:1986-05-01 00:00:00

  • First-pass elimination. Basic concepts and clinical consequences.

    abstract::First-pass elimination takes place when a drug is metabolised between its site of administration and the site of sampling for measurement of drug concentration. Clinically, first-pass metabolism is important when the fraction of the dose administered that escapes metabolism is small and variable. The liver is usually ...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-198409010-00001

    authors: Pond SM,Tozer TN

    更新日期:1984-01-01 00:00:00

  • Serum level monitoring of antibacterial drugs. A review.

    abstract::Serum concentration measurements of antibacterial agents are increasingly used to optimise drug dosage regimens. However, this approach is only justified for drugs with a low therapeutic index and poor predictability of serum concentrations, such as the aminoglycosides, chloramphenicol and vancomycin, whereas the peni...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,评审

    doi:10.2165/00003088-198409060-00001

    authors: Wenk M,Vozeh S,Follath F

    更新日期:1984-11-01 00:00:00

  • Population pharmacokinetic modelling and estimation of dosing strategy for NXY-059, a nitrone being developed for stroke.

    abstract:BACKGROUND AND OBJECTIVES:NXY-059 (disufenton sodium, Cerovive, a nitrone with neuroprotective and free radical trapping properties (in experimental stroke) is under development for the treatment of acute stroke. The objectives of this study were to develop a population pharmacokinetic model for NXY-059 in acute stroke...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章,多中心研究,随机对照试验

    doi:10.2165/00003088-200544080-00007

    authors: Jönsson S,Cheng YF,Edenius C,Lees KR,Odergren T,Karlsson MO

    更新日期:2005-01-01 00:00:00

  • Morphine pharmacokinetics and metabolism in humans. Enterohepatic cycling and relative contribution of metabolites to active opioid concentrations.

    abstract::Morphine, morphine-6-glucuronide (M6G), morphine-3-glucuronide (M3G) and normorphine were analysed with high performance liquid chromatography in plasma and urine, collected over 72 h after administration of single intravenous 5 mg and oral 20 mg doses of morphine to 7 healthy volunteers. Systemic plasma clearance of ...

    journal_title:Clinical pharmacokinetics

    pub_type: 杂志文章

    doi:10.2165/00003088-199324040-00007

    authors: Hasselström J,Säwe J

    更新日期:1993-04-01 00:00:00

  • Steady-state pharmacokinetics of controlled release oral morphine sulphate in healthy subjects.

    abstract::The pharmacokinetics of oral morphine sulphate as controlled release tablets ('MS-Contin') and solution were compared at steady-state. Plasma morphine concentrations were determined over 24 hours following the last dose of each drug when given in a randomised, crossover fashion to healthy subjects. Radioimmunoassay wa...

    journal_title:Clinical pharmacokinetics

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.2165/00003088-198611060-00006

    authors: Savarese JJ,Goldenheim PD,Thomas GB,Kaiko RF

    更新日期:1986-11-01 00:00:00