Showing papers in "Clinical and Translational Science in 2017"
TL;DR: Gene therapy has changed dramatically in the 28 years since the first human gene transfer experiment in 1989, and an rAAV2 product for a congenital form of blindness is currently under review in the United States, likely to be followed by numerous other gene therapies.
Abstract: Gene therapy has changed dramatically in the 28 years since the first human gene transfer experiment in 1989. Alipogene tiparvovec, GlyberaR®, a recombinant adeno‐associated virus (rAAV) product for lipoprotein lipase deficiency, and Strimvelis®, a lentivirus vector for severe combined immune deficiency are approved in Europe. An rAAV2 product for a congenital form of blindness is currently under review in the United States, likely to be followed by numerous other gene therapies.
Nonviral gene transfer
The success of gene therapy has largely been driven by improvements in nonviral and viral gene transfer vectors. An array of physical and chemical nonviral methods have been used to transfer DNA and mRNA to mammalian cells and a substantial number of these have been developed as clinical stage technologies for gene therapy, both ex vivo and in vivo.
Cationic liposome technology is based on the ability of amphipathic lipids, possessing a positively charged head group and a hydrophobic lipid tail, to bind to negatively charged DNA or RNA and form particles that generally enter cells by endocytosis. Some cationic liposomes also contain a neutral co‐lipid, thought to enhance liposome uptake by mammalian cells.4, 5, 6, 7 Similarly, other polycations, such as poly‐l‐lysine and polyethylene‐imine, complex with nucleic acids via charge interaction and aid in the condensation of DNA or RNA into nanoparticles, which are then substrates for endosome‐mediated uptake.8 Several of these cationic‐nucleic acid complex technologies have been developed as potential clinical products, including complexes with plasmid DNA (pDNA), oligodeoxynucleotides, and various forms of synthetic RNA.9, 10, 11
Modified (and unmodified or “naked”) DNA, RNA, and oligonucleotides have also been shown to mediate successful gene transfer in a number of circumstances. These include the use of pDNA by direct intramuscular injection for DNA vaccines, the use of intratumoral injection of pDNA to deliver cytokine and/or suicide genes, systemic (s.c. or i.v.) injection of antisense nucleotides to induce RNAse H1 or exon‐skipping.12, 13, 14 The most recent of these developed for induction of RNAi are discussed in a later section.
Ex vivo introduction of pDNA and/or other nucleotides using physical methods has been well developed for certain cell types, including T lymphocytes.15 Electroporation techniques have become the standard with T cells for the introduction of a variety of molecular cargoes, including ribonucleoproteins composed of Cas9 and short‐guide RNAs for genome editing (see section below) and transposons for long‐term integration of transgenes.
116 citations
TL;DR: This review highlights the advances made in estimating drug exposures in several compartments of interest and allows for more robust and often noninvasive assessments of drug pharmacokinetics at the site of action.
Abstract: Pharmacological activity depends on adequate drug levels at the effect site, but access to these sites for pharmacokinetic sampling is often limited. Thus, we often rely on plasma concentrations as surrogates in efforts to understand exposure– response relationships. Recent advances in analytical and quantitative methodologies allow for more robust and often noninvasive assessments of drug pharmacokinetics at the site of action. This review highlights the advances made in estimating drug exposures in several compartments of interest.
84 citations
TL;DR: In this paper, the authors reviewed strategic considerations for drug and assay development resulting in FDA-approved companion or complementary diagnostic status, which can inform on improving the benefit/risk ratio without restricting drug access.
Abstract: US Food and Drug Administration (FDA)-approved diagnostic assays play an increasingly common role in managing patients to prolong lifespan while also enhancing quality of life. Diagnostic assays can be essential for the safe and effective use of therapeutics (companion diagnostic), or may inform on improving the benefit/risk ratio without restricting drug access (complementary diagnostic). This tutorial reviews strategic considerations for drug and assay development resulting in FDA-approved companion or complementary diagnostic status.
74 citations
University of Florida1, University of Maryland, Baltimore2, Nemours Foundation3, University of Pittsburgh4, Indiana University – Purdue University Indianapolis5, University of North Carolina at Chapel Hill6, University of Alabama at Birmingham7, Icahn School of Medicine at Mount Sinai8, North Dakota State University9, Indiana University10, University of Pennsylvania11, Center for Applied Genomics12, University of South Dakota13, Vanderbilt University Medical Center14
TL;DR: The Clinical Pharmacogenetics Implementation Consortium (CPIC) was formed to provide consensus guidelines on interpretation and translation of genotype results into actionable prescribing decisions as discussed by the authors, which is increasingly recognized as an important factor influencing the likelihood for drug effectiveness or risk for adverse events.
