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Pharmacokinetics of indacaterol, glycopyrronium and mometasone furoate administered as an inhaled fixed-dose combination in Japanese and Caucasian healthy subjects
No full textBackground: A once-daily (o.d.) fixed-dose combination of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF) delivered via the Breezhaler® device (IND/GLY/MF) is being developed for treatment of asthma. This study compared steady-state pharmacokinetics of IND, GLY and MF between Japanese and Caucasian male subjects after multiple inhalations of IND/GLY/MF o.d. Methods: This was a single-center, open-label, 2-treatment crossover study with a 21-day washout period. Japanese and Caucasian subjects received IND/GLY/MF 150/50/80 μg (inhaled corticosteroid [ICS] medium-dose) or 150/50/160 μg o.d. (ICS high-dose) for 14 days in each period. Pharmacokinetics were characterized up to 24 h post-dose on Days 1 and 14. Results: In total, 16 Japanese (median age 31 years [range 20–40 years], mean weight 68.3 kg) and 17 Caucasian subjects (median age 27 years [range 21–43 years], mean weight 75.0 kg) were randomized. Geometric mean ratios (Japanese/Caucasian) [90% confidence interval (CI)] for Cmax for IND, GLY and MF at the high ICS dose on Day 14 were 1.31 [1.13, 1.51] 1.38 [1.13, 1.69] and 1.07 [0.969, 1.18], respectively. Geometric mean ratios (Japanese/Caucasian) [90% CI] for AUC0–24h on Day 14 for IND, GLY and MF at the high ICS dose were 1.17 [1.01, 1.35], 1.05 [0.920, 1.20] and 1.15 [1.05, 1.27] respectively. Similar trends were noted for all components for the medium ICS dose treatment. IND/GLY/MF was safe and well tolerated; no AEs suspected to be study drug-related were observed. Conclusion: Pharmacokinetics of IND, GLY and MF (high and medium dose) when delivered as a fixed-dose combination were comparable between Japanese and Caucasian subjects. The IND/GLY/MF combination at the administrated doses was safe and well tolerated in both ethnic groups. Trial registration: Japan Registry of Clinical Trial: jRCT2031200227, retrospectively registered on 04, December, 2020
Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease
No full textThe main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics. Recently, many high-resolution apo and inhibitor-bound structures of Mpro, a cysteine protease, have been determined, facilitating structure-based drug design. Mpro plays a central role in the viral life cycle by catalyzing the cleavage of SARS-CoV-2 polyproteins. In addition to the catalytic dyad His41–Cys145, Mpro contains multiple histidines including His163, His164, and His172. The protonation states of these histidines and the catalytic nucleophile Cys145 have been debated in previous studies of SARS-CoV-2 Mpro, but have yet to be investigated for SARS-CoV-2. In this work we have used molecular dynamics simulations to determine the structural stability of SARS-CoV-2 Mpro as a function of the protonation assignments for these residues. We simulated both the apo and inhibitor- bound enzyme and found that the conformational stability of the binding site, bound inhibitors, and the hydrogen bond networks of Mpro are highly sensitive to these assignments. Additionally, the two inhibitors studied, the peptidomimetic N3 and an a-ketoamide, display distinct His41/His164 protonation-state-dependent stabilities. While the apo and the N3-bound systems favored Nd (HD) and Ne (HE) protonation of His41 and His164, respectively, the a-ketoamide was not stably bound in this state. Our results illustrate the importance of using appropriate histidine protonation states to accurately model the structure and dynamics of SARS-CoV-2 Mpro in both the apo and inhibitor-bound states, a necessary prerequisite for drug-design efforts
Benzoheterocyclic Oxime Carbamates Active against Mycobacterium tuberculosis: Synthesis, Structure-Activity Relationship, Metabolism, and Biology Triaging
No full textScreening of a library of small polar molecules against Mycobacterium tuberculosis (Mtb) led to the identification of a potent benzoheterocyclic oxime carbamate hit series. This series was subjected to medicinal chemistry progression underpinned by structure-activity relationship studies toward identifying a compound for proof-of-concept studies and defining a lead optimization strategy. Carbamate and free oxime frontrunner compounds with good stability in liver microsomes and no hERG channel inhibition liability were identified and evaluated in vivo for pharmacokinetic properties. Mtb-mediated permeation and metabolism studies revealed that the carbamates were acting as prodrugs. Toward mechanism of action elucidation, selected compounds were tested in biology triage assays to assess their activity against known promiscuous targets. Taken together, these data suggest a novel yet unknown mode of action for these antitubercular hits
Pharmacokinetics of Ribociclib in Subjects With Hepatic Impairment
No full textRibociclib is an orally bioavailable, highly selective small-molecule inhibitor of cyclin-dependent kinases 4 and 6. It is currently approved for the treatment of hormone receptor–positive, human epidermal growth factor receptor 2–negative breast cancer with a starting dose of 600 mg. Both in vitro and in vivo studies indicate that ribociclib is primarily metabolized in the liver via cytochrome P450 3A4. A phase 1, open-label, multicenter, parallel cohort, single-oral-dose study was conducted to characterize the pharmacokinetics of ribociclib in subjects with varying degrees of hepatic impairment as measured by the Child-Pugh classification. Subjects were divided into 4 cohorts determined by their degree of hepatic impairment: normal, mild, moderate, or severe. Thirty subjects were enrolled and received a single 400 mg dose of ribociclib. Ribociclib exposure was similar in subjects with mild hepatic impairment compared with subjects with normal hepatic function, but was increased by approximately 30% in subjects with moderate and severe hepatic impairment. At a dose of 400 mg, ribociclib was generally well tolerated in all subjects regardless of the level of hepatic impairment. These results indicate that no dose adjustment (recommended dose of ribociclib is 600 mg daily, 3 weeks on and 1 week off) is necessary for patients with mild hepatic impairment but that a reduced dose of 400 mg daily, 3 weeks on and 1 week off in patients with moderate or severe hepatic impairment is recommended
Large-scale plasma proteomic analysis identifies proteins and pathways associated with dementia risk
No full textThe plasma proteomic changes that precede the onset of dementia could yield insights into disease biology and highlight
new biomarkers and avenues for intervention. We quantified 4,877 plasma proteins in nondemented older adults in the
Atherosclerosis Risk in Communities cohort and performed a proteome-wide association study of dementia risk over five years
(n = 4,110; 428 incident cases). Thirty-eight proteins were associated with incident dementia after Bonferroni correction. Of
these, 16 were also associated with late-life dementia risk when measured in plasma collected nearly 20 years earlier, during
mid-life. Two-sample Mendelian randomization causally implicated two dementia-associated proteins (SVEP1 and angiostatin)
in Alzheimer’s disease. SVEP1, an immunologically relevant cellular adhesion protein, was found to be part of larger dementiaassociated
protein networks, and circulating levels were associated with atrophy in brain regions vulnerable to Alzheimer’s
pathology. Pathway analyses for the broader set of dementia-associated proteins implicated immune, lipid, metabolic signaling
and hemostasis pathways in dementia pathogenesis
Engineering digitizer circuits for chemical and genetic screens in human cells.
