Safety biomarker applications in drug development

Abstract

Biomarkers are invaluable drug development tools to assess and monitor safety in early clinical trials especially when exposure margins are limiting for promising therapeutics. Although progress has been made towards identifying and implementing translational safety biomarkers for a number of organ toxicities such as kidney and liver, significant biomarker gaps still exist to monitor toxicities for testis, pancreas, etc. Several precompetitive consortia [e.g., Predictive Safety Testing Consortia (PSTC), Innovative Medicines Initiative (IMI)] are working with industry, academia, government, patient advocacy groups and foundations with a goal to qualify biomarkers such that they can be used in preclinical studies and clinical trials to accelerate drug development. This manuscript discusses the complexities of novel biomarker discovery, validation and international regulatory qualifications intended for clinical trial applications and shares specific examples from Pfizer Research and Development. As safety biomarkers become widely accepted and qualified by the regulatory agencies, they will increasingly be implemented in early clinical trials, play a key role in decision making and facilitate the progression of promising therapeutics from preclinical through clinical development.

Circulating microRNAs as promising testicular translatable safety biomarkers: current state and future perspectives

“…Regulatory guidance documents are available for preclinical risk assessment before bringing a potential testicular toxicant into the clinic and guidelines to monitor DITI in patients to assure safety. Several international consortia have been established to provide a forum for regulators, academic researchers, pharmaceutical scientists, clinicians and CRO colleagues to qualify, validate and utilize novel biomarkers of safety (Fader et al 2021;Gerlach et al 2018;Schomaker et al 2019). Among the global consortia, (1) the Predictive Safety Testing Consortium (PSTC) and (2) the Translational Safety Biomarker Pipeline (TransBioLine) consortium are very active in conducting preclinical and clinical studies, qualifying novel biomarkers and implementing in preclinical and clinical studies to assure safety.…”

Some Aspects of Drug Induced Nephrotoxicity Assessment

“…https://www.ema.europa.eu/en/documents/ other/letter-support-drug-induced-renal-tubular-injury-biomarkers_en.pdf по сравнению с креатинином как маркера для диагностики канальцевых повреждений почек была продемонстрирована в исследованиях с использованием цисплатина, ванкомицина, такролимуса и гентамицина. Установлено, что CLU наряду с KIM-1 является ранним биомаркером лекарственного поражения проксимальных канальцев почек [9,45].…”

“…Почечный биомаркер NAG -фермент с молекулярной массой более 130 кДа, продуцируемый клетками проксимальных канальцев. N-AG может быть определен в моче в очень небольших количествах у здоровых людей, повышение его уровня свидетельствует о повреждении канальцев, а высокий уровень коррелирует с неблагоприятным исходом [45].…”

Establishment of a Nanopatterned Renal Disease Model by Mimicking the Physical and Chemical Cues of a Diseased Mesangial Cell Microenvironment

“…Biomarkers are defined by National Institutes of Health (NIH) as the detectable and measurable indicators of normal physiological and pathological processes or cellular responses to therapeutic intervention. , Biomarkers are thus essential for improving diagnosis and monitoring drug activity in drug development and screening. , Reactive oxygen species (ROS) are composed of free radicals including superoxide anions (·O 2 – ), hydrogen peroxide (H 2 O 2 ), and hydroxyl radicals (·OH), which act in mediating TGF-β1-induced ECM induction and profibrotic activity during kidney injury and the progression of renal diseases. , The ROS production level has been implicated as the biomarker that is associated with pathophysiology of renal diseases . Therefore, ROS could be considered as a biomarker for TGF-β1-induced abnormal ECM induction.…”