The human skin connects the outer and inner environments and acts as a barrier protecting the internal organs from the external stressors. It consists of an intricate tissue communication (epidermis, dermis and subcutis) which involves direct connections to the immune, circulatory and nervous system. It functions as: 1) a regulator of water diffusion and temperature, 2) part of immune surveillance, 3) radiation protection, 4) mechanical protection, 5) chemical protection, 6) host to the biosynthesis of vitamins and to receptors for other hormones (Boer et al., 2016). The water retention properties, which function as a natural moisturizer, are partly due to the lipid content of this tissue (Holden et al., 2002). The intercellular lipid space is also key in the diffusion of substances through the skin, playing an important role in drug delivery (Matsui and Amagai 2015). Therefore, the role of a functional epidermis is pivotal for many of the protective and regulating characteristics of the skin. It also contains antimicrobial peptides (AMPs) and other substances that are produced by epidermis residing cells (including immune cells) and by the skin’s own microflora providing a direct defense against pathogens and the upkeep and activation of immune cells (Clausen and Agner 2016; Nakatsuji et al., 2017).

The skin varies in composition and response depending on anatomic region, sex, age, microflora and genetic predisposition resulting in a variation in response to environmental triggers between individuals (Grice et al., 2009; Machado et al., 2010). Of particular interest is the variation in barrier function, regeneration and repair of tissue, especially in extreme conditions such as space flight, where the changes in radiation, gravity levels and spacecraft nanoparticle content can result in skin changes, which can be more easily reverted with “shorter” space missions, but might lead to more permanent changes as the mission duration increases (Guo and Dipietro 2010; Machado et al., 2010). Learning to predict individual astronaut responses to specific environmental triggers and understanding when an exposure transitions from acute to chronic and the biological adaptation becomes the “new” normal, will be important tasks for deep space human flight missions in the future.

In the terrestrial environment the skin is exposed to biological and chemical stimuli such as weather conditions, ionizing radiation (IR) from the Sun, gravity, pathogens/microbiome and processes such as vitamin D synthesis. These stimuli are absent or significantly modified outside of Earth’s orbit. The ISS is a closed environment which has been accumulating parts of different microflora and particles (antigens) from different crews as well as animals (e.g., mice) over time (Crucian et al., 2016a; Crucian et al., 2016b). Astronauts have to adapt to a new habitat whilst visiting the ISS with reduced hygiene practices. This challenge has been manifested predominantly on the skin as rash and dermatitis. Other skin symptoms reported include dryness, redness, tissue oedema and acne (Crucian et al., 2016b; Dunn et al., 2018; Braun et al., 2019b). The skin also appears to “age” and it is believed to be connected to alterations in the composition of the dermis, which Braun et al. suggested could be linked to anemia and a reduction in oxygen saturation. (Braun et al., 2019b). Skin symptoms could be also linked to dehydration, partly due to insufficient water intake (Lane and Young 2012).

Even though these responses to the ISS environment might be considered as “mild”, they represent underlying biological conditions that can cause accumulation of stress or damage leading to more severe pathology later. Dysregulation of the immune response may be responsible for events such as erythema and dermatitis, but changes in oxygen levels leading to dermal extracellular matrix (ECM) stress are likely to contribute. In one study there was a 15% thinning of the epidermis in three subjects which may have a significant impact on its protective characteristics against environmental stressors (König 2012).

Wound healing presents a challenge in space as it is a vital and intricate process that is dependent on many cells working together and is classically divided into three phases: inflammation, proliferation, and remodeling. These phases have been reported to be altered in weightlessness and unloading (Delp 2008; Monica et al., 2011; Cialdai et al., 2017). Studies from the European Space Agency (ESA) driven expert working group “Tissue healing in space: techniques for promoting and monitoring tissue repair and regeneration” and the projects: “Wound Healing in space: problems and perspectives for tissue regeneration and engineering-WHISPER” and “Wound healing and sutures in unloading conditions-SUTURE IN SPACE”, which focused on surgical wounds, have the goal of providing an insight into tissue repair mechanisms in space flights. The research conducted so far demonstrated that microgravity causes a delay in healing and tissue structure alterations, as well as impairment in fibroblasts migration in wound repair and that platelet rich plasma (PRP) could be used to prevent these changes (Cialdai et al., 2020). PRP is widely used in wound repair and consists of a mixture of growth factors and cytokines obtained from total blood, activating the fraction enriched in platelets (Etulain 2018). This treatment could be used in future space flight, especially longer missions, where medically trained personnel and access to hospital care will be limited.

