235 results match your criteria dmpk profile

Absorption, metabolism, excretion, and safety of [C]almonertinib in healthy Chinese subjects.

Ann Transl Med 2021 May;9(10):867

Phase I Clinical Trial Unit, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Background: Almonertinib Mesilate Tablets (HS-10296, Hansoh Pharma, Shanghai, China) is a novel and selective third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). A phase I study of almonertinib in patients with non-small cell lung cancer (NSCLC) demonstrated a linear metabolic trend, a good tolerability/safety profile, and preliminary antitumor activity. However, the metabolism, excretion, and substance balance of almonertinib has not been clearly determined. Read More

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Use of Physiologically Based Pharmacokinetic Modeling for Predicting Drug-Food Interactions: Recommendations for Improving Predictive Performance of Low Confidence Food Effect Models.

AAPS J 2021 Jun 17;23(4):85. Epub 2021 Jun 17.

DMPK and Translational Modeling, AbbVie Inc., North Chicago, Illinois, USA.

Food can alter drug absorption and impact safety and efficacy. Besides conducting clinical studies, in vitro approaches such as biorelevant solubility and dissolution testing and in vivo dog studies are typical approaches to estimate a drug's food effect. The use of physiologically based pharmacokinetic models has gained importance and is nowadays a standard tool for food effect predictions at preclinical and clinical stages in the pharmaceutical industry. Read More

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Comparison of Various Approaches to Translate Non-Linear Pharmacokinetics of Monoclonal Antibodies from Cynomolgus Monkey to Human.

Eur J Drug Metab Pharmacokinet 2021 Jul 13;46(4):555-567. Epub 2021 Jun 13.

Translation Bioscience, Human Health Therapeutics, National Research Council of Canada, Ottawa, ON, Canada.

Background And Objectives: The prediction of pharmacokinetics of monoclonal antibodies (mAbs) exhibiting non-linear pharmacokinetics in preclinical species to human is challenging, and very limited scientific work has been published in this field of research. Therefore, we have conducted an elaborate comparative assessment to determine the most reliable preclinical to clinical scaling strategy for mAbs with non-linear pharmacokinetics.

Methods: We have compared three different scaling approaches to predict human pharmacokinetics from cynomolgus monkey. Read More

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Development of fluorescent-labeled trapping reagents based on cysteine to detect soft and hard electrophilic reactive metabolites.

Drug Metab Pharmacokinet 2021 Aug 15;39:100386. Epub 2021 Apr 15.

Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan. Electronic address:

Trapping assays are conducted at lead optimization stages to detect reactive metabolites (RMs) that can contribute to drug toxicity. The commonly used dansyl glutathione (dGSH) provides a sensitive analysis owing to the fluorescent label, however, it captures only soft electrophilic RMs. TRs for hard electrophilic RMs, few of which are labeled fluorescently, can detect hard electrophilic aldehydes only by forming unstable imine derivatives. Read More

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Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma.

J Med Chem 2021 Jun 3;64(12):8053-8075. Epub 2021 Jun 3.

Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.

Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. Read More

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Discovery of a novel series of GPR119 agonists: Design, synthesis, and biological evaluation of N-(Piperidin-4-yl)-N-(trifluoromethyl)pyrimidin-4-amine derivatives.

Bioorg Med Chem 2021 Jul 9;41:116208. Epub 2021 May 9.

Cardiovascular & Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.

We undertook an optimization effort involving propan-2-yl 4-({6-[5-(methanesulfonyl)-2,3-dihydro-1H-indol-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate 1, which we had previously discovered as a novel G protein-coupled receptor 119 (GPR119) agonist. To occupy a presumed hydrophobic space between the pyrimidine and piperidine rings in interaction with GPR119, we replaced the linker oxygen with nitrogen. Subsequently, the introduction of a substituent at the bridging nitrogen atom was explored. Read More

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Blocking endothelial lipase with monoclonal antibody MEDI5884 durably increases high density lipoprotein in nonhuman primates and in a phase 1 trial.

Sci Transl Med 2021 04;13(590)

Research and Early Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA.

