Clinical and Translational Science

Current noninvasive liver tests measure fibrosis, inflammation, or steatosis and do not measure function. The HepQuant platform of noninvasive tests uniquely assesses both liver function and physiology through the hepatic uptake of stable isotopes of cholate. However, the prototypical HepQuant SHUNT test (SHUNT V1.0) is cumbersome to administer, requiring intravenous and oral administration of cholate and six peripheral venous blood samples over 90 min. To alleviate the burden of test administration, we explored whether an oral only (DuO) version, and other simplified versions, of the test could provide reproducible measurements of liver function...

This study aims to assess clinical outcomes following switching from originator to generic amlodipine. This population-based, matched, cohort study included users of originator amlodipine using claims data during 2018-2020 from a health system in Tianjin, China, in which usage of generic amlodipine was promoted by a drug procurement policy, the national volume-based procurement. Non-switchers refer to those remained on originator after the policy, while pure-switchers were those who switched to and continued using generic amlodipine, and back-switchers were those switched to generic amlodipine but then back to the originator...

A quantitatively-driven evaluation of existing clinical data and associated knowledge to accelerate drug discovery and development is a highly valuable approach across therapeutic areas, but remains underutilized. This is especially the case for rare diseases for which development is particularly challenging. The current work outlines an organizational framework to support a quantitatively-based reverse translation approach to clinical development. This approach was applied to characterize predictors of the trajectory of cognition in Hunter syndrome (Mucopolysaccharidosis Type II; MPS-II), a rare X-linked lysosomal storage disorder, highly heterogeneous in its course...

SHR-1819 is a novel anti-IL-4Rα monoclonal antibody currently under clinical development for use in patients with type 2 inflammatory diseases. In this randomized, double-blind, placebo-controlled, single-dose escalation phase I trial, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of SHR-1819 in healthy subjects. Subjects received a single subcutaneous injection of SHR-1819 or placebo, with dose escalation starting at 60 mg and subsequently increasing to 120, 240, 360, and 720 mg...

Strategies to enhance autophagy flux have been suggested to improve outcomes in cardiac ischemic models. We explored the role of adiponectin in mediating cardiac autophagy under ischemic conditions induced by permanent coronary artery ligation. We studied the molecular mechanisms underlying adiponectin's cardio-protective effects in adiponectin knockout (Ad-KO) compared with wild-type (WT) mice subjected to ischemia by coronary artery ligation and H9c2 cardiomyocyte cell line exposed to hypoxia. Systemic infusion of a cathepsin-B activatable near-infrared probe as a biomarker for autophagy and detection via noninvasive three-dimensional fluorescence molecular tomography combined with computerized tomography to quantitate temporal changes, indicated increased activity in the myocardium of WT mice after myocardial infarction which was attenuated in Ad-KO...

Tislelizumab, an anti-programmed cell death protein 1 monoclonal antibody, has demonstrated improved survival benefits over standard of care for multiple cancer indications. We present the clinical rationale and data supporting tislelizumab dose recommendation in patients with advanced tumors. The phase I, first-in-human, dose-finding BGB-A317-001 study (data cutoff [DCO]: August 2017) examined the following tislelizumab dosing regimens: 0.5-10 mg/kg every 2 weeks (q2w), 2-5 mg/kg q2w or q3w, and 200 mg q3w...

Persea americana fruit (PAF) is a favorable nutraceutical resource that comprises diverse unsaturated fatty acids (UFAs). UFAs are significant dietary supplementation, as they relieve metabolic disorders, including obesity (OB). In another aspect, this study was focused on the anti-OB efficacy of the non-fatty acids (NFAs) in PAF through network pharmacology (NP). Natural product activity & species source (NPASS), SwissADME, similarity ensemble approach (SEA), Swiss target prediction (STP), DisGeNET, and online Mendelian inheritance in man (OMIM) were utilized to gather significant molecules and its targets...

Our aim was to evaluate biomarkers for organic anion transporting polypeptide 1B1 (OATP1B1) function using a hypothesis-free metabolomics approach. We analyzed fasting plasma samples from 356 healthy volunteers using non-targeted metabolite profiling by liquid chromatography high-resolution mass spectrometry. Based on SLCO1B1 genotypes, we stratified the volunteers to poor, decreased, normal, increased, and highly increased OATP1B1 function groups. Linear regression analysis, and random forest (RF) and gradient boosted decision tree (GBDT) regressors were used to investigate associations of plasma metabolite features with OATP1B1 function...

This study evaluated and characterized the pharmacological activity of the orally administered interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors BAY1834845 (zabedosertib) and BAY1830839 in healthy male volunteers. Participants received one of either IRAK4 inhibitors or a control treatment (prednisolone 20 mg or placebo) twice daily for 7 days. Localized skin inflammation was induced by topical application of imiquimod (IMQ) cream for 3 days, starting at Day 3 of treatment. The inflammatory response was evaluated by laser speckle contrast imaging (skin perfusion) and multispectral imaging (erythema)...

