Journal of Clinical Investigation

Reflection paper on investigation of pharmacokinetics in the obese population - Scientific guideline

Retrieved on: 
Wednesday, February 14, 2024
Leptin, PD, Metabolism, Toxicity, Body composition, Ciprofloxacin, Clinical Pharmacokinetics, Water, LBW, Perfusion, LBM, Canadian International Council, AUC, PLOS One, Bariatric surgery, Clopidogrel, CYP, Breast, Health, DNA-binding protein, BMC Public Health, Pharmacology, BMI, CRP, Pharmaceutical Research (journal), Organ, Draft, Guideline, Bypass surgery, WHO, Ageing, INT, Pharmacokinetics, Liver, Bioavailability, Chronic liver disease, Human, Incidence, Committee, Absorption, TBW, Cardiovascular disease, Anatomy, CYP2C19, PBPK, Cmax, Factorization of polynomials, European, Lancet, CHMP, Journal, NASH, Pharmacotherapy, Adipose tissue, Non-alcoholic fatty liver disease, Journal of Clinical Investigation, Medication package insert, Overweight, NPS MedicineWise, Permeability, Benzodiazepine, Meta-analysis, Liver disease, Half-life, Acetylcholine, Ciclosporin, AAG, Kinetics, Midazolam, Kidney, Safety, Biomarker, Clinical Pharmacology & Therapeutics, Peptide, Classification, Hypertension, Metabolic syndrome, Acute coronary syndrome, Insulin resistance, Fatty liver disease, CYP2E1, Lithium, Body mass index, Reproduction, EMA, IBW, Injection, Anker, NCA, Enzyme, Inflammation, Cancer, Weight loss, Gastrointestinal tract, Cardiac output, Public health, Adipokine, CYP2C9, E pluribus unum, Physiology, Agency, Risk, Steroid, Lymph, CYP2D6, BSA, GI, Cytokine, Systematic review, Vaccine

Reflection paper on investigations of pharmacokinetics in

Key Points: 
    • Reflection paper on investigations of pharmacokinetics in
      the obese population
      Table of contents
      1.
    • References .............................................................................................. 9

      Reflection paper on investigations of pharmacokinetics in the obese population
      EMA/CHMP/535116/2016

      Page 2/12

      1.

    • This is considered
      a shortcoming that is potentially compounded by obese patients often being poorly represented in
      clinical studies.
    • The specific aims of this reflection paper are to:
      ?

      describe how the effects of obesity can be investigated during clinical medicinal product
      development.

    • ?

      provide recommendations on when investigations of the effect of obesity on the PK of a
      medicinal product should be particularly considered.

    • Reflection paper on investigations of pharmacokinetics in the obese population
      EMA/CHMP/535116/2016

      Page 3/12

      ?

      discuss how to reflect PK (and/or PK/PD) findings in weight/weight-based dosing
      recommendations.

    • Absorption
      Reduced rate of absorption linked to locally reduced blood flow (8) is reported for the subcutaneous
      and transdermal routes in obese subjects.
    • Distribution
      The distribution of medicinal products is driven by body composition, regional blood flow and binding to
      tissue and plasma proteins.
    • Obese subjects have a larger absolute lean body weight (LBW) as well as fat mass.
    • The physicochemical properties of a medicinal product (lipophilicity, polarity, molecular size, and
      degree of ionization) influence its distribution in the body.
    • In BMI class III obese
      subjects, the blood flow per gram of fat is significantly lower than that observed in class I obese or
      lean subjects (4).
    • Reflection paper on investigations of pharmacokinetics in the obese population
      EMA/CHMP/535116/2016

      Page 4/12

      An increased amount of alpha-1-acid-glycoprotein (AAG), linked to a chronic inflammatory state, is
      reported in obese individuals.

    • Fatty infiltrations are present in the liver for 90% of obese subjects, with the extent of the infiltrations
      being proportional to the degree of obesity.
    • In some cases, in particular for CYP3A4 metabolized medicinal products,
      bodyweight normalized clearance can be lower in obese patients (23).
    • Based on presently available data, it has been suggested that uptake transporters

      Reflection paper on investigations of pharmacokinetics in the obese population
      EMA/CHMP/535116/2016

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      are downregulated while efflux transporters may be upregulated (31).