Abstract: Genotype is increasingly recognized as an important factor influencing the likelihood for drug effectiveness or risk for adverse events. Genetic information is now included in US Food and Drug Administration-approved labeling for over 130 drugs, and in some cases, the information is in the form of a boxed warning given the potentially serious implications of genotype on drug response. Based on the growing body of evidence supporting genetic contributions to drug response, the Clinical Pharmacogenetics Implementation Consortium (CPIC) was formed to provide consensus guidelines on interpretation and translation of genotype results into actionable prescribing decisions.1 Guidelines have been published for 18 drugs or drug classes as of late 2016. The Precision Medicine Initiative is expected to further drive discoveries in genomic medicine and their translation to patient care.2 In 2013, the National Institutes of Health (NIH)-funded Implementing GeNomics In praTticE (IGNITE) network was established to support the development and investigation of genomic medicine practice models to enhance its implementation into routine clinical practice.3 One of the challenges hindering genomic implementation is the limited data on the outcomes and cost-effectiveness of genotype-guided drug therapy. The IGNITE network, consisting of institutions funded in the network and affiliate members, includes a number of institutions that have implemented pharmacogenetic testing to assist with prescribing
71 citations
TL;DR: This review discusses challenges, and suggestions to overcome them, associated with the development of BsAbs, specifically those pertaining to clinical pharmacology, pharmacometrics, and bioanalysis.
Abstract: Development of bispecific antibodies (BsAbs) as therapeutic agents has recently attracted significant attention, and investments in this modality have been steadily increasing. This review discusses challenges, and suggestions to overcome them, associated with the development of BsAbs, specifically those pertaining to clinical pharmacology, pharmacometrics, and bioanalysis. These challenges and possible solutions are discussed by presenting several case studies of BsAbs that have gained regulatory approval or that are currently in clinical development.
BsAbs, also termed “dual‐targeting” or “dual‐specificity” antibodies, have the ability to bind two different targets on the same or different cell(s); the targets may be cell‐surface receptors or soluble ligands, as shown in Figure 1.1. These dual‐nature antibodies have key advantages that can potentially enhance therapeutic efficacy compared with monotherapy or traditional combination therapies by: i) simultaneously blocking two different targets or mediators that have a primary role in the disease pathogenesis; ii) inducing cell signaling pathways (e.g., proliferation or inflammation); iii) retargeting to mediate antibody‐dependent cell‐mediated cytotoxicity (ADCC); iv) avoiding the development of resistance and increasing antiproliferative effects, specifically in oncology; and v) temporarily engaging a patient's own cytotoxic T cells to target cancer cells, thus activating cytotoxic T cells to cause tumor lysis (e.g., bispecific T‐cell engagers (BiTE)).
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Figure 1
Various designs for BsAb molecules (a) Dimers inhibition: BsAbs can bind to two receptors/targets (HER2/HER3, HER2/HER4) on the same cell (e.g., MM‐111); (b) Dual inhibition: BsAbs can inhibit two different cytokines simultaneously, for example, COVA322 that inhibits TNF‐α and IL17A; (c) Triomabs: The antigen binding site binds to target cell receptors (EpCAM, HER2, or CD20) and the T‐cell receptors (CD3). The heavy chain site binds to NK cells or dendritic cells or macrophages/phagosome (e.g., catumaxomab, ertumaxomab, FBTA05); (d) Two‐ligand inactivation: two arms bind to different ligands on different cells belonging to the same population, such as DLL4 x VEGF, TNF‐α x IL17A, IL4 x IL13 (e.g., OMP‐305B83, COVA322, SAR156597); (e) Transmembrane/transcytosis: The BsAbs are designed specifically to cross the barriers/membrane via receptor transport (transferrin receptor) and bind to enzymes/receptors (BACE1) on the other side; (f) BiTE antibody construct: These are designed to bridge T cells and target cells by binding to CD3/CD28 or CD19/CD20/CD22/CEA/EpCAM, respectively (e.g., blinatumomab, MEDI‐565, MT110). The examples mentioned above can be found in Table 2 for further information. BACE1, β‐secretase 1; BiTE, bispecific T‐cell engagers; BsAbs, bispecific antibodies; DDL4, delta‐like ligand 4; EpCAM, epithelial cell adhesion molecule; HER, human epidermal growth factor receptor; IL, interleukin; NK, Natural Killer; TNF‐α, tumor necrosis factor‐alpha; VEGF, vascular endothelial growth factor.