With regards to the skin microbiome it was reported by Voorhies et al. that there is a shift in the microbial composition seen in all crew members during space flight (Voorhies et al., 2019). There was a significant reduction of Proteobacteria, with an increase in Staphylococcal and Streptococcal species. The decrease in Proteobacteria has also been seen in individuals with atopy (Ruokolainen et al., 2015), which could partially explain the high frequency of skin hypersensitivity reactions/rashes and infections experienced by astronauts (Crucian et al., 2016a).

Skin cancer is considered by many to be like a “wound that won’t heal” (because of the deregulation of VEGF and fibrin deposits in early wound healing) (Dvorak 1986; Dvorak, 2015) and a disease of aging (in which inheritance, damage accumulation and changes in dermal tissue play a role) (Cho 2017). There are no reports of skin cancer developing during missions but the main concerns are related to the long-term effects of radiation on astronaut skin. A study of 312 astronauts from the US showed that there was an increase in non-melanoma skin cancer prevalence suggesting that radiation from space flight could be an important factor for development of skin cancer (Burgdorf and Hoenig 2015). However, it is also important to take into account the amount of underlying and accumulated damage and ultraviolet (UV) exposure before and after the space flights (Chancellor et al., 2014).

Studies that have investigated the effects of microgravity on cancer cells have demonstrated altered lymphocyte response and activation of known oncogenic pathways (e.g., KRAS) (Sahebi and Halvaei, 2017). Future research for skin cancer should focus on factors in human space flight that have the potential to activate and maintain oncogenic pathways. Signs of pre-malignancy in astronaut skin (e.g., Bowen’s disease) and assessment of progression are of importance as together it would indicate if the extra-terrestrial environment (like microgravity, radiation, nanoparticles) together with epigenetic and genetic factors lead to higher cancer risk from space flight.

During their permanence in space, astronauts are exposed to IR. Space radiation differs from the types of radiation experienced on Earth. It consists of atoms in which electrons have been stripped away as they accelerate in interstellar space to velocities close to the speed of light - and in the end, only the nucleus of the atom remains. Space radiation consists of three types: 1) particles that are trapped in the Earth’s magnetic field, 2) particles released into space during solar flares (solar particle events); and 3) galactic cosmic rays, which are composed of high-energy protons and heavy ions originating from outside our Solar System (Figure 3).

In principle, IR interacts along charged particle tracks with biological molecules such as DNA. The process is largely stochastic, and can damage DNA via direct interactions (e.g., ionization and excitation) or via indirect interactions such as through the production of reactive oxygen species (ROS) as a result of radiolysis of water molecules.

There are three main factors that determine the amount of radiation that astronauts receive or how the IR affects astronauts: 1) altitude above ground: at higher altitudes, the protection of the Earth’s atmosphere no longer exists and the magnetic field is weaker, so there is less protection against ionizing particles, and the spacecraft pass through the trapped radiation belts more often. 2) solar cycle: the Sun has a cycle of 11 years, which culminates in a significant increase in the number and intensity of solar flares, especially during periods of many sunspots. 3) Individual susceptibility: genetic as well as epigenetic factors determine what makes one individual more vulnerable to the effects of space radiation than another. The use of biomarkers for radiation sensitivity will be further reviewed here.

IR is a well-known cause of negative health effects in humans and the development of preventive measures and guidelines, requires an understanding of the risks of radiation exposure.

Immediate effects of IR exposure are mainly seen in organs with rapidly dividing cells, like the hematopoietic system and linked immune system, gastrointestinal tract, and the skin. However, it also affects the eyes and the reproductive system (Dalci et al., 2004).

With regards to the skin, acute exposure to IR, primarily involves cellular alterations and inflammation. The effects can be seen as erythema, oedema, pigment changes, and depilation. Severe radiation injury results in the complete loss of the epidermis after which the re-epithelialization process begins within 10–14 days after radiation exposure in the absence of infection (McQuestion 2011). It has been shown that space IR also produces a unique cross talk between epidermis and dermis, where a cascade of cytokines and chemokines are secreted in response to these stress activation signals. Here, keratinocytes, fibroblasts, and endothelial cells have been shown to stimulate resident (i.e., LC, DC, mast cells, T cells) and circulating immune cells involving the immune response (Muller and Meineke 2007; Muller and Meineke, 2011).