    • Platelet hyper-reactivity is also observed,
      which can impair the response to anti-platelet medicinal products in obese patients (42, 43).
    • Reflection paper on investigations of pharmacokinetics in the obese population
      EMA/CHMP/535116/2016

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      3.

      the medicinal product properties and scientific literature indicate that obesity may lead to a
      marked effect on elimination and/or distribution or on the PK/PD relationship.

    • These
      models may aid in extrapolating the known efficacy and safety in the non-obese population to the
      obese population.
    • The Pharmacokinetics of the CYP3A Substrate Midazolam in Morbidly Obese Patients
      Before and One Year After Bariatric Surgery.
    • Reflection paper on investigations of pharmacokinetics in the obese population
      EMA/CHMP/535116/2016

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      41.

    • Reflection paper on investigations of pharmacokinetics in the obese population
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Cardio Diagnostics Holdings, Inc. Accelerates Cardiac Care Innovation with Appointment of Dr. Vimal Ramjee as Strategic Advisor

Retrieved on: 
Wednesday, January 24, 2024
Cardiology, Biotechnology, Technology, Other Health, Health, General Health, Health Technology, Medical Devices, Software, Artificial Intelligence, Genetics, Nuclear medicine, Entrepreneurship, Artificial intelligence, Patient, Internal medicine, Research, American College of Physicians, MD, Cardio, Emory University, JACC, Innovation, University, Algorithm, Journal of Clinical Investigation, FACC, ACP, ACC, Journal, NIH, Cardiovascular disease, Bachelor of Science, Hospital, Society for Vascular Surgery, Mount Sinai School, American College, Growth, Medical device

Cardio Diagnostics Holdings, Inc. (Nasdaq: CDIO), an AI-driven precision cardiovascular medicine company, today announced the appointment of Dr. Vimal Ramjee, MD FACC CCMS , as a Strategic Advisor.

Key Points: 
  • Cardio Diagnostics Holdings, Inc. (Nasdaq: CDIO), an AI-driven precision cardiovascular medicine company, today announced the appointment of Dr. Vimal Ramjee, MD FACC CCMS , as a Strategic Advisor.
  • The appointment of Dr. Ramjee as a Strategic Advisor to Cardio Diagnostics is a significant development to the Company’s continued growth and market expansion.
  • “I am excited to join Cardio Diagnostics and contribute to the company’s mission of improving cardiovascular health,” said Dr. Ramjee.
  • Dr. Ramjee will also work to raise awareness of Cardio Diagnostics’ innovative technologies and their potential to improve patient care.

NextCure Provides Year-End Clinical Pipeline Updates

Retrieved on: 
Thursday, December 14, 2023
Cancer, Journal of Clinical Investigation, GMP, Patient, Acute myeloid leukemia, ADC, Pembrolizumab, Environment

BELTSVILLE, Md., Dec. 14, 2023 (GLOBE NEWSWIRE) -- NextCure, Inc. (Nasdaq: NXTC), a clinical-stage biopharmaceutical company committed to discovering and developing novel, first-in-class immunomedicines to treat cancer and other immune-related diseases, today provided an update on its clinical pipeline.

Key Points: 
  • BELTSVILLE, Md., Dec. 14, 2023 (GLOBE NEWSWIRE) -- NextCure, Inc. (Nasdaq: NXTC), a clinical-stage biopharmaceutical company committed to discovering and developing novel, first-in-class immunomedicines to treat cancer and other immune-related diseases, today provided an update on its clinical pipeline.
  • Given evidence of clinical activity to date, additional patients are being added to the 100 mg cohort of patients with microsatellite stable / microsatellite instable-low immune checkpoint inhibitor naïve colorectal cancer without active liver metastasis.
  • Clinical data, including results from additional patients, are expected in the first half of 2024.
  • Data defining the mechanism of action were published in Journal of Clinical Investigation in November.