57 citations
TL;DR: Oral D‐ 4F dosing rendered HDL less inflammatory, affirming oral D‐4F as a potential therapy to improve HDL function, suggesting plasma penetration is unnecessary.
Abstract: A single dose of the apolipoprotein (apo)A-I mimetic peptide D-4F rendered high-density lipoprotein (HDL) less inflammatory, motivating the first multiple-dose study. We aimed to assess safety/tolerability, pharmacokinetics, and pharmacodynamics of daily, orally administered D-4F. High-risk coronary heart disease (CHD) subjects added double-blinded placebo or D-4F to statin for 13 days, randomly assigned 1:3 to ascending cohorts of 100, 300, then 500 mg (n = 62; 46 men/16 women). D-4F was safe and well-tolerated. Mean ± SD plasma D-4F area under the curve (AUC, 0–8h) was 6.9 ± 5.7 ng/mL*h (100 mg), 22.7 ± 19.6 ng/mL*h (300 mg), and 104.0 ± 60.9 ng/mL*h (500 mg) among men, higher among women. Whereas placebo dropped HDL inflammatory index (HII) 28% 8 h postdose (range, 1.25–0.86), 300–500 mg D-4F effectively halved HII: 1.35–0.57 and 1.22–0.63, respectively (P < 0.03 vs. placebo). Oral D-4F peptide dose predicted HII suppression, whereas plasma D-4F exposure was dissociated, suggesting plasma penetration is unnecessary. In conclusion, oral D-4F dosing rendered HDL less inflammatory, affirming oral D-4F as a potential therapy to improve HDL function.
53 citations
TL;DR: Physiologically based pharmacokinetic modeling reproduced the renal clearance of baricitinib and the inhibitory effect of probenecid and suggested clinically relevant drug‐drug interactions (DDIs) with ibuprofen and diclofenac are unlikely.
Abstract: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, undergoes active renal tubular secretion. Baricitinib was not predicted to inhibit hepatic and renal uptake and efflux drug transporters, based on the ratio of the unbound maximum eliminating-organ inlet concentration and the in vitro half-maximal inhibitory concentrations (IC50). In vitro, baricitinib was a substrate for organic anion transporter (OAT)3, multidrug and toxin extrusion protein (MATE)2-K, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Probenecid, a strong OAT3 inhibitor, increased the area under the concentration-time curve from time zero to infinity (AUC[0–∞]) of baricitinib by twofold and decreased renal clearance to 69% of control in healthy subjects. Physiologically based pharmacokinetic (PBPK) modeling reproduced the renal clearance of baricitinib and the inhibitory effect of probenecid using the in vitro IC50 value of 4.4 μM. Using ibuprofen and diclofenac in vitro IC50 values of 4.4 and 3.8 μM toward OAT3, 1.2 and 1.0 AUC(0–∞) ratios of baricitinib were predicted. These predictions suggest clinically relevant drug-drug interactions (DDIs) with ibuprofen and diclofenac are unlikely.
48 citations
TL;DR: The public health need, a proposed framework, and the anticipated impact for the adoption of precision dosing are outlined.
Abstract: “Precision dosing” focuses on the individualization of drug treatment regimens based on patient factors known to alter drug disposition and/or response. In 2015, over 8 in 10 nonfederal acute care hospitals in the United States had adopted a basic electronic health record (EHR) system,1 which will facilitate the application of precision dosing. Expanding on recent publications,2, 3 we outline the public health need, a proposed framework, and the anticipated impact for the adoption of precision dosing.
48 citations
TL;DR: The aim of the Microphysiological Systems (MPS) for Drug Efficacy and Toxicity Testing program, funded by the National Institutes of Health, was to address difficulties in drug and therapeutic development by creation of human organ microsystems.
Abstract: The aim of the Microphysiological Systems (MPS) for Drug Efficacy and Toxicity Testing program, funded by the National Institutes of Health (NIH), was to address difficulties in drug and therapeutic development by creation of human organ microsystems. This program, now entering its fifth year, has achieved all milestones, and is expected to transform the predictive assessment of safety and effectiveness of promising therapeutics by pharmaceutical and regulatory agencies.
46 citations
TL;DR: A previously unrecognized, OCT2‐independent pathway of cisplatin‐induced renal injury is reported that is mediated by the organic anion transporters OAT1 and OAT3, which regulates renal uptake of a mercapturic acid metabolite of cisPlatin that acts as a precursor of a potent nephrotoxin.