Age, sex, genetic susceptibility, comorbidities, and a variety of other factors (like genetic syndromes, inflammatory state or viral infections) may have an impact on the radiosensitivity of distinct subpopulations too, making the acceptable levels of radiation quite individualized. There is growing evidence of an association between radiation sensitivity and age-related health impacts, including cancer development. Individuals exposed to IR are the most radiosensitive at a young age, which decreases up to maturity, and then increases again at older ages with a higher level of cancer risk. Furthermore, the long-term response to radiation exposure may be influenced by sex-related variables. According to the available evidence, women’s long-term radio-sensitivity is higher than men’s when they are exposed to the same amount of radiation (Figure 4) (ICRP 2007).

Because of advances in our understanding of the space radiation environments inside the spacecraft, on IR effects on tissues, the emergence of new epidemiological data, and changes in the ages and sex makeup of astronauts, NASA (National Aeronautics and Space Administration) has adopted numerous distinct guidelines on radiation limitations since the Apollo era. The high-risk nature of space missions means that radiation protection in manned space flight differs philosophically from that of terrestrial workers. There are guidelines for occupational doses, which have been proposed for NASA to employ in long-term mission design and manned operations. The following is a summary of the approaches that could be used in determining acceptable levels of radiation risk and their possibilities of being effective tools for human long-term deep space missions (Cucinotta 2010).

1) Comparison with occupational fatalities in riskier industries. In riskier industries the number of lives lost as a result of attributable radiation cancer is known to be lower than the number of lives lost as a result of most other occupational deaths. Furthermore, because of continuing advancements in ground-based occupational safety during the last 20 years, this comparison would be quite restricted for ISS operations or Lunar and Mars missions at this time and might not give a broad comparative setup.

The implication for precision medicine in radiation protection of astronauts is that specific gene mutations, gene expression patterns or biomarkers should be studied to identify radiation-sensitive and radiation-resistant individuals before space missions are taking place. Therefore, identification of useful radiation biomarkers of sensitivity is currently being developed to potentially and hopefully stratify and tailor, at term, radiation exposure schemes for individual astronauts, to further help and guide the decision process of specific space missions, considering higher risk exposures during extravehicular activities.

The term “radiation sensitivity” refers to an organism’s susceptibility to the effects of IR. Inadequate repair and/or misrepair of radiation-damaged genetic material of the cells (DNA), for example, due to deficient repair processes, may be the cause of radiation sensitivity. Each person’s radiation sensitivity or radiation resistance is determined by his or her genetic composition. Biomarkers and bioassays for measuring individual radiation sensitivity in the moderate to high dose range may become accessible in the next years, allowing for the routine and reliable identification of individuals with higher radiation sensitivity. Although these approaches for precision radiation protection in astronauts have the potential to refine the radiation exposure program of individual astronauts for future missions, prospective testing and validation in well-designed sets-up will be required before they are broadly implemented in the future. Gene expression through transcriptomics can also be utilized to define a radiation sensitivity index of astronauts that has the potential to be used to personalize mission programs and exposure to radiation. This would allow radiation protection to move toward a future of precision medicine based in part on genomic features of the individual, as it is important to recognize the challenge of human body heterogeneity which is composed of multiple cell types, each potentially harboring different radiation sensitivity (Rosen et al., 2000).

Space exploration is one of the most difficult and risky efforts to undertake; thus, decreasing the dangers of planetary EVAs is critical in allowing such tasks to take place. It is critical to define and categorize the risks in order to reduce them (Vuolo et al., 2017).

To ensure astronaut safety and mission success, it is imperative to also identify and mitigate the inherent risks and challenges associated with EVAs and to develop an individualized space suit according to these challenges. Prevention of hypercapnia prevention (increase of carbon dioxide partial pressure in the arterial blood >45 mmHg), thermal regulation and humidity control, nutrition, hydration, waste management, health and fitness, decompression sickness, radiation shielding, and dust mitigation are all factors in spacesuit design.

Although EVA performance has improved significantly, further research and development is still required to enable safer and more effective surface exploration activities in the future. In particular, as we continue to explore beyond low Earth orbit (LEO) and embark on missions back to the Moon and onward to Mars, it becomes critical to reassess EVA IR risks in the context of a planetary surface, rather than in microgravity. Spacesuits provide protection from UV rays, but they provide a very limited protection from all forms of IR. Therefore, research is required to investigate enhanced spacesuit materials with better IR protection characteristics. As IR sensitivity varies depending on biological sex, sizes, organs etc., a spacesuit should be designed on an individualized basis by modelling at the personal level (Thomas et al., 2012).