ZyVersa Therapeutics Announces Research Published in The Journal of Clinical Investigation Reinforcing IC 100’s Rationale for Inhibiting ASC Specks to Attenuate Spread of Inflammation into Surrounding Tissues

Retrieved on: 
Friday, September 22, 2023
Tissue, Heart, ASC, Chronic kidney disease, Inflammasome, Serum, Atrial fibrillation, Inflammation, NLRP3, IL-6, Research, Super Meat Boy, Journal of Clinical Investigation, Journal, CRP, Patient, AF, Therapy, CKD, Atrial enlargement, Vaccine, Pharmaceutical industry

Patients with chronic kidney disease (“CKD”) exhibit chronic systemic inflammation characterized by increased circulating levels of IL-1β, IL-6, and CRP.

Key Points: 
  • Patients with chronic kidney disease (“CKD”) exhibit chronic systemic inflammation characterized by increased circulating levels of IL-1β, IL-6, and CRP.
  • ZyVersa is developing Inflammasome ASC Inhibitor IC 100, designed to inhibit inflammasomes and their associated extracellular ASC specks to attenuate propagation of IL-1β that triggers damaging inflammation and its spread to surrounding tissues.
  • ZyVersa is developing Inflammasome ASC Inhibitor IC 100 to inhibit multiple inflammasomes, including NLRP3, and their associated ASC specs to attenuate release and perpetuation of circulating IL-1β to control inflammation in various inflammatory diseases.
  • “The research published in The Journal of Clinical Investigation reinforces the importance of attenuating extracellular propagation of IL-1β to minimize induction and perpetuation of inflammation in surrounding tissues,” commented Stephen C. Glover, ZyVersa’s Co-founder, Chairman, CEO, and President.

Oscotec/ADEL Announce FDA Clearance of IND Application of ADEL-Y01 for the Treatment of Alzheimer's Disease

Retrieved on: 
Thursday, September 14, 2023
Partnership, Lysine, Clinical trial, Mild cognitive impairment, Pharmacokinetics, Brain, Tauopathy, Aggregation, Journal, Patient, Immunoglobulin G, Journal of Clinical Investigation, AD, FDA, Regulation of food and dietary supplements by the U.S. Food and Drug Administration, IND, Alzheimer's disease, Food, Safety, Pharmaceutical industry, Vaccine

PANGYO, South Korea, Sept. 14, 2023 /PRNewswire/ -- Oscotec Inc. and ADEL Inc. announced that the U.S. Food and Drug Administration (FDA) has cleared the investigational new drug (IND) application of ADEL-Y01 for the treatment of Alzheimer's disease (AD).

Key Points: 
  • PANGYO, South Korea, Sept. 14, 2023 /PRNewswire/ -- Oscotec Inc. and ADEL Inc. announced that the U.S. Food and Drug Administration (FDA) has cleared the investigational new drug (IND) application of ADEL-Y01 for the treatment of Alzheimer's disease (AD).
  • Oscotec and ADEL are jointly developing a novel disease-modifying immunotherapy agent (ADEL-Y01) targeting tau protein accumulation in the AD brain.
  • "The IND clearance by the FDA represents a major achievement for us, especially in light of our first candidate entering into clinical trials," said Seung-Yong Yoon, M.D., CEO of ADEL.
  • "We are enthusiastic about commencing the clinical trial, as it brings us closer to providing therapeutic solutions for the patients grappling with tauopathies including AD."

Research Reveals Novel Insights into Transplant Rejection and New Drug Development Targets

Retrieved on: 
Wednesday, June 28, 2023
Weapon, United Network for Organ Sharing, Kidney transplantation, Surgeon, Tacrolimus, University, Biopsy, Union Christian College, Aluva, Diabetes, Half-life, Urine, Infection, Survival, Everolimus, Clinical trial, Research, Gene expression, Cincinnati Children's Hospital Medical Center, RNA, Cell, Doctor of Philosophy, JCI, TCR, Dialysis, B cell, Lung transplantation, Journal, CD8, Novartis, MD, UC, Smouldering, Journal of Clinical Investigation, Patient, University of Cincinnati, Division, Immune system, Overmyer Network, Kidney, UNOS, Liver, Injury, Notre Dame, Transplant, Health, Women's Choice Awards, Gene, People's Choice Awards, Dentistry, Pharmaceutical industry, Vaccine, Medical device, Gene Woodling

CINCINNATI, June 28, 2023 /PRNewswire/ -- Imagine a day when a urine test could inform a doctor precisely why a kidney transplant patient was experiencing organ rejection and suggest the best medication for specifically addressing the problem.  

