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Yohimbine pharmacokinetics were determined after oral administration of a single oral dose of yohimbine 5 mg and a microdose of yohimbine 50 µg in relation to different cytochrome P450 (CYP) 2D6 genotypes. The CYP2D6 inhibitor paroxetine was used to investigate the influence on yohimbine pharmacokinetics. Microdosed midazolam was applied to evaluate a possible impact of yohimbine on CYP3A activity and the possibility of combining microdosed yohimbine and midazolam to simultaneously determine CYP2D6 and C...
Inability of Current Dosing to Achieve Carboplatin Therapeutic Targets in People with Advanced Non-Small Cell Lung Cancer: Impact of Systemic Inflammation on Carboplatin Exposure and Clinical Outcomes.
The presence of elevated systemic inflammation in people with advanced non-small cell lung cancer (NSCLC) is associated with significantly shorter survival following carboplatin-based chemotherapy.
Levobupivacaine is a long-acting amide local anaesthetic used in analgesia and anaesthesia. Like other local anaesthetic drugs, levobupivacaine exhibits effects on motor and sensory nerves by inhibiting the opening of voltage-gated sodium channels, and hence propagation of neuronal action potentials. Levobupivacaine is the S(-) stereoisomer of dextrobupivacaine, although both are used commercially in the racemic form bupivacaine. A favourable safety and drug effect profile for levobupivacaine has led to wid...
MCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors and is in development to overcome HER3-mediated resistance to anti-HER2 therapies. The aims of this analysis were to characterize the population pharmacokinetics of MCLA-128 in patients with various solid tumors, to evaluate patient-related factors that affect the disposition of MCLA-128, and to assess whether flat dosing is appropriate.
Multidrug-resistant tuberculosis has much poorer treatment outcomes compared with drug-susceptible tuberculosis because second-line drugs for treating multidrug resistant tuberculosis are less effective and are frequently associated with side effects. Optimization of drug treatment is urgently needed. Cycloserine is a second-line tuberculosis drug with variable pharmacokinetics and thus variable exposure when programmatic doses are used. The objective of this study was to develop a population pharmacokineti...
Risankizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody developed and approved for the treatment of moderate-to-severe plaque psoriasis at a dose of 150 mg administered subcutaneously at weeks 0 and 4, and every 12 weeks thereafter. Ongoing trials are investigating the use of risankizumab in other inflammatory autoimmune diseases. Risankizumab exhibits linear pharmacokinetics when administered intravenously (0.01 mg/kg-1200 mg) or subcutaneously (0.25 mg/kg-300 mg), with a long termina...
Fetal blood and plasma volume and binding components are critical parameters in a fetal physiologically based pharmacokinetic model. To date, a comprehensive review of their changes during fetal development has not been reported.
Preterm neonates are usually not part of a traditional drug development programme, however they are frequently administered medicines. Developing modelling and simulation tools, such as physiologically based pharmacokinetic (PBPK) models that incorporate developmental physiology and maturation of drug metabolism, can be used to predict drug exposure in this group of patients, and may help to optimize drug dose adjustment.
Non-Linear Rituximab Pharmacokinetics and Complex Relationship between Rituximab Concentrations and Anti-Neutrophil Cytoplasmic Antibodies (ANCA) in ANCA-Associated Vasculitis: The RAVE Trial Revisited.
Rituximab is approved in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and leads to a decrease of ANCA levels. The objectives of this study were to investigate the non-linear pharmacokinetics of rituximab and the relationship between its concentrations and ANCA levels in AAV patients.
Venetoclax is a selective inhibitor of B-cell lymphoma-2, which plays a role in the development of various autoimmune diseases including systemic lupus erythematosus. The aim of these analyses was to quantify the exposure-response relationship for venetoclax effects on B-lymphocyte and total lymphocyte counts as pharmacodynamic markers of efficacy and safety, respectively, in women with systemic lupus erythematosus. The developed modeling framework was also used to evaluate venetoclax effects following cycl...
Sustained low-efficiency dialysis (SLED) is a hybrid form of dialysis that is increasingly used in critically ill patients with kidney injury and hemodynamic instability. Antimicrobial dosing for patients receiving SLED is informed by pharmacokinetic studies that describe the drug clearance. Studies available to assist in the dosing of vancomycin in the context of SLED are lacking.
The rates of antibiotic resistance in Gram-negative bacteria are increasing. One method to minimize resistance emergence may be optimization of antibiotic dosing regimens to achieve drug exposure that suppress the emergence of resistance.