The immune system plays a central role in our bodies’ surveillance of both outer and inner danger signals. Maintenance of immunity and the response to environmental stressors such as radiation involves a complex interplay between many physiological aspects including nutrition, endocrine regulation, bone marrow activity, exercise or sleep quality (Crucian et al., 2018). Dysregulation of the immune system during space flight has been detected by reactivation and shedding of latent herpesviruses in astronauts on the ISS (Mehta et al., 2017). Proposed mechanisms for immune dysregulation include reduced function and altered distribution of leukocytes and T helper type 2 (Th2) shifting of cytokine profiles (Mehta et al., 2013).

Interestingly, one study in particular has shown a transient reduction of thymopoiesis in 16 astronauts returning from flight, which would connect to changes in the T-cell response and the reduced ability to combat infections (Benjamin et al., 2016). On the contrary, another group was able to show that from a 6-month mission to the ISS, the B-cell counts and phenotypes were maintained in 23 astronauts suggesting that vaccination could be used as a preventive measure by using the “stability” of B-cell response in different treatment strategies (Spielmann et al., 2019).

Additionally, recent data of crew members revealed that the IgM antibody repertoire experienced significant changes during a 6-month mission on the ISS. Such modifications were quantified to be persistent even 4 weeks after landing and likely affected the specificities of IgM binding sites. These effects were individually different, correlated with changes in the V(D)J recombination process, responsible for creating antibodies, and coincided with a higher stress response that in some cases correlated with mission characteristics (Buchheim et al., 2020).

This interaction between stress and altered immune response as a function of long-duration exposure to space flight conditions was quantified by measuring a stress dependent release of endocannabinoids which showed an aberrant immune activation pattern seen in the elderly (“inflammaging”) (Buchheim et al., 2019). Therefore, there is a possibility that this type of exposure triggers an immune response that is highly individual, which may depend on experience and mission type and can result in long lasting changes.

After examining the medical records of crew members for 46 long duration missions on the ISS (20.57 crew flight years), Crucian et al. reported on the incidence of immune-related health adverse events (Crucian et al., 2016a). A striking 83% of crew members experienced a medical event with 46% of crew members reporting a “notable” event. Notable events were defined as prolonged duration, repeated or recurring and/or unresponsive to treatment. The connection between skin and the immune system made skin rashes the most commonly reported notable event (40%) followed by infectious diseases (29%) and atypical allergies (17%). The most prescribed medications during flight missions were antihistamines used for chronic conditions which persisted longer than 7 days (Wotring 2012). Characterization of on-orbit rashes manifested as redness with irritation and could be found in a variety of body locations. Whereas these skin rashes and allergic type of events seem to occur at the onset of missions infectious events tend to develop as the mission progresses from month three onwards. Interestingly, susceptibility to immunological events differed between astronauts with 11 crew members experiencing a single notable event, ten crew members experiencing two notable events, two crew members reporting three notable events, one crew member experiencing four notable events and one member even experiencing nine notable in flight events. Therefore, the reasons for interindividual variability in susceptibility to immune events during space flight requires further investigation through appropriate longitudinal non-invasive monitoring tools for prevention and early treatment.

Very few pharmacokinetic studies have been conducted during space flight and all have relied on PK measurements using saliva samples (Cintron et al., 1981; Kovachevich et al., 2009). During human space flight, acetaminophen (2 × 325 mg) tended to show decreased Cmax on flight day (FD) 0 and an increased Cmax on FD2 and FD3 whilst Tmax tended to increase although there was significant variability within the data (Putcha and Cintron 1991). Intersubject variability was minimal preflight suggesting that PK responses to space flight show variability between individuals.

More recently, a study compared single dose 500 mg acetaminophen tablets and encapsulated forms in ten astronauts, divided into two groups of five men, preflight and during long-term space flight (Kovachevich et al., 2009). Salivary concentrations were determined up to 6 h. The tablet form demonstrated reduced rate of absorption but substantial increase in bioavailability during space flight compared with terrestrial conditions. The encapsulated form demonstrated decreased time of absorption whilst the elimination half-life, retention time and distribution volume increased considerably but overall bioavailability was similar in comparison with terrestrial conditions. The elimination curves were similar particularly for ground studies.