Key Points: 
  • Findings suggests that multiple organ rejection events may actually be one, longer, smoldering rejection event.
  • "Having a precision-medicine approach to treating organ rejection has the potential to markedly reduce the threat rejection poses to transplanted organs," Woodle says.
  • However, once a kidney transplant recipient experiences acute rejection, many go on to lose their transplant and return to dialysis within 1-3 years.
  • "Thanks to insights like these, we may be able to substantially reduce loss of transplanted organs to rejection, thereby freeing up donated organs for new transplant recipients."

CoImmune Obtains License to Target DLL3 with IL-18 Armored CAR Technology

Retrieved on: 
Tuesday, June 27, 2023
SHIELD, Memorial Sloan Kettering Cancer Center, Roswell Park Comprehensive Cancer Center, Carcinoma, Interleukin, CIK, CD19, ALL, Acute lymphoblastic leukemia, Lymphoid leukemia, B cell, Armour, SCLC, CAR, Journal of Clinical Investigation, DLL3, Investigational New Drug, Chandos Chair of Medicine and Anatomy, MSK, PD-1, IND, Disease, Pharmaceutical industry, Vaccine

DURHAM, N.C., June 27, 2023 /PRNewswire/ -- CoImmune, Inc., a clinical stage immuno-oncology company working to redefine cancer treatment using best-in-class cellular immunotherapies, today announced it has exercised its option to obtain an exclusive license in the Delta-like Ligand 3 (DLL3)-targeted, allogeneic Chimeric Antigen Receptor-Cytokine Induced Killer (CAR-CIK) cell therapy field to interleukin-18 (IL-18) Armored CAR technology under a prior agreement with Memorial Sloan Kettering Cancer Center (MSK). The company is coupling the technology with allogeneic CIK cells and launched a development program focused on solid tumors with initial trials planned in small cell lung cancer (SCLC).

Key Points: 
  • CoImmune has the option to select up to three targets for IL-18 CAR products in the allogeneic cell therapy field under the agreement with MSK.
  • In March 2023, the company announced it had selected CD19 as the first target to support the clinical development of CMN-008 (Armored CAR-CIK cells) in B-cell malignancies.
  • The DLL3 target has been identified as a tumor-specific cell surface marker on neuroendocrine cancers including SCLC.
  • We saw strong synergy with PD1 checkpoint inhibition, suggesting a potential for curative responses at lower, subtherapeutic administrations of IL-18 armored anti-DLL3 CAR T cells.

CalciMedica Announces Publication of Preclinical Data in Journal of Clinical Investigation (JCI) Insight Supporting the Development of CRAC Channel Inhibitors for Chronic Pancreatitis (CP)

Retrieved on: 
Tuesday, June 6, 2023
Overload, Pancreatitis, University, RAP, Inflammation, Terminal, SOCE, University of Szeged, CRAC, Hepatic stellate cell, CP, Research, JCI, Fibrosis, Journal, HIV disease progression rates, Patient, Manuscript, SARAF, Journal of Clinical Investigation, Mouse, PSC, Insight, Pharmaceutical industry

LA JOLLA, Calif., June 06, 2023 (GLOBE NEWSWIRE) -- CalciMedica Inc. (“CalciMedica”) (OTCQB: CALC), a clinical-stage biopharmaceutical company focused on developing therapies for life-threatening inflammatory diseases with high unmet need, today announced the publication of preclinical data in The Journal of Clinical Investigation (JCI) Insight that details the potential benefit of CRAC channel inhibitors for chronic pancreatitis (CP). The study, titled “Orai1 calcium channel inhibition prevents progression of chronic pancreatitis,” was conducted by József Maléth, M.D., Ph.D., and his team at University of Szeged and the manuscript was co-authored by CalciMedica’s co-founder and Chief Scientific Officer, Ken Stauderman, Ph.D., and CalciMedica’s Chief Medical Officer, Sudarshan Hebbar, M.D.