The thrombin inhibitor dabigatran is administered as the prodrug dabigatran etexilate, which is a substrate of esterases and P-glycoprotein (P-gp). Dabigatran is eliminated via renal excretion but is also a substrate of uridine 5'-diphospho (UDP)-glucuronosyltransferases (UGTs). The objective of this study was to build a physiologically based pharmacokinetic (PBPK) model comprising dabigatran etexilate, dabigatran, and dabigatran 1-O-acylglucuronide to describe the pharmacokinetics in healthy adults and ren...
The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6 months when combined with pyrazinamide in the first 2 months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600 mg (8-12 mg/kg body weight). At...
On 27 August, 2018, the US Food and Drug Administration approved eravacycline, a fluorocycline antimicrobial agent within the tetracycline class of antibacterial drugs, for the treatment of complicated intra-abdominal infections in patients aged 18 years and older. This decision was based on substantial clinical and pre-clinical data, including rigorous pharmacokinetic and pharmacodynamic work. This paper examines the in-vivo pharmacokinetic/pharmacodynamic work that led to the approval of eravacycline and...
Phase 0 microdose trials are exploratory studies to early assess human pharmacokinetics of new chemical entities, while limiting drug exposure and risks for participants. The microdose concept is based on the assumption that microdose pharmacokinetics can be extrapolated to pharmacokinetics of a therapeutic dose. However, it is unknown whether microdose pharmacokinetics are actually indicative of the pharmacokinetics at therapeutic dose. The aim of this review is to investigate the predictive value of micro...
GLPG1690 is an autotaxin inhibitor in development for the treatment of idiopathic pulmonary fibrosis. Several publications suggested a role of autotaxin in the control of disease-affected lung function and of lysophosphatidic acid in lung remodeling processes. The aim of the current article was to describe the exposure-response relationship of GLPG1690 and further develop a rational basis to support dose selection for clinical trials in patients with idiopathic pulmonary fibrosis.
Olaparib, a potent oral poly(ADP-ribose) polymerase inhibitor, is partially renally cleared. We investigated the pharmacokinetics and safety of olaparib in patients with mild or moderate renal impairment to provide dosing recommendations.
Unfractionated heparin (UFH) is a commonly used anticoagulant therapy for the acute treatment and prevention of thrombosis. Its short duration of action, reversibility of effect by protamine sulfate, and extensive clinical experience are some of the advantages that support its use. However, the choice of dose and dosing regimen of UFH remains challenging for several reasons. First, UFH has a narrow therapeutic window and wide variability in the dose-response relationship. Second, its pharmacodynamic (PD) pr...
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 metabolized antibiotic trimethoprim (TMP)-sulfamethoxazole (SMX).
Eculizumab is the first drug approved for the treatment of complement-mediated diseases, and current dosage schedules result in large interindividual drug concentrations. This review provides insight into the pharmacokinetic and pharmacodynamic properties of eculizumab, both for reported on-label (paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis) and off-label (hematopoietic stem cell transplantation-associated thrombotic microangiopathy) indications. Fu...
Membrane transporters play an essential role in the pharmacokinetics of drugs as they mediate exchanges between biological compartments. Tacrolimus is characterized by wide interpatient variability in terms of its pharmacokinetics that may in part be due to genetic factors. The pharmacogenetics of drug transporters is therefore a promising area to explore in the clinical pharmacology of tacrolimus. The aim of this review is to provide an overview of currently available data regarding the pharmacogenetics of...
As pazopanib plasma trough concentrations are correlated with treatment outcome, we explored whether single nucleotide polymorphisms in the elimination pathway of pazopanib affect systemic pazopanib concentrations.
The In Vivo Mechanistic Static Model (IMSM) is a powerful method used to predict the magnitude of drug-drug interactions (DDIs) mediated by cytochromes. The objective of this study was to extend the IMSM paradigm to DDIs mediated by efflux transporters and cytochromes.
Avibactam is a non-β-lactam, β-lactamase inhibitor of the diazabicyclooctane class that covalently acylates its β-lactamase targets, encompassing extended spectrum of activities that cover serine β-lactamases but not metallo-β-lactamases. Ceftazidime and avibactam have complementary pharmacokinetic (PK) profiles. Both drugs have a half-life of approximately 2 h, making them suitable to be combined in a fixed-dose combination ratio of 4:1 (ceftazidime:avibactam). Renal clearance is the primary eliminati...