Scopolamine in conjunction with dextroamphetamine is a commonly used medication to counteract space motion sickness (Davis et al., 1993). A PK study in three astronauts taking scopolamine 0.4 mg and dextroamphetamine 5 mg demonstrated significant inter-astronaut variability (Cintron N et al., 1981). In one astronaut a reduction in Cmax was observed with prolonged Tmax; the second astronaut showed increased Cmax with unchanged Tmax whilst in the third crew member there was a decrease in Cmax and increase in Tmax at FD0-1 and increased Cmax and decreased Tmax on FD 2–3. In this astronaut, the PK profile for scopolamine appeared to be abnormal at FD0-1, with two concentration peaks observed, suggesting that mission day may also have an impact on PK studies. There were significant gaps in PK sampling during Space flight due to dry mouth and as a side effect of the scopolamine.

Taken together, these data suggest that the rate of exposure to medicines is more likely to be affected by microgravity rather than the amount of exposure. However, these studies were of short duration and cannot be extrapolated to longer flight missions. Salivary PK samples may not be as accurate as blood PK samples. However, blood sampling would be constrained by the technical challenges of collection, storage and return of samples during human space flight. Additional pre-clinical organ or tissue-based methods should be developed and used to supplement the clinical endpoints.

Pharmacogenetics is the study of genetic variability and its influence on drug response. Variation in drug metabolizing enzymes, transporters, receptors and ion channels can alter the efficacy and risk of adverse reaction to a medication. The Food and Drug Administration (FDA) publishes a list of pharmacogenetic associations with gene-drug interactions and therapeutic recommendations where these exist (US-Food-Drug-Administration 2021). Eight medicines present on the FDA table of pharmacogenetic associations also form part of the formulary on the ISS (Table 2). The majority of these are associations with polymorphisms in cytochrome P450 genes. CYP2D6 is a very important pharmacogene that is highly polymorphic and responsible for metabolism of up to 25% of medicines, including many psychotropic drugs which are also used for the treatment of motion-sickness (for reference of the CYP2D6 psychotropic substrates and pharmacogenetic variability, see Stingl Mol Psychiatry 2013) (Owen et al., 2009; Stingl et al., 2013). The ability of the CYP2D6 enzyme to metabolize substrates is dependent on the haplotype and subjects are classified into four categories depending on enzyme activity: ultra-rapid metabolizers (UM), normal (extensive) metabolizers (EM), intermediate metabolizers and poor metabolizers (PM) (Taylor et al., 2020). Population frequencies for different CYP2D6 alleles demonstrate significant variability across World populations. For example, PM status was observed in 8.45% of Europeans, 5.38% African Americans and only 0.84% of East Asians (Gaedigk et al., 2017). Astronauts are derived from diverse backgrounds and pharmacogenetic screening will need to include rare variants to ensure equality and equitable access.

Many drugs used in psychiatric illness, such as antidepressants, antipsychotics, and mood stabilizers, are affected by pharmacogenetic polymorphisms, with CYP2D6 being involved in the metabolism of approximately half of the commonly prescribed psychotropic drugs (Mulder et al., 2007). Since differences in plasma concentration, due to variability in drug clearance, often vary by ten-fold or more, pharmacogenetic dose adjustments have been issued (Swen et al., 2011; Hicks et al., 2013; Stingl et al., 2013). Inadequate drug exposure causes a risk for nonresponse or toxicity depending on the therapeutic range of the drug. In antidepressant drug treatment, PM for CYP2D6 have been associated with longer time requirements to find the most appropriate drug and with more frequent drug switches (Bijl et al., 2008). PM may suffer more frequently from ADRs than EM require longer hospital stays, whereas ultrarapid metabolizers (UM) have a higher risk of therapeutic failure (Chou et al., 2000; Bijl et al., 2008; Ruano et al., 2013). Pharmacogenetic guidelines are available with dosing recommendations for specific drug-genotype pairs (Relling and Klein 2011; Hicks et al., 2013). Of all genes involved in these evaluations, CYP2C19 and CYP2D6 have been shown to mainly affect the outcome and the risk of ADRs of antidepressants and antipsychotics. The effect of the CYP2D6 genotype on adverse drug effects and nonresponse, as well as on non-adherence during treatment with CYP2D6-dependent antidepressants, has been shown in several studies (Jukic et al., 2018; Jukic et al., 2019; Braten et al., 2020; Milosavljevic et al., 2021).

