scholarly journals Drug-development, dose-selection, rational combinations from bench-to-bedside: are there any lessons worth revisiting?

Oncotarget ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1032-1036
Author(s):  
Alexander J. Bridges ◽  
Ranjit K. Mehta ◽  
Sushmita Shukla ◽  
Matthew J. Schipper ◽  
Theodore S. Lawrence ◽  
...  
Keyword(s):  
Drug Development ◽  
Dose Selection

scholarly journals Progress in Drug Development–Pediatric Dose Selection: Workshop Summary

2021 ◽  
Vol 61 (S1) ◽  
Author(s):  
Jian Wang ◽  
John N. den Anker ◽  
Gilbert J. Burckart
Keyword(s):  
Drug Development ◽  
Dose Selection ◽  
Pediatric Dose ◽  
Workshop Summary

scholarly journals Approaches to Dose Finding in Neonates, Illustrating the Variability between Neonatal Drug Development Programs

Pharmaceutics ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 685 ◽  
Author(s):  
John N. Van den Anker ◽  
Susan McCune ◽  
Pieter Annaert ◽  
Gerri R. Baer ◽  
Yeruk Mulugeta ◽  
...  
Keyword(s):  
Drug Development ◽  
Safety Information ◽  
Disease Process ◽  
Development Program ◽  
Dose Finding ◽  
Development Programs ◽  
Sources Of Information ◽  
Older Children ◽  
Dose Selection

Drug dosing in neonates should be based on integrated knowledge concerning the disease to be treated, the physiological characteristics of the neonate, and the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. It is critically important that all sources of information be leveraged to optimize dose selection for neonates. Sources may include data from adult studies, pediatric studies, non-clinical (juvenile) animal models, in vitro studies, and in silico models. Depending on the drug development program, each of these modalities could be used to varying degrees and with varying levels of confidence to guide dosing. This paper aims to illustrate the variability between neonatal drug development programs for neonatal diseases that are similar to those seen in other populations (meropenem), neonatal diseases related but not similar to pediatric or adult populations (clopidogrel, thyroid hormone), and diseases unique to neonates (caffeine, surfactant). Extrapolation of efficacy from older children or adults to neonates is infrequently used. Even if a disease process is similar between neonates and children or adults, such as with anti-infectives, additional dosing and safety information will be necessary for labeling, recognizing that dosing in neonates is confounded by maturational PK in addition to body size.

scholarly journals Biomarkers in Pharmaceutical Research

2015 ◽  
Vol 61 (11) ◽  
pp. 1343-1353 ◽  
Author(s):  
Xuemei Zhao ◽  
Vijay Modur ◽  
Leonidas N Carayannopoulos ◽  
Omar F Laterza
Keyword(s):  
Drug Development ◽  
Patient Selection ◽  
Biomarker Discovery ◽  
Pharmaceutical Research ◽  
Growth Factor Receptor ◽  
Target Engagement ◽  
Dose Selection ◽  
Pharmaceutical Development ◽  
Candidate Drug ◽  
Pubmed Search

Abstract BACKGROUND Biomarkers are important tools in drug development and are used throughout pharmaceutical research. CONTENT This review focuses on molecular biomarkers in drug development. It contains sections on how biomarkers are used to assess target engagement, pharmacodynamics, safety, and proof-of-concept. It also covers the use of biomarkers as surrogate end points and patient selection/companion diagnostics and provides insights into clinical biomarker discovery and biomarker development/validation with regulatory implications. To survey biomarkers used in drug development—acknowledging that many pharmaceutical development biomarkers are not published—we performed a focused PubMed search employing “biomarker” and the names of the largest pharmaceutical companies as keywords and filtering on clinical trials and publications in the last 10 years. This yielded almost 500 entries, the majority of which included disease-related (approximately 60%) or prognostic/predictive (approximately 20%) biomarkers. A notable portion (approximately 8%) included HER2 (human epidermal growth factor receptor 2) testing, highlighting the utility of biomarkers for patient selection. The remaining publications included target engagement, safety, and drug metabolism biomarkers. Oncology, cardiovascular disease, and osteoporosis were the areas with the most citations, followed by diabetes and Alzheimer disease. SUMMARY Judicious biomarker use can improve pharmaceutical development efficiency by helping to select patients most appropriate for treatment using a given mechanism, optimize dose selection, and provide earlier confidence in accelerating or discontinuing compounds in clinical development. Optimal application of biomarker technology requires understanding of candidate drug pharmacology, detailed modeling of biomarker readouts relative to pharmacokinetics, rigorous validation and qualification of biomarker assays, and creative application of these elements to drug development problems.