Abstract: Cisplatin is among the most widely used anticancer drugs and known to cause a dose-limiting nephrotoxicity, which is partially dependent on the renal uptake carrier OCT2. We here report a previously unrecognized, OCT2-independent pathway of cisplatin-induced renal injury that is mediated by the organic anion transporters OAT1 and OAT3. Using transporter-deficient mouse models, we found that this mechanism regulates renal uptake of a mercapturic acid metabolite of cisplatin that acts as a precursor of a potent nephrotoxin. The function of these two transport systems can be simultaneously inhibited by the tyrosine kinase inhibitor nilotinib through noncompetitive mechanisms, without compromising the anticancer properties of cisplatin. Collectively, our findings reveal a novel pathway that explains the fundamental basis of cisplatin-induced nephrotoxicity, with potential implications for its therapeutic management.
42 citations
TL;DR: The launch of the International Consortium of Personalised Medicine, which brings together health research funders and policy making organisations, European countries aim to coordinate research and health policy to advance the implementation of personalised medicine.
Abstract: Personalised medicine is a promising new concept for dealing with challenges of health and health systems. With the launch of the International Consortium of Personalised Medicine, which brings together health research funders and policy making organisations, European countries aim to coordinate research and health policy to advance the implementation of personalised medicine.
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TL;DR: The utility of stakeholder engagement has been well established in the literature, but there are few examples of measurement and evaluation of the degree to which stakeholders are engaged in these activities and the impact of engagement on positive outcomes.
Abstract: Stakeholder engagement in research has received increasing attention in recent years1, 2 The term “stakeholder engagement” refers to the process of meaningful involvement of those who are engaged in making decisions about programs3 Engaging members of the target population is often key to improving the relevance of the issues studied, the procedures used for study, and the interpretation of outcomes of research studies, health promotion activities, and disease prevention initiatives4, 5, 6 The utility of stakeholder engagement has been well established in the literature,7, 8, 9 but there are few examples of measurement and evaluation of the degree to which stakeholders are engaged in these activities and the impact of engagement on positive outcomes These types of evaluations have been limited in scope, and largely focused on qualitative approaches10, 11, 12, 13, 14 Qualitative methods cannot be easily compared across programs or institutions15 Necessary reliability and validity information describing self‐reported levels of stakeholder engagement are also lacking, and is essential to identifying the impact of engagement on the scientific process and scientific discovery
TL;DR: High-throughput assays that have been developed to assess a variety of the functional impacts of genetic variants are reviewed to facilitate the implementation of many more variants in genomic-driven medicine.
Abstract: Genome-wide genotyping and DNA sequencing has led to the identification of large numbers of genetic variants that are associated with many clinical phenotypes. The functional impacts of most of the variants are unknown. In this article, we review high-throughput assays that have been developed to assess a variety of the functional impacts of the variants. A better understanding of their functions should facilitate the implementation of many more variants in genomic-driven medicine. A cornerstone of precision medicine is the incorporation of genetic information into healthcare decisions. This approach relies on understanding the genome complexity, the genetic differences that exist between individuals, and the functional consequences of the genetic variants. In the personal genome era, improvements in sequencing technologies are leading to continuous identification of new variants and further illustrating the complexity of the human genome and the genetic diversity between populations.
TL;DR: The safety of acebilustat, a leukotriene A4 hydrolase inhibitor, and its effect on inflammation biomarkers in patients with cystic fibrosis were evaluated, and favorable trends were observed for reduction of serum C‐reactive protein and sputum neutrophil DNA in acebilUSTat‐treated patients.
Abstract: There is a significant unmet need for safe and effective anti-inflammatory treatment for cystic fibrosis. The aim of this study was to evaluate the safety of acebilustat, a leukotriene A4 hydrolase inhibitor, and its effect on inflammation biomarkers in patients with cystic fibrosis. Seventeen patients with mild to moderate cystic fibrosis were enrolled and randomized into groups receiving placebo or doses of 50 mg or 100 mg acebilustat administered orally, once daily for 15 days. Sputum neutrophil counts were reduced by 65% over baseline values in patients treated with 100 mg acebilustat. A modestly significant 58% reduction vs. placebo in sputum elastase was observed with acebilustat treatment. Favorable trends were observed for reduction of serum C-reactive protein and sputum neutrophil DNA in acebilustat-treated patients. No changes in pulmonary function were observed. Acebilustat was safe and well tolerated. The results of this study support further clinical development of acebilustat for treatment of cystic fibrosis.
TL;DR: The Trial Innovation Network, an initiative of the Clinical and Translational Science Award (CTSA) Program, is a national multidisciplinary platform that will enable multicenter clinical trials and studies.