The phenotypical manifestations of asthma among children are diverse and exhibit varying responses to therapeutic interventions. There is a need to develop objective biomarkers to improve the characterization of allergic and inflammatory responses relevant to asthma to predict therapeutic treatment responses. We have previously investigated histamine iontophoresis with laser Doppler flowmetry (HILD) as a potential surrogate biomarker that characterizes histamine response and may be utilized to guide the treatment of allergic and inflammatory disease...

Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations represent ~6%-12% of all EGFR-mutated non-small cell lung cancer (NSCLC) cases. First-, second-, and third-generation tyrosine kinase inhibitors (TKIs) have limited clinical activity against EGFR ex20ins mutations. Mobocertinib is a first-in-class oral EGFR TKI that selectively targets in-frame EGFR ex20ins mutations in NSCLC; accelerated approval in the United States was granted for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations whose disease has progressed on or after platinum-based chemotherapy...

Administration of oral medicinal products as crushed tablets or open capsules is an important delivery option for patients suffering from dysphagia. To obtain full interchangeability of generics with the original products, demonstration of bioequivalence (BE) between both products administered as crushed tablets/open capsules was required for poorly soluble product by European Medicines Agency (EMA) at the time of development of our rivaroxaban and deferasirox generic products. We present the results of two BE studies with modified administration of these products, which compared relative bioavailability between generic and reference products...

PF614, a trypsin-activated abuse protection oxycodone prodrug designed to reduce recreational drug abuse, was compared to OxyContin for safety and pharmacokinetics (PKs) of plasma oxycodone following oral administration. This study was a two-part design including a multi-ascending dose (part A) and a bioequivalence (BE) study (part B) in healthy volunteers. In part A, 24 subjects were randomized 3:1 to receive PF614 (50, 100, or 200 mg, n = 6/cohort) or OxyContin (20, 40, or 80 mg; n = 2/cohort) in ascending cohorts, delivered every 12 h for a total of nine doses...

Renal fibrosis is a typical pathological change from chronic kidney disease (CKD) to end-stage renal failure, which presents significant challenges in prevention and treatment. The progression of renal fibrosis is closely associated with the "gut-kidney axis," therefore, although clinical intervention to modulate the "gut-kidney axis" imbalance associated with renal fibrosis brings hope for its treatment. In this study, we first identified the close relationship between renal fibrosis development and the intestinal microenvironment through fecal microtransplantation and non-absorbable antibiotics experiments...

No abstract text is available yet for this article.

Genetic variants affect drug responses, making pre-emptive genotyping crucial for averting serious adverse events (SAEs) and treatment failure. However, assessing the benefits of pre-emptive genotyping based on genetic distribution, drug exposure, and demographics is challenging. This study aimed to estimate the population-level benefits of pre-emptive genotyping in the Korean population using nationwide cohort data. We reviewed actionable gene-drug combinations recommended by both the Clinical Pharmacogenomics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) as of February 2022, identifying high-risk phenotypes...

Aminobenzotriazole (ABT) is commonly used as a non-selective inhibitor of cytochrome P450 (CYP) enzymes to assign contributions of CYP versus non-CYP pathways to the metabolism of new chemical entities. Despite widespread use, a systematic review of the drug-drug interaction (DDI) potential for ABT has not been published nor have the implications for using it in plated hepatocyte models for low clearance reaction phenotyping. The goal being to investigate the utility of ABT as a pan-CYP inhibitor for reaction phenotyping of low clearance compounds by evaluating stability over the incubation period, inhibition potential against UGT and sulfotransferase enzymes, and interaction with nuclear receptors involved in the regulation of drug metabolizing enzymes and transporters...

Relapsed/refractory (r/r) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) outcomes remain poor. A targeted cluster of differentiation (CD)33 × CD3 bispecific antibody, JNJ-67571244, was assessed to identify the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety and tolerability, and preliminary clinical activity in patients with r/rAML or r/rMDS. This first-in-human, open-label, phase I, dose-escalation/dose-expansion study included patients with r/rAML or r/rMDS who were ineligible for or had exhausted standard therapeutic options...

This study aimed to investigate the mechanism of FAK-dependent hypoxia-induced proliferation on human pulmonary artery smooth muscle cells (HPASMCs). Primary HPASMCs were isolated and cultured in vitro under normal and hypoxia conditions to assess cell proliferation with cell counting kit-8. FAK and mitochondrial transcription termination factor 1 (mTERF1) were silenced with siRNA, mRNA, and protein levels of FAK, mTERF1, and cyclin D1 were determined. HPASMC proliferation increased under hypoxia compared to normal conditions...

The purpose of this study was to investigate changes in the lipidome of patients with sepsis to identify signaling lipids associated with poor outcomes that could be linked to future therapies. Adult patients with sepsis were enrolled within 24h of sepsis recognition. Patients meeting Sepsis-3 criteria were enrolled from the emergency department or intensive care unit and blood samples were obtained. Clinical data were collected and outcomes of rapid recovery, chronic critical illness (CCI), or early death were adjudicated by clinicians...