scholarly journals Prediction of Repeat-Dose Occupancy from Single-Dose Data: Characterisation of the Relationship between Plasma Pharmacokinetics and Brain Target Occupancy

2010 ◽  
Vol 31 (3) ◽  
pp. 944-952 ◽  
Author(s):  
Sergio Abanades ◽  
Jasper van der Aart ◽  
Julien AR Barletta ◽  
Carmine Marzano ◽  
Graham E Searle ◽  
...  
Keyword(s):  
Single Dose ◽  
Drug Development ◽  
Time Course ◽  
Adaptive Design ◽  
Model Parameters ◽  
Repeat Dose ◽  
Dose Selection ◽  
Direct Model ◽  
Brain Target ◽  
The Relationship

Positron emission tomography (PET) is used in drug development to assist dose selection and to establish the relationship between blood and tissue pharmacokinetics (PKs). We present a new biomathematical approach that allows prediction of repeat-dose (RD) brain target occupancy (TO) using occupancy data obtained after administration of a single dose (SD). A PET study incorporating a sequential adaptive design was conducted in 10 healthy male adults who underwent 4 PET scans with [11C]DASB ([11C] N, N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine): 1 at baseline, 2 after 20 mg SD of the 5-hydroxytryptamine transporter (5-HTT) inhibitor duloxetine, and 1 after 4 days daily administration of 20 mg duloxetine. An adaptive design was used to select optimal times after SD for measurement of occupancy. Both direct and indirect PK/TO models were fitted to the SD data to characterise the model parameters and then applied to a predicted RD duloxetine plasma time course to predict the 5-HTT occupancy after RD. Repeat-dose prediction from the indirect model (OC50=2.62±0.93 ng/mL) was significantly better ( P<0.05) than that from the direct model (OC50=2.29±1.11 ng/mL). This approach increases the value of SD occupancy studies that are performed as part of first time in human drug development programmes by providing an estimate of the dose required to achieve the desired TO at RD.

scholarly journals Considerations for Dose Selection and Clinical Pharmacokinetics/Pharmacodynamics for the Development of Antibacterial Agents

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
M. L. Rizk ◽  
S. M. Bhavnani ◽  
G. Drusano ◽  
A. Dane ◽  
A. E. Eakin ◽  
...  
Keyword(s):  
Drug Development ◽  
Drug Efficacy ◽  
Clinical Effectiveness ◽  
Critical Parameters ◽  
Antibacterial Drug ◽  
Development Programs ◽  
Dose Selection ◽  
Clinical Pharmacokinetics ◽  
New Antibiotics ◽  
Human Pharmacokinetic

ABSTRACT In June 2017, The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, organized a workshop entitled “Pharmacokinetics-Pharmacodynamics (PK/PD) for Development of Therapeutics against Bacterial Pathogens” to discuss details and critical parameters of various PK/PD methods and identify approaches for linking human pharmacokinetic (PK) data and drug efficacy analyses. The workshop participants included individuals from academia, industry, and government. This and the accompanying minireview on nonclinical PK/PD summarize the workshop discussions and recommendations. It is important to consider how information like PK/PD can support the clinical effectiveness of new antibacterial drugs, as PK/PD data have become central to antibacterial drug development programs. Key clinical considerations for antibacterial dose selection and clinical PK/PD characterization discussed in this minireview include a robust assessment of PK in the patient population of interest, critical considerations for assessing drug penetration in the lung for the treatment of pneumonia, and an emphasis on special populations, including patients with renal impairment and augmented renal function, as well as on dosing in obese and pediatric patients. Successful application of such approaches is now used to provide a more informative drug development package to support the approval of new antibiotics.

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