Abstract: The Trial Innovation Network, an initiative of the Clinical and Translational Science Award (CTSA) Program, is a national multidisciplinary platform that will enable multicenter clinical trials and studies. A key goal of the Trial Innovation Network is to increase the efficiency and effectiveness of clinical trials and studies by focusing on innovation, excellence, and collaboration; leveraging the strength and expertise of the CTSA Program; and fostering partnerships among the Institutes and Centers of the National Institutes of Health (NIH), researchers, participants, providers, industry, and other stakeholders.
TL;DR: A mouse‐to‐human translational pharmacokinetics – pharmacodynamics model built on a rich mouse database may improve clinical trial outcome predictions and suggest that the model can inform regimen optimization and predict outcomes of ongoing trials.
Abstract: Disappointing results of recent tuberculosis chemotherapy trials suggest that knowledge gained from preclinical investigations was not utilized to maximal effect A mouse-to-human translational pharmacokinetics (PKs) - pharmacodynamics (PDs) model built on a rich mouse database may improve clinical trial outcome predictions The model included Mycobacterium tuberculosis growth function in mice, adaptive immune response effect on bacterial growth, relationships among moxifloxacin, rifapentine, and rifampin concentrations accelerating bacterial death, clinical PK data, species-specific protein binding, drug-drug interactions, and patient-specific pathology Simulations of recent trials testing 4-month regimens predicted 65% (95% confidence interval [CI], 55-74) relapse-free patients vs 80% observed in the REMox-TB trial, and 79% (95% CI, 72-87) vs 82% observed in the Rifaquin trial Simulation of 6-month regimens predicted 97% (95% CI, 93-99) vs 92% and 95% observed in 2RHZE/4RH control arms, and 100% predicted and observed in the 35 mg/kg rifampin arm of PanACEA MAMS These results suggest that the model can inform regimen optimization and predict outcomes of ongoing trials
TL;DR: Recognizing that research policies must evolve with science and ensure both efficiency and protections for research participants, NIH released a Policy on the Use of a Single Institutional Review Board for Multi-Site Research in June 2016.
Abstract: For nearly 50 years, the Common Rule has required Institutional Review Board (IRB) oversight of federally-funded research to protect the rights and welfare of human research participants. Over time, research has changed and research studies often involve multiple sites. Recognizing that research policies must evolve with science and ensure both efficiency and protections for research participants, NIH released a Policy on the Use of a Single Institutional Review Board for Multi-Site Research in June 2016.
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TL;DR: Dosing adjustments in CKD require refinement; in addition to GFR, biomarkers of tubular function are needed for secreted drugs, and failure of GFR to predict changes in secretory clearance is indicated.
Abstract: Drug-dose modification in chronic kidney disease (CKD) utilizes glomerular filtration rate (GFR) with the implicit assumption that multiple renal excretory processes decline in parallel as CKD progresses. We compiled published pharmacokinetic data to evaluate if GFR predicts renal clearance changes as a function of CKD severity. For each drug, we calculated ratio of renal clearance to filtration clearance (Rnf). Of 21 drugs with Rnf >0.74 in subjects with GFR >90 mL/min (implying filtration and secretion), 13 displayed significant change in Rnf vs. GFR (slope of linear regression statistically different from zero), which indicates failure of GFR to predict changes in secretory clearance. The dependence was positive (n = 3; group A) or negative (n = 10; group B). Eight drugs showed no correlation (group C). Investigated drugs were small molecules, mostly hydrophilic, and ionizable, with some characterized as renal transporter substrates. In conclusion, dosing adjustments in CKD require refinement; in addition to GFR, biomarkers of tubular function are needed for secreted drugs.
TL;DR: It is found that SG transport by OATP1B1 or murine Oatp1b2 was effectively inhibited by rifampin, and that this agent can significantly increase plasma levels of SG in wildtype mice, but not in Oat p1b 2‐deficient animals.
Abstract: The oral multikinase inhibitor sorafenib undergoes extensive UGT1A9-mediated formation of sorafenib-β-D-glucuronide (SG). Using transporter-deficient mouse models, it was previously established that SG can be extruded into bile by ABCC2 or follow a liver-to-blood shuttling loop via ABCC3-mediated efflux into the systemic circulation, and subsequent uptake in neighboring hepatocytes by OATP1B-type transporters. Here we evaluated the possibility that this unusual process, called hepatocyte hopping, is also operational in humans and can be modulated through pharmacological inhibition. We found that SG transport by OATP1B1 or murine Oatp1b2 was effectively inhibited by rifampin, and that this agent can significantly increase plasma levels of SG in wildtype mice, but not in Oatp1b2-deficient animals. In human subjects receiving sorafenib, rifampin acutely increased the systemic exposure to SG. Our study emphasizes the need to consider hepatic handling of xenobiotic glucuronides in the design of drug-drug interaction studies of agents that undergo extensive phase II conjugation.