Cardiovascular disease (CVD) is the leading global cause of death, and treatments that further reduce CV risk remain an unmet medical need. Epidemiological studies have consistently identified low high-density lipoprotein cholesterol (HDL-C) as an independent risk factor for CVD, making HDL elevation a potential clinical target for improved CVD resolution. Endothelial lipase (EL) is a circulating enzyme that regulates HDL turnover by hydrolyzing HDL phospholipids and driving HDL particle clearance. Read More

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Synthesis and Characterization of the Novel Rodent-Active and CNS-Penetrant P2X7 Receptor Antagonist Lu AF27139.

J Med Chem 2021 04 6;64(8):4891-4902. Epub 2021 Apr 6.

Neuroinflammation Disease Biology Unit Lundbeck Research USA, 215 College Road, Paramus, New Jersey 07652, United States.

There remains an insufficient number of P2X7 receptor antagonists with adequate rodent potency, CNS permeability, and pharmacokinetic properties from which to evaluate CNS disease hypotheses preclinically. Herein, we describe the molecular pharmacology, safety, pharmacokinetics, and functional CNS target engagement of Lu AF27139, a novel rodent-active and CNS-penetrant P2X7 receptor antagonist. Lu AF27139 is highly selective and potent against rat, mouse, and human forms of the receptors. Read More

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Evaluation of domain of unknown function 1220 (DUF1220) for detection of human genome by quantitative polymerase chain reaction: Potential use in assessing the biodistribution of transplanted therapeutic human cells.

Drug Metab Pharmacokinet 2021 Jun 11;38:100366. Epub 2020 Nov 11.

Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan; Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan. Electronic address:

The biodistribution profile of cell-based therapy products in animal models is important for evaluation of their safety and efficacy. Because of its quantitative nature and sensitivity, the quantitative polymerase chain reaction (qPCR) is a useful method for detecting and quantifying xenogeneic cell-derived DNA in animal models, thereby allowing a biodistribution profile to be established. Although the restriction endonuclease family from Arthrobacter luteus (Alu) of repetitive elements in human genome sequences has been used to assess the biodistribution of human cells, high background signals are detected. Read More

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High throughput screening for expanded CTG repeats in myotonic dystrophy type 1 using melt curve analysis.

Mol Genet Genomic Med 2021 Apr 24;9(4):e1619. Epub 2021 Feb 24.

Department of Human Genetics, University of Utah, Salt Lake City, Utah, USA.

Background: Myotonic dystrophy type 1 (DM1) is caused by CTG repeat expansions in the DMPK gene and is the most common form of muscular dystrophy. Patients can have long delays from onset to diagnosis, since clinical signs and symptoms are often nonspecific and overlapping with other disorders. Clinical genetic testing by Southern blot or triplet-primed PCR (TP-PCR) is technically challenging and cost prohibitive for population surveys. Read More

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Discovery of a novel series of indolinylpyrimidine-based GPR119 agonists: Elimination of ether-a-go-go-related gene liability using a hydrogen bond acceptor-focused approach.

Bioorg Med Chem 2021 Mar 23;34:116034. Epub 2021 Jan 23.

Cardiovascular & Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.

We previously identified a novel series of indolinylpyrimidine derivatives exemplified by 2 in Figure 1, which is an indoline based derivative, as potent GPR119 agonists. Despite the attractive potency of 2, this compound inhibited the human ether-a-go-go-related gene (hERG) K channel. We elucidated crucial roles of the methylsulfonyl group of 2 in its interaction with the hERG channel and the GPR119 receptor, presumably as a hydrogen bond acceptor (HBA). Read More

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Thiophene-Pyrazolourea Derivatives as Potent, Orally Bioavailable, and Isoform-Selective JNK3 Inhibitors.

ACS Med Chem Lett 2021 Jan 13;12(1):24-29. Epub 2020 Dec 13.

Department of Biological Chemistry & Pharmacology, Ohio State University College of Medicine, Columbus, Ohio 43210, United States.

Potent JNK3 isoform selective inhibitors were developed from a thiophenyl-pyrazolourea scaffold. Through structure activity relationship (SAR) studies utilizing enzymatic and cell-based assays, and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies, potent and highly selective JNK3 inhibitors with oral bioavailability and brain penetrant capability were developed. Inhibitor was a potent and isoform selective JNK3 inhibitor (IC = 35 nM), had significant inhibition to only JNK3 in a panel profiling of 374 wild-type kinases, had high potency in functional cell-based assays, had high stability in human liver microsome ( = 66 min) and a clean CYP-450 inhibition profile, and was orally bioavailable and brain penetrant. Read More

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January 2021

Preclinical screening of newly synthesised amidino substituted benzimidazoles and benzothiazoles.

