A phase 1 study of intravenously administered TR-701 FA in subjects with advanced renal impairment
Ontology highlight
ABSTRACT:
SUBMITTER: Flanagan S
PROVIDER: S-EPMC3891555 | biostudies-literature | 2013 Jan
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Felcisetrag (formerly known as TAK-954) is a selective serotonin receptor agonist under investigation for use in patients with postoperative gastrointestinal dysfunction. The safety, tolerability, and pharmacokinetics (PK) of intravenous (i.v.) felcisetrag have been studied, but little is known about the effect of hepatic impairment on the PK of the drug. This phase 1, non-randomized, open-label study compared the PK of a single 60-minute i.v. infusion of felcisetrag between healthy individuals (n = 8) and patients with moderate (n = 10) or severe (n = 7) hepatic impairment. The primary study end points were the total and free maximum observed plasma concentration of felcisetrag at the end of infusion (Cmax ), area under the concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUClast ), and AUC from time 0 to infinity (AUCinf ). Concentration-time profiles of felcisetrag were similarly shaped between groups but revealed lower concentrations of total plasma felcisetrag with increasing severity of hepatic impairment, whereas concentrations of free felcisetrag increased. The ratios of AUClast and AUCinf for patients with severe hepatic impairment were up to 29.3% lower for total felcisetrag and up to 29.2% higher for free felcisetrag than found in healthy individuals (P < .05). Infusions were well tolerated with no discontinuations, severe adverse events, or deaths during the study. Overall, the effect of hepatic impairment on exposure to felcisetrag was minimal, suggesting that dose adjustment may be unnecessary in patients with hepatic impairment.
| S-EPMC9542772 | biostudies-literature
Project description:Explosions account for 79% of combat-related injuries, leading to multiorgan hemorrhage and uncontrolled bleeding. Uncontrolled bleeding is the leading cause of death in battlefield traumas as well as in civilian life. We need to stop the bleeding quickly to save lives, but, shockingly, there are no treatments to stop internal bleeding. A therapy that halts bleeding in a site-specific manner and is safe, stable at room temperature, and easily administered is critical for the advancement of trauma care. To address this need, we have developed hemostatic nanoparticles that are administered intravenously. When tested in a model of blast trauma with multiorgan hemorrhaging, i.v. administration of the hemostatic nanoparticles led to a significant improvement in survival over the short term (1 h postblast). No complications from this treatment were apparent out to 3 wk. This work demonstrates that these particles have the potential to save lives and fundamentally change trauma care.
| S-EPMC4104920 | biostudies-literature
Project description:The use of nanobiomaterials (NBMs) is becoming increasingly popular in the field of medicine. To improve the understanding on the biodistribution of NBMs, the present study aimed to implement and parametrize a physiologically based pharmacokinetic (PBPK) model. This model was used to describe the biodistribution of two NBMs after intravenous administration in rats, namely, poly(alkyl cyanoacrylate) (PACA) loaded with cabazitaxel (PACA-Cbz), and LipImage™ 815. A Bayesian parameter estimation approach was applied to parametrize the PBPK model using the biodistribution data. Parametrization was performed for two distinct dose groups of PACA-Cbz. Furthermore, parametrizations were performed three distinct dose groups of LipImage™ 815, resulting in a total of five different parametrizations. The results of this study indicate that the PBPK model can be adequately parametrized using biodistribution data. The PBPK parameters estimated for PACA-Cbz, specifically the vascular permeability, the partition coefficient, and the renal clearance rate, substantially differed from those of LipImage™ 815. This emphasizes the presence of kinetic differences between the different formulations and substances and the need of tailoring the parametrization of PBPK models to the NBMs of interest. The kinetic parameters estimated in this study may help to establish a foundation for a more comprehensive database on NBM-specific kinetic information, which is a first, necessary step towards predictive biodistribution modeling. This effort should be supported by the development of robust in vitro methods to quantify kinetic parameters.
| S-EPMC9360077 | biostudies-literature
Project description:The pharmacokinetics of small interfering RNAs (siRNAs) is a pivotal issue for siRNA-based drug development. In this study, we comprehensively investigated the behavior of siRNAs in vivo in various tissues and demonstrated that intravenously-injected naked siRNA accumulated remarkably in the submandibular gland, bulbourethral gland, and pancreas, with a respective half-life of ~22.7, ~45.6, and ~30.3 h. This was further confirmed by gel separation of tissue homogenates and/or supernatants. In vivo imaging and cryosectioning suggested that delivery carriers significantly influence the distribution and elimination profiles of siRNA. Gene-silencing assays revealed that neither naked nor liposome-formulated siRNA resulted in gene knockdown in the submandibular and bulbourethral glands after systemic administration, suggesting that these glands function as drug reservoirs that enable slow siRNA release into the circulation. But robust gene-silencing was achieved by local injection of liposome-encapsulated siRNA into the submandibular gland. Our results enhance understanding of the pharmacokinetic properties of siRNAs and we believe that they will facilitate the development of siRNA therapy, especially for the submandibular gland.