TL;DR: Leukocyte cell-derived chemotaxin-2 is a highly conserved protein with roles in cell development, sepsis, liver disease, metabolic syndrome, arthritis, cancer, and amyloidosis, among others.
Abstract: INTRODUCTION Leukocyte cell-derived chemotaxin-2 (LECT2) is a highly conserved protein with roles in cell development, sepsis, liver disease, metabolic syndrome, arthritis, cancer, and amyloidosis, among others. We will review its genetics, structure, role in physiology, and its future as a biomarker and therapeutic target across many diseases. Studies involving LECT2 were identified using PubMed and compiled into a single review paper. Research on LECT2 suggests a future as a biomarker of disease and potential therapeutic target.
TL;DR: Single‐dose and multiple‐dose regimens were generally well tolerated and increase in the maximal observed letermovir plasma concentration (Cmax) was dose proportional, while accumulation ratios in AUC and Cmax were 1.22 and 1.03, respectively.
Abstract: Letermovir is a novel antiviral in clinical development for prophylaxis against human cytomegalovirus in immunocompromised transplant recipients. This two-part, single-center, randomized, double-blind, placebo-controlled trial evaluated the safety and pharmacokinetics of a hydroxypropyl β-cyclodextrin (HPβCD)-based intravenous formulation of letermovir in healthy women. Subjects received single, escalating doses (120, 240, 480, 720, and 960 mg; 6 letermovir, 2 placebo per cohort) or multiple, once-daily doses (240 mg; 8 letermovir, 4 placebo) of HPβCD-formulated letermovir and the associated pharmacokinetic profiles and adverse events were investigated. Single-dose and multiple-dose regimens were generally well tolerated. Single-dose escalation resulted in a slightly more-than-dose-proportional increase in the area under the letermovir plasma concentration–time curve (AUC), whereas increase in the maximal observed letermovir plasma concentration (Cmax) was dose proportional. After once-daily dosing, accumulation ratios in AUC and Cmax were 1.22 and 1.03, respectively. The terminal half-life was 28.3 h, supporting once-daily dosing (EudraCT Number: 2012-001603-20).
TL;DR: Plasma concentrations of TNF‐α and IL‐6 were positively correlated with TLR4 and negatively correlated with caveolin‐1 in patients with DPN, suggesting reduced expression of caveolin-1 in monocytes could aggravate theTLR4‐mediated inflammatory cascade.
Abstract: The purpose of this study was to investigate the expression of TLR4 and caveolin-1 in monocytes among healthy volunteers as well as those with type-2 diabetes mellitus (T2DM) and diabetic peripheral neuropathy (DPN). Nineteen healthy control subjects, 18 patients with T2DM, and 20 patients with DPN were enrolled. Toll-like receptor (TLR)4, caveolin-1, MyD88, phosphorylated IκB, and plasma TNF-α and interleukin (IL)-6 were measured using real-time polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assay. Compared with the other two groups, the DPN group had higher expression of TLR4, MyD88, phosphorylated IκB, TNF-α, and IL-6, but significantly lower levels of caveolin-1 and total IκB in monocytes. Plasma concentrations of TNF-α and IL-6 were positively correlated with TLR4 and negatively correlated with caveolin-1 in patients with DPN. Plasma concentration of TLR4 was negatively correlated with caveolin-1 in patients with DPN. Reduced expression of caveolin-1 in monocytes could aggravate the TLR4-mediated inflammatory cascade.
TL;DR: The influence of PEAR1 rs12041331 on platelet aggregation is pathway‐specific and is altered by aspirin at therapeutic doses, but not in a dose‐dependent manner.
Abstract: Genetic variation in the platelet endothelial aggregation receptor 1 (PEAR1) gene, most notably rs12041331, is implicated in altered on-aspirin platelet aggregation and increased cardiovascular event risk. We prospectively tested the effects of aspirin administration at commonly prescribed doses (81, 162, and 324 mg/day) on agonist-induced platelet aggregation by rs12041331 genotype in 67 healthy individuals. Prior to aspirin administration, rs12041331 minor allele carriers had significantly reduced adenosine diphosphate (ADP)-induced platelet aggregation compared with noncarriers (P = 0.03) but was not associated with other platelet pathways. In contrast, rs12041331 was significantly associated with on-aspirin platelet aggregation when collagen and epinephrine were used to stimulate platelet aggregation (P < 0.05 for all associations), but not ADP. The influence of PEAR1 rs12041331 on platelet aggregation is pathway-specific and is altered by aspirin at therapeutic doses, but not in a dose-dependent manner. Additional studies are needed to determine the impact of PEAR1 on cardiovascular events in aspirin-treated patients.