J Enzyme Inhib Med Chem 2021 Dec;36(1):163-174

Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Zagreb, Croatia.

Newly synthesised benzimidazole/benzotiazole derivatives bearing amidino, namely 3,4,5,6-tetrahydropyrimidin-1-ium chloride, substituents have been evaluated for their potential antitumor activity . Compounds and standard drugs (doxorubicin, staurosporine and vandetanib) were tested on three human lung cancer cell lines A549, HCC827 and NCI-H358. We tested compounds in MTS citotoxicity assay and in BrdU proliferative assay performed on 2 D and 3 D assay format. Read More

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December 2021

Anti-Aβ Antibody Aducanumab Regulates the Proteome of Senile Plaques and Closely Surrounding Tissue in a Transgenic Mouse Model of Alzheimer's Disease.

J Alzheimers Dis 2021 ;79(1):249-265

Neuroscience, H. Lundbeck A/S, Valby, Denmark.

Background: Alzheimer's disease (AD) is characterized by accumulation of amyloid-β (Aβ) species and deposition of senile plaques (SPs). Clinical trials with the anti-Aβ antibody aducanumab have been completed recently.

Objective: To characterize the proteomic profile of SPs and surrounding tissue in a mouse model of AD in 10-month-old tgAPPPS1-21 mice after chronic treatment with aducanumab for four months with weekly dosing (10 mg/kg). Read More

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January 2021

Inhibition of PDE2 and PDE4 synergistically improves memory consolidation processes.

Neuropharmacology 2021 02 26;184:108414. Epub 2020 Nov 26.

Target Discovery & Behavioral Pharmacology, Dart Neuroscience, LLC, 12278 Scripps Summit Drive, San Diego, CA, 92131, USA; Neurobiology and Behavior & Center for the Neurobiology of Learning and Memory, University of California Irvine, 213 Qureshey Research Lab, Irvine, CA, 92697, USA. Electronic address:

Phosphodiesterases (PDE) are the only enzymes that degrade cAMP and cGMP which are second messengers crucial to memory consolidation. Different PDE inhibitors have been developed and tested for their memory-enhancing potential, but the occurrence of side effects has hampered clinical progression. As separate inhibition of the PDE2 and PDE4 enzyme family has been shown to enhance memory, we investigated whether concurrent treatment with a PDE2 and PDE4 inhibitor can have synergistic effects on memory consolidation processes. Read More

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February 2021

Human plasma concentration-time profiles of troglitazone and troglitazone sulfate simulated by in vivo experiments with chimeric mice with humanized livers and semi-physiological pharmacokinetic modeling.

Drug Metab Pharmacokinet 2020 Dec 30;35(6):505-514. Epub 2020 Jul 30.

Showa Pharmaceutical University, Machida, Tokyo, Japan.

Troglitazone and its major metabolite troglitazone sulfate were intravenously administered to chimeric mice with different ratios of liver replacement by human hepatocytes. Total clearances were converted to hepatic intrinsic clearances normalized to their liver weight, with the assumption that extra-hepatic elimination of these compounds was negligible. These values were plotted against the replacement indices, and postulated values for virtual 100% chimeric mice were assumed to be equivalent to those in humans. Read More

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December 2020

Cognitive Decline and White Matter Integrity Degradation in Myotonic Dystrophy Type I.

J Neuroimaging 2021 01 16;31(1):192-198. Epub 2020 Sep 16.

Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, 04510, México.

Background And Purpose: Myotonic Dystrophy Type I (DM1) is a neurodegenerative, genetic, and multisystemic disorder with a large variety of symptoms due to a CTG trinucleotide expansion located on Dystrophia Myotonica Protein Kinase (DMPK) gene. Previous reports have shown cognitive deterioration in these patients. Given that white matter (WM) degradation has also been reported in DM1 patients, here we explored if alterations in the cognitive profile of DM1 patients could be related to the deterioration of WM. Read More

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January 2021

Predictors of respiratory decline in myotonic dystrophy type 1 (DM1): a longitudinal cohort study.

Acta Neurol Belg 2021 Feb 10;121(1):133-142. Epub 2020 Jul 10.