| S-EPMC4955053 | biostudies-literature
Project description:Tedizolid (TR-700, formerly torezolid) is the active moiety of the prodrug tedizolid phosphate (TR-701), a next-generation oxazolidinone, with high potency against Gram-positive species, including methicillin-resistant Staphylococcus aureus (MRSA). A recently completed randomized, double-blind phase 2 trial evaluated 200, 300, or 400 mg of oral tedizolid phosphate once daily for 5 to 7 days in patients with complicated skin and skin structure infections. This report examines the in vitro activity of tedizolid and Zyvox (linezolid) against Gram-positive pathogens isolated at baseline and describes the microbiological and clinical efficacy of tedizolid. Of 196 isolates tested, 81.6% were S. aureus, and of these, 76% were MRSA. The MIC(50) and MIC(90) of tedizolid against both methicillin-susceptible S. aureus (MSSA) and MRSA were 0.25 μg/ml, compared with a MIC(50) of 1 μg/ml and MIC(90) of 2 μg/ml for linezolid. For coagulase-negative staphylococci (n = 7), viridans group streptococci (n = 15), and beta-hemolytic streptococci (n = 3), the MICs ranged from 0.03 to 0.25 μg/ml for tedizolid and from 0.12 to 1 μg/ml for linezolid. The microbiological eradication rates at the test-of-cure visit (7 to 14 days posttreatment) in the microbiologically evaluable population (n = 133) were similar in all treatment groups, with overall eradication rates of 97.7% for all pathogens, 97.9% for MRSA, and 95.7% for MSSA. The clinical cure rates for MRSA and MSSA infections were 96.9% and 95.7%, respectively, across all dose groups. This study confirms the potent in vitro activity of tedizolid against pathogenic Gram-positive cocci, including MRSA, and its 4-fold-greater potency in comparison with linezolid. All dosages of tedizolid phosphate showed excellent microbiological and clinical efficacy against MRSA and MSSA.
| S-EPMC3421864 | biostudies-literature
Project description:IntroductionNipocalimab is a high-affinity, fully human, aglycosylated, effectorless, immunoglobulin G (IgG) 1 monoclonal antibody that targets the neonatal Fc receptor (FcRn), decreases systemic IgG including autoantibodies, and is under development in several IgG autoantibody- and alloantibody-mediated diseases, including generalized myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, maternal-fetal medicine, and multiple other therapeutic areas. An initial phase 1 study with single and multiple ascending doses of nipocalimab infused intravenously (IV) over 2 h demonstrated dose-dependent serum pharmacokinetics and IgG reductions, with an adverse event (AE) profile comparable to placebo.MethodsThe current investigation evaluates the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of nipocalimab across various IV infusion rates in a randomized, double-blind, placebo-controlled, sequential-dose study. Forty participants were randomized to receive nipocalimab 30 mg/kg over 60, 30, 15 or 7.5 min (0.5, 1, 2, or 4 mg/kg/min); nipocalimab 60 mg/kg over 15 min (4 mg/kg/min); or matching placebo.ResultsAt doses up to 60 mg/kg and infusion rates up to 4 mg/kg/min (maximum clinically feasible rate), single doses of nipocalimab were tolerable, with 12 (40%) participants experiencing AEs across nipocalimab cohorts compared with 1 (10%) participant in the placebo cohort. AEs deemed treatment related occurred in 6 (20%) participants receiving nipocalimab and 1 (10%) participant receiving placebo. None of the AEs were severe, and no participants discontinued treatment due to AEs. Nipocalimab provided consistent, dose-dependent serum pharmacokinetics and IgG reductions, regardless of infusion rate.DiscussionThis study supports the use of shortened durations of nipocalimab infusion for future studies.
| S-EPMC10867144 | biostudies-literature
Project description:AimsIn light of the growing recognition of renal disease in thalassemia, it is important to understand the impact of renal impairment on the pharmacokinetics of iron chelators. This study evaluated the pharmacokinetics and safety of the iron chelator deferiprone (DFP) in subjects with renal impairment in comparison with healthy volunteers (HVs).MethodsThirty-two subjects were categorized into four groups based on degree of renal impairment: none, mild, moderate or severe, as determined by estimated glomerular filtration rate (eGFR). All subjects received a single oral dose of 33 mg kg(-1) DFP, provided serum and urine samples for pharmacokinetic assessment over 24 h and were monitored for safety.ResultsRenal clearance of DFP decreased as renal impairment increased. However, based on Cmax , AUC(0,t) and AUC(0,∞), there were no significant group differences in systemic exposure, because less than 4% of the drug was excreted unchanged in the urine. DFP is extensively metabolized to a renally excreted, pharmacologically inactive metabolite, deferiprone 3-O-glucuronide (DFP-G), which exhibited higher Cmax , AUC(0,t), AUC(0,∞) and longer tmax and t1/2 in the renally impaired groups compared with HVs. The Cmax and AUCs of DFP-G increased as eGFR decreased. Overall, 75%-95% of the dose was retrieved in urine, either as DFP or DFP-G, regardless of severity of renal impairment. With respect to safety, DFP was well tolerated.ConclusionsThese data suggest that no adjustment of the DFP dosage regimen in patients with renal impairment is necessary, as there were no significant changes in the systemic exposure to the drug.
