Clinical Pharmacology & Therapeutics

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

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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
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?

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
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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
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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
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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.
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41.
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Aetion® Publishes Screening Tool to Identify Candidate Programs for Using Real-World Evidence to Support Effectiveness Claims in FDA Applications in Peer-Reviewed Journal

Retrieved on:

Friday, August 25, 2023

ECA, SPACE, Isabella Tree, Clinical Pharmacology & Therapeutics, SURF, Food and Drug Administration, RCT, RWD, Aetion, Evaluation, RWE, FDA, Eduardo Toda y Güell, Food, Medical device, Pharmaceutical industry, Agency

SURF intends to help sponsors make an initial feasibility assessment for using real-world data (RWD) to provide substantial evidence of effectiveness to support a U.S. Food and Drug Administration (FDA) approval.

Key Points:

SURF intends to help sponsors make an initial feasibility assessment for using real-world data (RWD) to provide substantial evidence of effectiveness to support a U.S. Food and Drug Administration (FDA) approval.
In recent years, FDA has made considerable progress in advancing its RWE program.
"The SURF tool is based on Aetion's experience, and our review of FDA guidance and RWE uses in Agency approvals.
To learn more about how Aetion can support your business leaders with using RWE in regulatory applications, please visit https://www.aetion.com to request a meeting today.

Researchers Use the Simulations Plus DILIsym® Platform to Predict Safety of Combined CBD and VPA Treatment

Retrieved on:

Tuesday, August 15, 2023

CBD is an FDA-approved treatment for seizures in patients diagnosed with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex.

Key Points:

CBD is an FDA-approved treatment for seizures in patients diagnosed with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex.
During the pre-approval clinical trials, treatment with CBD was occasionally associated with elevation in blood levels of ALT, a marker of liver injury, but this was much more common in patients already receiving treatment with VPA for seizures.
To identify potential underlying mechanisms, researchers used DILIsym to predict ALT levels in simulated populations that were treated with CBD alone, treated with VPA alone, and then treated with VPA before they were treated with CBD.
DILIsym predicted dose-dependent ALT elevations for CBD treatment and ALT elevations for VPA treatment when each was given alone, but the combined VPA and CBD treatment protocol mimicking the clinical trials did not increase the incidence of ALT elevations relative to CBD treatment on its own.

Relmada Therapeutics Announces Top-line Results from Phase 3 RELIANCE I Trial for REL-1017 as an Adjunctive Treatment for Major Depressive Disorder

Retrieved on:

Wednesday, December 7, 2022

Therapy, Neurodegeneration, Psilocybin, PMID, Major depressive disorder, Central nervous system, Risk, Combination, NMDA, Clinical Pharmacology & Therapeutics, NMDAR, NCE, Nature, Safety, Failure, CNS, MDD, Pharmaceutical industry, Patient

CORAL GABLES, Fla., Dec. 7, 2022 /PRNewswire/ -- Relmada Therapeutics, Inc. (Nasdaq: RLMD), a late-stage biotechnology company addressing diseases of the central nervous system (CNS), today announced results of the RELIANCE I study (REL-1017-301), evaluating REL-1017 as an adjunctive treatment for Major Depressive Disorder (MDD). The same factors that negatively affected the previously announced results from the RELIANCE III study, a limited number of high enrolling sites with unplausible placebo response, also affected RELIANCE I and the study did not achieve its primary endpoint, which was a statistically significant improvement in depression symptoms compared to placebo as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) on Day 28. RELIANCE I evaluated the use of REL-1017 in addition to a standard antidepressant for patients who had inadequate response to at least one and up to three standard antidepressant therapies.

Key Points:

REL-1017 (Esmethadone) as Adjunctive Treatment in Patients With Major Depressive Disorder: A Phase 2a Randomized Double-Blind Trial.
In a Phase 2 trial, REL-1017 demonstrated rapid, robust, and sustained antidepressant effects with statistically significant improvements compared to placebo.
Relmada Therapeutics is a late-stage biotechnology company addressing diseases of the central nervous system (CNS), with focus on major depressive disorder (MDD).
Relmada undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.

TLC Announces Acceptance of Manuscript on Anti-COVID-19 Program by Clinical and Translational Science Journal

Retrieved on:

Tuesday, November 3, 2020

Chemistry, Organic compounds, Chemical compounds, HIV protease inhibitors, Ureas, Hepatotoxins, Clinical Pharmacology & Therapeutics, Lopinavir, Favipiravir, Remdesivir, Clinical Pharmacology: Advances and Applications, Ritonavir

CTS highlights original research that helps bridge laboratory discoveries with the diagnosis and treatment of human disease and is an official journal of the American Society of Clinical Pharmacology and Therapeutics (ASCPT).

Key Points:

CTS highlights original research that helps bridge laboratory discoveries with the diagnosis and treatment of human disease and is an official journal of the American Society of Clinical Pharmacology and Therapeutics (ASCPT).
We are honored to be sharing this peer-reviewed manuscript in an internationally acclaimed journal, said George Yeh, President of TLC.
CTS has a collection of clinical pharmacology research from various potential treatments such as remdesivir, favipiravir, and lopinavir/ritonavir.
Acknowledgment of our work by CTS further fortifies the soundness of our strategy of preferential delivery to the lungs.

Steven Shafer, MD, Highly-Regarded Anesthesiologist and Clinical Pharmacology Expert, Joins NDA Partners

Retrieved on:

Wednesday, July 25, 2018

Health, Medicine, Steven Shafer, Anesthesia, Clinical pharmacology, Clinical Pharmacokinectics, Clinical Pharmacology & Therapeutics, Anesthesiologist, Pharmacology

ROCHELLE, Va., July 25, 2018 /PRNewswire-PRWeb/ --NDA Partners Chairman Carl Peck, MD, announced today that Steven Shafer, MD, a highly-regarded anesthesiologist and clinical pharmacology expert with a focus on intravenous anesthetic drugs, has joined the firm as an Expert Consultant.

Key Points:

ROCHELLE, Va., July 25, 2018 /PRNewswire-PRWeb/ --NDA Partners Chairman Carl Peck, MD, announced today that Steven Shafer, MD, a highly-regarded anesthesiologist and clinical pharmacology expert with a focus on intravenous anesthetic drugs, has joined the firm as an Expert Consultant.
"Dr. Shafer is a highly-regarded anesthesiologist and clinical pharmacology expert.
He is the former Editor-in-Chief of Anesthesia & Analgesia, the oldest journal in perioperative medicine, and a former Editor of Clinical Pharmacology & Therapeutics, the Journal of Pharmacokinetics and Biopharmaceutics, and Clinical Pharmacokinetics.
Services include product development and regulatory strategy, expert consulting, high-impact project teams, and management of client product development programs.