Key Points: 
  • “We are encouraged by the data gathered in this study, which illustrate the potential benefit of Orai1 inhibition with a selective CRAC channel inhibitor for the treatment of chronic pancreatitis,” said Dr. Stauderman.
  • In addition, a decrease in fibrosis was observed in the mouse model, consistent with a significant reduction in the severity of CP.
  • These results support the initiation of clinical studies to assess the beneficial effects of Orai1 inhibition in patients with RAP and early CP.
  • These compounds are moving through pre-IND studies and could be ready for clinical studies in late 2024.”

LIXTE BIOTECHNOLOGY HOLDINGS REPORTS NEWLY PUBLISHED INDEPENDENT PRE-CLINICAL RESEARCH

Retrieved on: 
Tuesday, February 14, 2023
WHEN, Journal, Immunotherapy, Animal, Assistant, Journal of Clinical Investigation, RESEARCH, UCSF School of Medicine, PP2A, Neurology, Cancer, Pharmaceutical industry

PASADENA, CA, Feb. 14, 2023 (GLOBE NEWSWIRE) -- LIXTE Biotechnology Holdings, Inc. (“LIXTE” or the “Company”) (Nasdaq: LIXT) announced that, as recently reported in The Journal of Clinical Investigation, PP2A, the pharmacologic target of LIXTE’s lead clinical compound, LB-100, when deficient, enhances the effects of immune checkpoint blockade of cancer in a mouse model by a previously unappreciated mechanism.

Key Points: 
  • THE RESEARCH SHOWS THAT PP2A, THE TARGET OF LIXTE’S LEAD CLINICAL COMPOUND, LB-100, WHEN DEFICIENT, ENHANCES EFFECTS OF IMMUNE CHECKPOINT BLOCKADE OF CANCER BY A PREVIOUSLY UNAPPRECIATED MECHANISM
    PASADENA, CA, Feb. 14, 2023 (GLOBE NEWSWIRE) -- LIXTE Biotechnology Holdings, Inc .
  • (“LIXTE” or the “Company”) ( Nasdaq: LIXT ) announced that, as recently reported in The Journal of Clinical Investigation, PP2A, the pharmacologic target of LIXTE’s lead clinical compound, LB-100, when deficient, enhances the effects of immune checkpoint blockade of cancer in a mouse model by a previously unappreciated mechanism.
  • John S. Kovach, M.D., CEO and Founder of LIXTE, said, “This paper lends additional support to the potential immunotherapy application of LB-100 in cancer treatment.
  • Studies in animals show that low doses of LB-100 enhance the effectiveness of immunotherapy against a variety of cancer types by several mechanisms ( Ho et al., Nature Comm 2018 ; Yen et al.

Publication Analyzes Clinical Efficacy of Deep TMS™ in Treating Different Brain Regions Associated with Major Depressive Disorder

Retrieved on: 
Tuesday, January 31, 2023
TASE, Mental health, Journal of Clinical Investigation, Journal, Insight, Brain stimulation, Psychiatry, H1, Comparison, EEG, TMS, Ben-Gurion University of the Negev, Depression, Patient, Prefrontal cortex, Anxiety, JCI, Brainsway, Deep, Research, Pharmaceutical industry, Medical imaging

The primary endpoint of the study – non-inferiority of the H7 Coil in reducing depressive scores when compared to the H1 Coil – was successfully demonstrated among the overall patient population.

Key Points: 
  • The primary endpoint of the study – non-inferiority of the H7 Coil in reducing depressive scores when compared to the H1 Coil – was successfully demonstrated among the overall patient population.
  • This study served as the basis for BrainsWay’s August 2022 H7 Coil FDA clearance for depression.
  • This retrospective analysis was referred to in the publication as the “Clinical Differential Predictor” for TMS H-Coils.
  • Once we apply the categorization technique employed in this study, the potential exists to increase depression response rates even further.