Neurology Unit, Department of Biomedical, Metabolic and Neural Sciences, University Hospitals of Modena, Via P. Giardini, 1355, Modena, Italy.

We studied 33 patients affected by juvenile and adult myotonic dystrophy type 1 (DM1). The aim of the study was to assess clinical and laboratory parameters that could predict the requirement of noninvasive ventilation (NIV) in DM1. Secondary outcome was to assess the interplay between genetic profile, muscle impairment severity and presence of cardiac comorbidities. Read More

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February 2021

Identification, molecular characterization and segregation analysis of a variant pre-mutation allele in a three-generation Italian family.

Acta Myol 2020 Mar 1;39(1):13-18. Epub 2020 Mar 1.

Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.

DM1 is an autosomal dominant multisystemic disease caused by an unstable CTG repeat expansion in the 3'-untranslated region (UTR) of the gene. The complex variant expanded the alleles containing CAG, CCG, CTC and/or GGC interruptions repetition sequences have been reported in 3-8% of DM1 patients. To date, very few information is available about the frequency and clinical consequences of pre-mutated variant allele. Read More

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Discovery of a new class of orthosteric antagonists with nanomolar potency at extrasynaptic GABA receptors.

Sci Rep 2020 06 22;10(1):10078. Epub 2020 Jun 22.

Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen Ø, Denmark.

Brain GABA receptors are ionotropic receptors belonging to the class of Cys-loop receptors and are important drug targets for the treatment of anxiety and sleep disorders. By screening a compound library (2,112 compounds) at recombinant human αβδ GABA receptors heterologously expressed in a HEK cell line, we identified a scaffold of spirocyclic compounds with nanomolar antagonist activity at GABA receptors. The initial screening hit 2027 (IC of 1. Read More

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Discovery of RO7185876, a Highly Potent γ-Secretase Modulator (GSM) as a Potential Treatment for Alzheimer's Disease.

ACS Med Chem Lett 2020 Jun 27;11(6):1257-1268. Epub 2020 Apr 27.

F. Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.

γ-Secretase (GS) is a key target for the potential treatment of Alzheimer's disease. While inhibiting GS led to serious side effects, its modulation holds a lot of potential to deliver a safe treatment. Herein, we report the discovery of a potent and selective gamma secretase modulator (GSM) ()- (RO7185876), belonging to a novel chemical class, the triazolo-azepines. Read More

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Metabolism and Pharmacokinetic Drug-Drug Interaction Profile of Vericiguat, A Soluble Guanylate Cyclase Stimulator: Results From Preclinical and Phase I Healthy Volunteer Studies.

Clin Pharmacokinet 2020 11;59(11):1407-1418

Clinical Pharmacology, Bayer AG, Aprather Weg 18a, 41113, Wuppertal, Germany.

Background: Vericiguat is a stimulator of soluble guanylate cyclase currently under investigation as a first-in-class therapy for worsening chronic heart failure (NCT02861534). Patients with heart failure often require polypharmacy because of comorbidities. Hence, understanding the clearance mechanisms, elimination, and potential for pharmacokinetic drug-drug interactions of vericiguat is important for dose recommendations in this patient population. Read More

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November 2020

Metabolism and drug-drug interaction assessment of viloxazine.

Chungping Yu

Xenobiotica 2020 Nov 10;50(11):1285-1300. Epub 2020 Jun 10.

Preclinical DMPK and Pharmacology, Supernus Pharmaceuticals, Inc., Rockville, MD, USA.

Viloxazine is currently being developed as a treatment for attention deficit/hyperactivity disorder (ADHD). The aim of these studies is to update the understanding of the rat and human metabolism and the drug-drug interaction profile of viloxazine to a degree where it meets current regulatory standards for such investigations. absorption-distribution-metabolism-excretion (ADME) studies demonstrated that in humans 5-hydroxylation followed by glucuronidation is the major metabolic route. Read More

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November 2020

Comparative Cerebroprotective Potential of d- and l-Carnosine Following Ischemic Stroke in Mice.

Int J Mol Sci 2020 Apr 26;21(9). Epub 2020 Apr 26.