No full textCell-based transcriptional reporters are invaluable in high-throughput compound and CRISPR screens for identifying compounds or genes that can impact a pathway of interest. However, many transcriptional reporters have weak activities and transient responses. This can result in overlooking therapeutic targets and compounds that are difficult to detect, necessitating the resource-consuming process of running multiple screens at various timepoints. Here, we present RADAR, a digitizer circuit for amplifying reporter activity and retaining memory of pathway activation. Reporting on the AP-1 pathway, our circuit identifies compounds with known activity against PKC-related pathways and shows an enhanced dynamic range with improved sensitivity compared to a classical reporter in compound screens. In the first genome-wide pooled CRISPR screen for the AP-1 pathway, RADAR identifies canonical genes from the MAPK and PKC pathways, as well as non-canonical regulators. Thus, our scalable system highlights the benefit and versatility of using genetic circuits in large-scale cell-based screening
Essential (and Largely Untaught) Skills for Clinical Pharmacology in Oncology Drug Development
No full textNo abstrac
Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease
No full textMutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Here, the identification and characterization of a high throughput screening hit 6 as a potentiator of mutant human F508del and wild type CFTR channels is reported. The design, synthesis and biological evaluation of compounds 7 to 33 to establish structure activity relationships (SAR) of the scaffold are described, leading to the identification of clinical development compound icenticaftor (QBW251) 33, which has subsequently progressed to deliver two positive clinical proofs of concept in patients with CF and COPD and is now being further developed as a novel therapeutic approach for COPD patients
New insights into molecular changes in skeletal muscle aging and disease: Differential alternative splicing and senescence
No full textProgressive loss of muscle mass and function due to muscle fiber atrophy and loss in the elderly and chronically ill is now defined as sarcopenia. It is a major contributor to loss of independence, disability, need of long-term care as well as overall mortality. Sarcopenia is a heterogenous disease and underlying mechanisms are not completely understood. Here, we newly identified and used Tmem158, alongside Cdkn1a, as relevant senescence and denervation markers (SDMs), associated with muscle fiber atrophy. Subsequent application of laser capture microdissection (LCM) and RNA analyses revealed age- and disease-associated differences in gene expression and alternative splicing patterns in a rodent sarcopenia model. Of note, genes exhibiting such differential alternative splicing (DAS) are mainly involved in the contractile function of the muscle. Many of these splicing events are also found in a mouse model for myotonic dystrophy type 1 (DM1), underscoring the premature aging phenotype of this disease. We propose to add differential alternative splicing to the hallmarks of aging
The effects of imatinib and food on the pharmacokinetics of asciminib
No full textAsciminib, a first-in-class, Specifically Targeting the ABL Myristoyl Pocket (STAMP) inhibitor of BCR-ABL1 with the potential to overcome resistance to ATP-competitive tyrosine kinase inhibitors (TKIs), is being investigated in leukemias as monotherapy and in combination with TKIs including imatinib. This Phase 1 study in healthy volunteers assessed the effect of imatinib (steady-state; 400 mg once daily, with a low-fat meal) or food (to improve tolerability of imatinib) on the pharmacokinetics (PK) of asciminib (40 mg single dose; final market formulation). Asciminib + imatinib resulted in a 2-fold increase in asciminib exposure (area under the curve, AUC) and a 1.6-fold increase in asciminib Cmax compared with single-agent asciminib. The PK of imatinib was not substantially impacted by asciminib. Compared with fasted conditions, asciminib administered with food decreased asciminib AUC by 30-60%, depending on the meal’s fat content. Asciminib + imatinib was well tolerated with no new safety signals. Overall, co-administration of imatinib 400 mg once daily with asciminib 40 mg once daily under low-fat meal conditions resulted in increased asciminib exposure, similar to that provided with the recommended asciminib single-agent dose (40 mg twice daily) under fasted conditions. Single-agent asciminib should be administered in the fasted state to avoid suboptimal exposure