TL;DR: A double‐blinded, genotype‐based stratification study to explore the pharmacokinetics and pharmacodynamics of amitriptyline according to CYP2C19 and CYp2D6 genotype in Korean subjects will provide useful information on individualized drug treatment with amitripyline considering both CYP 2D6 and CYP1C19 gene variations.
Abstract: We performed a double-blinded, genotype-based stratification study to explore the pharmacokinetics and pharmacodynamics of amitriptyline according to CYP2C19 and CYP2D6 genotype in Korean subjects. Twenty-four healthy adults were grouped by genotype of CYP2C19 and CYP2D6. After a single dose of 25 mg of amitriptyline, blood samples were collected and anticholinergic effects were measured. The extent of N-demethylation of amitriptyline significantly decreased in subjects carrying two nonfunctional alleles of CYP2C19. The extent of hydroxylation of amitriptyline or nortriptyline was significantly reduced in subjects carrying two CYP2D6 decreased functional alleles compared with those with no or one decreased functional allele. The overall metabolic pathway of amitriptyline was more likely to be dominated by CYP2C19 than CYP2D6. The gene variations of CYP2C19 and CYP2D6 did not change the pharmacodynamic effect. The findings of this study will provide useful information on individualized drug treatment with amitriptyline considering both CYP2D6 and CYP2C19 gene variations.
TL;DR: These findings demonstrate sequential changes in the process of AC‐DILI, including metabolic changes, increased miR‐122 level, increased liver enzyme activity, and enhanced lymphocyte proliferation after drug administration.
Abstract: To explore potential biomarkers for amoxicillin/clavulanate-induced liver injury (AC-DILI), we conducted a clinical trial in 32 healthy subjects based on multi-omics approaches Every subject was administered amoxicillin/clavulanate for 14 days The liver-specific microRNA-122 (miR-122) level increased prior to and correlated well with the observed alanine aminotransferase (ALT) level increase This result indicates its potential as a sensitive early marker for AC-DILI We also identified urinary metabolites, such as azelaic acid and 7-methylxanthine, with levels that significantly differed among the groups classified by ALT elevation level on day 8 after drug administration (P < 005) Lymphocyte proliferation in response to the drug was also observed These findings demonstrate sequential changes in the process of AC-DILI, including metabolic changes, increased miR-122 level, increased liver enzyme activity, and enhanced lymphocyte proliferation after drug administration In conclusion, this study provides potential biomarkers for AC-DILI based on currently known mechanisms using comprehensive multi-omics approaches
TL;DR: Key aspects to consider when conducting and evaluating early clinical biomarker research are discussed, including overarching principles to consider for reproducibility and scientific credibility.
Abstract: Biomarkers underlie many clinical tests that are integral to the practice of personalized medicine. Reproducibility and scientific credibility of clinical biomarker early development studies are critical to avoid advancing worthless or potentially harmful biomarker-based tests into late-phase clinical studies and clinical practice. This commentary discusses key aspects to consider when conducting and evaluating early clinical biomarker research. Greater attention to these aspects would enhance research reproducibility and better prioritize biomarkers for further clinical development. Recognition of the problem of irreproducibility of preclinical drug development research led to a call for transparent reporting standards and recommendations for improved study designs.1 Similar principles apply to early research aiming to develop clinical biomarker tests (henceforth termed “early clinical biomarker research”), but there are important differences too. A major difference between preclinical drug development studies and early clinical biomarker development studies is that the latter are often conducted retrospectively using stored specimens collected in routine clinical care settings or in the context of research studies originally addressing different questions. Thus, early clinical biomarker research has features of retrospective observational studies that extend beyond the experimentally controlled settings typical for preclinical drug development research. The development process for biomarker-based tests usually begins with a study aiming to establish whether a biomarker is associated with some clinical outcome or other phenotype. The test may be based on a single biomarker or a panel of biomarkers combined via a statistical prediction model; for example, using “omics” assay technologies that measure “related sets of biological molecules in a comprehensive fashion.”2 Further development requires a series of studies to gather more evidence and eventually incorporate the biomarker into a clinical test that is validated for a specific clinical use. The clinical role for a biomarker-based test typically falls into one or more of the following categories (see US Food and Drug Administration / National Institutes of Health glossary at https://www.ncbi.nlm.nih.gov/books/NBK326791/): diagnostic, monitoring, pharmacodynamics/response, predictive, prognostic, safety, and susceptibility/risk. This commentary focuses on overarching principles to consider in
TL;DR: Results support continued clinical study of once‐daily oral acebilustat in CF at doses of 50 and 100 mg and investigate the food effect and CYP3A4 induction in healthy volunteers.