| S-EPMC5137824 | biostudies-literature
Project description:Recently, concerns have been raised about potential adverse effects of synthetic amorphous silica, commonly used as food additive (E551), since silica nanoparticles have been detected in food containing E551. We examined the biodistribution and excretion in female Sprague-Dawley rats of NM-200, a well characterized nanostructured silica representative for food applications. A single intravenous injection of NM-200 was applied at a dose of 20 mg/kgbw, followed by autopsy after 6 and 24 h. The main organs where silicon accumulated were liver and spleen. The silicon concentration significantly decreased in spleen between 6 and 24 h. In liver the tendency was the same but the effect was not significant. This could be due to clearance of the spleen to the liver via the splenic vein, while liver clearance takes more time due to hepatic processing and biliary excretion. In treated animals the liver showed in addition a prominent increase of macrophages between both evaluation moments. Within the first 24 h, silicon was mainly excreted through urine. Further studies are necessary to evaluate the toxicokinetics of different types of silica nanomaterials at lower exposure doses in order to be able to predict kinetics and toxicity of silica nanoparticles depending on their physicochemical characteristics.
| S-EPMC6318342 | biostudies-literature
Project description:BackgroundAsiDNA, a first-in-class oligonucleotide-mimicking double-stranded DNA breaks, acts as a decoy agonist to DNA damage response in tumour cells. It also activates DNA-dependent protein kinase and poly (adenosine diphosphate [ADP]-ribose) polymerase enzymes that induce phosphorylation of H2AX and protein PARylation.MethodsThe aim of this Phase 1 study was to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety and pharmacokinetics/pharmacodynamics of AsiDNA administered daily for 3 days in the first week then weekly thereafter. Twenty-two patients with advanced solid tumours were enrolled in 5 dose levels: 200, 400, 600, 900, and 1300 mg, using a 3 + 3 design.ResultsThe MTD was not reached. IV AsiDNA was safe. Two DLTs (grade 4 and grade 3 hepatic enzymes increased at 900 and 1300 mg), and two related SAE at 900 mg (grade 3 hypotension and grade 4 hepatic enzymes increased) were reported. AsiDNA PK increased proportionally with dose. A robust activation of DNA-PK by a significant posttreatment increase of γH2AX was evidenced in tumour biopsies.ConclusionThe dose of 600 mg was identified as the optimal dose for further clinical development.Clinical trial registrationClinical trial registration (NCT number): NCT03579628.
| S-EPMC7653034 | biostudies-literature
Project description:Cerebellar Purkinje cells (PCs) show conspicuous damages in many ataxic disorders. Targeted delivery of short nucleic acids, such as antisense oligonucleotides, to PCs may be a potential treatment for ataxic disorders, especially spinocerebellar ataxias (SCAs), which are mostly caused by a gain of toxic function of the mutant RNA or protein. However, oligonucleotides do not cross the blood-brain barrier (BBB), necessitating direct delivery into the central nervous system (CNS) through intra-thecal, intra-cisternal, intra-cerebral ventricular, or stereotactic parenchymal administration. We have developed a novel liposome (100 to 200 nm in diameter) formulation, DCL64, composed of dipalmitoyl-phosphatidylcholine, cholesterol, and poloxamer L64, which incorporates oligonucleotides efficiently (≥ 70%). Confocal microscopy showed that DCL64 was selectively taken up by brain microvascular endothelial cells by interacting with low-density lipoprotein receptor (LDLr) family members on cell surface, but not with other types of lipid receptors such as caveolin or scavenger receptor class B type 1. LDLr family members are implicated in brain microvascular endothelial cell endocytosis/transcytosis, and are abundantly localized on cerebellar PCs. Intravenous administration of DCL64 in normal mice showed distribution of oligonucleotides to the brain, preferentially in PCs. Mice that received DCL64 showed no adverse effect on hematological, hepatic, and renal functions in blood tests, and no histopathological abnormalities in major organs. These studies suggest that DCL64 delivers oligonucleotides to PCs across the BBB via intravenous injection with no detectable adverse effects. This property potentially makes DCL64 particularly attractive as a delivery vehicle in treatments of SCAs.
| S-EPMC6326905 | biostudies-literature