The FDA pharmacogenetics report is not exhaustive and there are many other pharmacogenetic associations reported in the literature with medicines that form part of the ISS formulary. For example, sleeping aids, such as zolpidem, zaleplon and diazepam, were the most commonly used medicines by US astronauts on the ISS (Wotring 2015). A study in Han Chinese patients has shown that CYP3A4*18 (increased CYP3A4 activity) and CYP2C19*2 (reduced CYP2C19 activity) significantly affect the metabolism of zolpidem with the potential to reduce efficacy and increase toxicity (Shen et al., 2013). Astronauts that possess these polymorphisms may need their dosage adjusted or treatment with an alternative therapeutic agent. The major histocompatibility complex encodes human leukocyte antigens (HLA) which play a key role in the regulation of the adaptive immune response through presentation of processed peptide antigens (Wieczorek et al., 2017). Carriage of specific HLA alleles has been associated with susceptibility to severe adverse effects to certain medicines. Trimethoprim-sulfamethoxazole (TMP-SMX) is an antibiotic available in the ISS formulary. Carriage of HLA-B*14:01 has been associated with TMP-SMX drug induced liver injury in European Americans and HLA-B*35:01 may be a risk factor for African Americans (Li et al., 2021). Similarly, HLA-B*15:02, HLA-C*06:02 and HLA-C*08:01 have been associated with TMP-SMX-induced severe cutaneous reactions (Kongpan et al., 2015). These types of reactions can be life threatening and would be catastrophic if they occurred during space flight. Prospective astronauts could be HLA genotyped prior to the mission and a personalized formulary created to avoid HLA-associated risk medicines.

The flight surgeon is responsible for ensuring the health, safety and performance of astronauts from selection, training and space flight through to postflight rehabilitation and long-term health (Houtchens 1993). Pre-flight pharmacogenetic screening from astronauts could be incorporated into electronic health records as part of CDSS designed to support the flight surgeons in selecting the most appropriate medicines and dosages for each astronaut to maximize efficacy and reduce toxicity (Figure 5). One of the challenges for pharmacogenetics is translating pharmacogenetic information into actionable prescribing decisions. Not all of the FDA pharmacogenetics associations are accompanied by prescribing recommendations. Organizations such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) produce clinical guidelines and prescribing recommendations for pharmacogenetic associations. Space agencies will need to decide on the strength of such evidence and whether or not to incorporate it into their CDSS. The interface for CDSS will be critical and lessons should be learned from terrestrial implementation of similar systems such as the eMERGE network (Herr et al., 2019). Flight surgeons and astronauts will be critical to this process. The CDSS will need to be regularly reviewed and updated to incorporate the latest pharmacogenetic research.

It is surprising that so few PK studies have been conducted during space flight given the fundamental relationship between PK and the therapeutic and toxic effects of medicines in such a high stakes environment. We suggest that PK studies with blood sampling and pharmacogenetic screening are prioritized for future LEO missions (e.g., ISS). Space agencies should focus on medicines that are most frequently used (e.g., sleeping agents) and which have the most potential for harm if they were to be ineffective (e.g., antibiotics). Interestingly and of importance for PK monitoring are the use of new micro and nanotechnologies such as microneedle biosensors that allow real time minimally invasive monitoring of drug levels with the potential for personalized dosage adjustments (Rawson et al., 2019). The data derived from these missions could be incorporated into physiologically based PK models allowing extrapolation of microgravity PK effects to other medicines (Srinivasan et al., 1994). Additionally, this form of minimal invasive procedure would pave the way to use this technique to deliver drugs transdermally, with motion sickness treatment being one of the most obvious candidates to start with. Here the incorporation of skin equivalents in preclinical PK (and PD) trials would be beneficial. Other formats for the delivery of drugs could include the use of nanoparticles which can more effectively deliver the drug or substance to the tissue or organ needed or remodel microenvironments in tissues or organs in a non-invasive way (Mitchell et al., 2021). This technique is already revolutionizing the way drugs are developed and should certainly be considered for space flight missions.

Integration of pharmacogenetics and CDSS allied with better understanding of PK for medicines administered in microgravity will be critical to ensure that the right medicines are administered at the optimum dose to the astronaut to treat and maintain health.