Department of Neuroscience, SITraN, University of Sheffield, Sheffield S10 2HQ, UK.

l-carnosine is an attractive therapeutic agent for acute ischemic stroke based on its robust preclinical cerebroprotective properties and wide therapeutic time window. However, large doses are needed for efficacy because carnosine is rapidly degraded in serum by carnosinases. The need for large doses could be particularly problematic when translating to human studies, as humans have much higher levels of serum carnosinases. Read More

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Discovery and pharmacological characterization of AZD3229, a potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors.

Sci Transl Med 2020 04;12(541)

Bioscience, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Boston, MA 02451, USA.

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma driven by mutations in or platelet-derived growth factor α (α). Although first-line treatment, imatinib, has revolutionized GIST treatment, drug resistance due to acquisition of secondary /α mutations develops in a majority of patients. Second- and third-line treatments, sunitinib and regorafenib, lack activity against a plethora of mutations in KIT/PDGFRα in GIST, with median time to disease progression of 4 to 6 months and inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) causing high-grade hypertension. Read More

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Species differences in liver accumulation and metabolism of nucleotide prodrug sofosbuvir.

Drug Metab Pharmacokinet 2020 Jun 16;35(3):334-340. Epub 2020 Apr 16.

Gilead Sciences, Inc, 333, Lakeside Drive, Foster City, CA, USA. Electronic address:

Sofosbuvir (SOF) is a nucleotide prodrug which has been used as a backbone for the clinical treatment of hepatitis C viral infection. Because sofosbuvir undergoes complex first pass metabolism, including metabolic activation to form its pharmacologically active triphosphate (GS-331007-TP) to inhibit the viral RNA polymerase in the liver, it is difficult to project the human dose for clinical evaluation based on preclinical data. Selecting an appropriate animal model for drug exposure in the target tissue is challenging due to differences in absorption, stability, hepatic uptake, and intracellular activation across species. Read More

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Ideal pharmacokinetic profile of dotinurad as a selective urate reabsorption inhibitor.

Drug Metab Pharmacokinet 2020 Jun 9;35(3):313-320. Epub 2020 Mar 9.

Medical R&D Division, FUJI YAKUHIN CO., LTD., 4-383, Sakuragicho, Ohmiya Ward, Saitama City, Saitama, 330-9508, Japan.

Dotinurad, a novel selective urate reabsorption inhibitor (SURI), has potent inhibitory effects at low doses on the uptake of urate by urate transporter 1 (URAT1, solute carrier family 22 member 12 [SLC22A12]), localized at the apical membrane of renal proximal tubular cells. This study sought to clarify the pharmacokinetic (PK) profile of dotinurad. In rats, monkeys, and humans, the apparent distribution volume (0. Read More

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The Novel In Vitro Method to Calculate Tissue-to-Plasma Partition Coefficient in Humans for Predicting Pharmacokinetic Profiles by Physiologically-Based Pharmacokinetic Model With High Predictability.

J Pharm Sci 2020 07 10;109(7):2345-2355. Epub 2020 Apr 10.

Research Laboratory for Development, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka, Osaka 561-0825, Japan.

Proper prediction of human pharmacokinetic (PK) profiles can accelerate the compound selection in drug discovery. Recently, we reported a robust bottom-up physiologically-based pharmacokinetic (PBPK) approach (J Pharm Sci. 2019 Aug; 108(8):2718-2727), which uses the in vivo rat distribution volume at the steady state (V) to determine human tissue-to-plasma partition coefficients (Kp). Read More

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A phase I study investigation of metabolism, and disposition of [C]-anlotinib after an oral administration in patients with advanced refractory solid tumors.

Cancer Chemother Pharmacol 2020 05 7;85(5):907-915. Epub 2020 Apr 7.

Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China.

Purpose: Anlotinib is a novel oral multi-targeted receptor tyrosine kinase inhibitor, which selectively inhibits VEGFR2/3, FGFR1-4, PDGFR α/β, c-kit, and Ret. It shows antitumor effect in patients with advanced refractory solid tumors. The detailed absorption, metabolism, and excretion pathways of anlotinib have not yet been fully investigated. Read More

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A candidate drug administered subcutaneously to rodents as drug particles showing hepatic recirculation which influenced the sustained release process.

Int J Pharm 2020 May 30;581:119252. Epub 2020 Mar 30.

Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

The aim of the present study was to evaluate and interpret the pharmacokinetic profiles after subcutaneous (s.c.) administration of crystalline AZ'72 nano- and microsuspensions to rodents. Read More

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