Abstract: Acebilustat is a new once-daily oral antiinflammatory drug in development for treatment of cystic fibrosis (CF) and other diseases It is an inhibitor of leukotriene A4 hydrolase; therefore, production of leukotriene B4 (LTB4) in biological fluids provides a direct measure of the pharmacodynamic (PD) response to acebilustat treatment Here we compare the pharmacokinetics (PK) and PD between CF patients and healthy volunteers, and investigate the food effect and CYP3A4 induction in healthy volunteers No significant differences between study populations were observed for peak plasma level (Cmax ) or exposure (AUC) In healthy volunteers, a shift in time to Cmax (Tmax ) was observed after a high-fat meal, but there was no change in AUC LTB4 production was reduced in the blood of both populations and in sputum from CF patients Acebilustat did not induce CYP3A4 These results support continued clinical study of once-daily oral acebilustat in CF at doses of 50 and 100 mg
TL;DR: RN317 demonstrated a longer half‐life, greater exposure, and increased bioavailability vs. bococizumab, and was well tolerated, with no subjects discontinuing because of treatment‐related adverse events.
Abstract: This phase I study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of RN317 (PF-05335810), a specifically engineered, pH-sensitive, humanized proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibody, in hypercholesterolemic subjects (low-density lipoprotein cholesterol (LDL-C) ≥ 80 mg/dl) 18-70 years old receiving statin therapy. Subjects were randomized to: single-dose placebo, RN317 (subcutaneous (s.c.) 0.3, 1, 3, 6, or intravenous (i.v.) 1, 3, 6 mg/kg), or bococizumab (s.c. 1, 3, or i.v. 1 mg/kg); or multiple-dose RN317 (s.c. 300 mg every 28 days; three doses). Of 133 subjects randomized, 127 completed the study. RN317 demonstrated a longer half-life, greater exposure, and increased bioavailability vs. bococizumab. RN317 was well tolerated, with no subjects discontinuing because of treatment-related adverse events. RN317 lowered LDL-C by up to 52.5% (day 15) following a single s.c. dose of 3.0 mg/kg vs. a maximum of 70% with single-dose bococizumab s.c. 3.0 mg/kg. Multiple dosing of RN317 produced LDL-C reductions of ∼50%, sustained over an 85-day dosing interval.
TL;DR: The human dose of 16 mg/kg obiltoxaximab provided exposure beyond that of 16mg/kg in animals, ensuring a sufficient duration of PA neutralization to allow for adaptive immunity development and may be applicable to other agents being developed under the Animal Rule.
Abstract: Obiltoxaximab, a monoclonal antibody against protective antigen (PA), is approved for treatment of inhalational anthrax under the US Food and Drug Administration's (FDA) Animal Rule. The human dose was selected and justified by comparing observed obiltoxaximab exposures in healthy and infected New Zealand White rabbits and cynomolgus macaques to observed exposures in healthy humans, to simulated exposures in healthy and infected humans, and to serum PA levels in infected animals. In humans, at 16 mg/kg intravenous, obiltoxaximab AUC was >2 times that in animals, while maximum serum concentrations were comparable to those in animals and were maintained in excess of the concentration required for PA neutralization in infected animals for 2-3 weeks. Obiltoxaximab 16 mg/kg in humans provided exposure beyond that of 16 mg/kg in animals, ensuring a sufficient duration of PA neutralization to allow for adaptive immunity development. Our approach to dose translation may be applicable to other agents being developed under the Animal Rule.
TL;DR: It is suggested that additional costs incurred by increasing the power of phase II studies are offset by the increase in productivity, and corrective measures are proposed.
Abstract: The "false-negatives" of clinical development are the effective treatments wrongly determined ineffective. Statistical errors leading to "false-negatives" are larger than those leading to "false-positives," especially in typically underpowered early-phase trials. In addition, "false-negatives" are usually eliminated from further testing, thereby limiting the information available on them. We simulated the impact of early-phase power on economic productivity in three developmental scenarios. Scenario 1, representing the current status quo, assumed 50% statistical power at phase II and 90% at phase III. Scenario 2 assumed increased power (80%), and Scenario 3, increased stringency of alpha (1%) at phase II. Scenario 2 led, on average, to a 60.4% increase in productivity and 52.4% increase in profit. Scenario 3 had no meaningful advantages. Our results suggest that additional costs incurred by increasing the power of phase II studies are offset by the increase in productivity. We discuss the implications of our results and propose corrective measures.