“…All the above steps are influenced by the chemical features of the drug, its formulation, its ability to cross membranes and barriers, and time in contact with these structures. However, these last features can be significantly altered by microgravity and other space environmental stressors, leading to potential modifications of drug safety and efficacy in space (Eyal, 2020; Eyal & Derendorf, 2019; Wotring, 2011, 2018). In particular, space radiation can affect drug stability, which is a complicating factor that can variably contribute to modifications of drug effects and whose magnitude is difficult to predict in space (Blue, Chancellor, et al, 2019).…”
As human spaceflight progresses with extended mission durations, the demand for effective and safe drugs will necessarily increase. To date, the accepted medications used during missions (for space motion sickness, sleep disturbances, allergies, pain, and sinus congestion) are administered under the assumption that they act as safely and efficaciously as on Earth. However, physiological changes have been documented in human subjects in spaceflight involving fluid shifts, muscle and bone loss, immune system dysregulation, and adjustments in the gastrointestinal tract and metabolism. These alterations may change the pharmacokinetics (PK) and pharmacodynamics of commonly used medications. Frustratingly, the information gained from bed rest studies and from in‐flight observations is incomplete and also demonstrates a high variability in drug PK. Therefore, the objectives of this review are to report (i) the impact of the space environmental stressors on human physiology in relation to PK; (ii) the state‐of‐the‐art on experimental data in space and/or in ground‐based models; (iii) the validation of ground‐based models for PK studies; and (iv) the identification of research gaps.
“…All the above steps are influenced by the chemical features of the drug, its formulation, its ability to cross membranes and barriers, and time in contact with these structures. However, these last features can be significantly altered by microgravity and other space environmental stressors, leading to potential modifications of drug safety and efficacy in space (Eyal, 2020; Eyal & Derendorf, 2019; Wotring, 2011, 2018). In particular, space radiation can affect drug stability, which is a complicating factor that can variably contribute to modifications of drug effects and whose magnitude is difficult to predict in space (Blue, Chancellor, et al, 2019).…”
As human spaceflight progresses with extended mission durations, the demand for effective and safe drugs will necessarily increase. To date, the accepted medications used during missions (for space motion sickness, sleep disturbances, allergies, pain, and sinus congestion) are administered under the assumption that they act as safely and efficaciously as on Earth. However, physiological changes have been documented in human subjects in spaceflight involving fluid shifts, muscle and bone loss, immune system dysregulation, and adjustments in the gastrointestinal tract and metabolism. These alterations may change the pharmacokinetics (PK) and pharmacodynamics of commonly used medications. Frustratingly, the information gained from bed rest studies and from in‐flight observations is incomplete and also demonstrates a high variability in drug PK. Therefore, the objectives of this review are to report (i) the impact of the space environmental stressors on human physiology in relation to PK; (ii) the state‐of‐the‐art on experimental data in space and/or in ground‐based models; (iii) the validation of ground‐based models for PK studies; and (iv) the identification of research gaps.
“…Adverse effects associated with these changes must be explored and defined, as they will have a major impact on the efficacy and safety of the medications administered to astronauts. The pharmacokinetic and pharmacodynamic changes in space have been reviewed elsewhere, which we direct curious readers towards for further details that are otherwise not discussed in this review ( Eyal, 2020 ; Kast et al, 2017 ). Fig.…”
Section: Altered Clinical Effects Of Medicines In Spacementioning
confidence: 99%
“…There was also significant variability in sampling time, food consumption, and route of administration. Nevertheless, existing evidence point towards altered drug disposition during spaceflight compared to measurements on Earth ( Eyal, 2020 ). Rodent models and bed rest models are often used to simulate physiological changes seen during microgravity, as they can mimic microgravity-induced fluid changes ( Mulavara et al, 2018 ; Qaisar et al, 2020 ).…”
Section: Altered Clinical Effects Of Medicines In Spacementioning
“…In addition to expanding applications in vulnerable populations, phase 0 research can also expand into other safety-related scenarios, such as pharmacotherapy in extreme environments. As humans venture into new environments, such as space, hyperthermic and hypothermic environments (for example, polar environments) and hyperbaric and hypobaric environments (underwater and high altitude), exposures to physiology-and pharmacology-altering conditions necessitate dedicated clinical research to inform pharmacotherapy [200][201][202][203] . Such environments are unlikely to have access to emergency medical services that typical research centres rely on, and hence the attractiveness of the inherent safety of phase 0 approaches 33,138,139 .…”
Phase 0 approaches-which include microdosing-evaluate subtherapeutic exposures of new drugs in first-inhuman studies known as exploratory clinical trials. Recent progress extends phase 0 benefits beyond assessment of pharmacokinetics to include understanding of mechanism of action and pharmacodynamics. Phase 0 approaches have the potential to improve preclinical candidate selection and enable safer, cheaper, quicker and more informed developmental decisions. Here, we discuss phase 0 methods and applications, highlight their advantages over traditional strategies and address concerns related to extrapolation and developmental timelines. Although challenges remain, we propose that phase 0 approaches be at least considered for application in most drug development scenarios.
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