Search results for "PHARMACOKINETICS"
showing 10 items of 458 documents
Pharmacokinetics of a sustained release formulation of PDGFβ-receptor directed carrier proteins to target the fibrotic liver
2018
Liver fibrogenesis is associated with excessive production of extracellular matrix by myofibroblasts that often leads to cirrhosis and consequently liver dysfunction and death. Novel protein-based antifibrotic drugs show high specificity and efficacy, but their use in the treatment of fibrosis causes a high burden for patients, since repetitive and long-term parenteral administration is required as most proteins and peptides are rapidly cleared from the circulation. Therefore, we developed biodegradable polymeric microspheres for the sustained release of proteinaceous drugs. We encapsulated the drug carrier pPB-HSA, which specifically binds to the PDGF beta R that is highly upregulated on a…
A phase I dose-escalation study of IMAB362 (Zolbetuximab) in patients with advanced gastric and gastro-oesophageal junction cancer
2018
Introduction IMAB362 (Zolbetuximab) is a chimeric monoclonal antibody that binds to Claudin-18.2, a target antigen specific to cancer cells. In vitro, IMAB362 mediates cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity; thus, IMAB362 may serve as a potent, targeted immunotherapeutic agent. Methods This first-in-human phase I study enroled adult patients (N = 15) with advanced gastric or gastro-oesophageal junction cancer into five sequential single dose-escalation cohorts (33, 100, 300, 600, and 1000 mg/m2) following a 3 + 3 design. Safety/tolerability, including determination of maximum tolerated dose and recommended phase II dose, were the pr…
Dosing of caspofungin based on a pharmacokinetic/pharmacodynamic index for the treatment of invasive fungal infections in critically ill patients on …
2017
Abstract Introduction The study objective was to evaluate the efficacy of different dosages of caspofungin in the treatment of invasive candidiasis and aspergillosis, in relation to the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment, using modelling and Monte Carlo simulations in critically ill adult patients on continuous haemodiafiltration. Methods Critically ill adult patients on continuous venovenous haemodiafiltration treated with caspofungin were analysed. A population PK model was developed. Four caspofungin dosing regimens were simulated: the licensed regimen, 70 mg/day, 100 mg/day or 200 mg/day. A PK/PD target was defined as the ratio between the area unde…
Sex-dependent metabolism of nevirapine in rats: impact on plasma levels, pharmacokinetics and interaction with nortriptyline.
2017
Abstract Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) widely used in the treatment of human immunodeficiency virus type 1 (HIV-1) and is the first-choice NNRTI during pregnancy. NVP shows a sex dimorphic profile in humans with sex differences in bioavailability, biotransformation and toxicity. In this study, sex differences in NVP metabolism and inhibition of NVP metabolism by the antidepressant nortriptyline (NT) were evaluated using rats as experimental animals. NVP was administered orally to male and female rats and sex differences in plasma levels and pharmacokinetic parameters were analysed. NVP plasma levels were higher in female compared with male rats…
Chemistry, Pharmacodynamics, and Pharmacokinetics of NSAIDs
2016
Numerous chemically different entities are clustered under the label of nonsteroidal anti-inflammatory drugs (NSAIDs). They share the ability to inhibit prostanoid synthesis by blocking the activity of the cyclooxygenase enzymes and, as a consequence, to exert anti-inflammatory, analgesic, and antipyretic effects. On the other hand, by hindering the housekeeping roles of prostaglandins, they also deteriorate the gastrointestinal mucosal barrier and the renal and endothelial hemodynamic regulation. The present chapter compiles available pharmacokinetic and pharmacodynamic data that may help to understand the different therapeutic profiles reported for particular agents.
A phase I study of nintedanib combined with cisplatin/gemcitabine as first-line therapy for advanced squamous non-small cell lung cancer (LUME-Lung 3)
2018
Abstract Background There are limited treatment options for squamous non-small cell lung cancer (sqNSCLC) and prognosis remains poor. The safety and pharmacokinetics (PK) of nintedanib, a triple angiokinase inhibitor, plus cisplatin/gemcitabine as first-line treatment for advanced sqNSCLC patients, were evaluated. Materials and methods A phase I, dose-escalation study administering drugs in a 21-day cycle: cisplatin (75 mg/m2, Day 1), gemcitabine (1250 mg/m2, Days 1 and 8) and nintedanib (Days 2–7, 9–21) were given for 4–6 cycles, followed by monotherapy until disease progression or adverse events (AEs). Two nintedanib doses were tested, 150 mg twice daily (bid) and 200 mg bid, to determine…
Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants.
2019
Abstract Objectives In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates. Methods A ‘meta-model’ with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0–24 of 400 mg·h/L at steady-state in at least 80% of neonates. Results A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <…
Comparison Study of Two Differently Clicked 18F-Folates—Lipophilicity Plays a Key Role
2018
Within the last decade, several folate-based radiopharmaceuticals for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been evaluated; however, there is still a lack of suitable 18F-folates for clinical PET imaging. Herein, we report the synthesis and evaluation of two novel 18F-folates employing strain-promoted and copper-catalyzed click chemistry. Furthermore, the influence of both click-methods on lipophilicity and pharmacokinetics of the 18F-folates was investigated. 18F-Ala-folate and 18F-DBCO-folate were both stable in human serum albumin. In vitro studies proved their high affinity to the folate receptor (FR). The lipophilic character of …
Assessment of in vivo organ-uptake and in silico prediction of CYP mediated metabolism of DA-Phen, a new dopaminergic agent
2017
Abstract The drug development process strives to predict metabolic fate of a drug candidate, together with its uptake in major organs, whether they act as target, deposit or metabolism sites, to the aim of establish a relationship between the pharmacodynamics and the pharmacokinetics and highlight the potential toxicity of the drug candidate. The present study was aimed at evaluating the in vivo uptake of 2-Amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-Phen) − a new dopaminergic neurotransmission modulator, in target and non-target organs of animal subjects and integrating these data with SMARTCyp results, an in silico method that predicts the sites of cytochrome P450-m…
Monitoring few molecular binding events in scalable confined aqueous compartments by raster image correlation spectroscopy (CADRICS)
2016
The assembly of scalable liquid compartments for binding assays in array formats constitutes a topic of fundamental importance in life sciences. This challenge can be addressed by mimicking the structure of cellular compartments with biological native conditions. Here, inkjet printing is employed to develop up to hundreds of picoliter aqueous droplet arrays stabilized by oil-confinement with mild surfactants (Tween-20). The aqueous environments constitute specialized compartments in which biomolecules may exploit their function and a wide range of molecular interactions can be quantitatively investigated. Raster Image Correlation Spectroscopy (RICS) is employed to monitor in each compartmen…