Accepted Manuscript

Drugs in space: Pharmacokinetics and pharmacodynamics in

astronauts

Johannes Kast, Yichao Yu, Christoph N. Seubert, Virginia E.

Wotring, Hartmut Derendorf

PII: S0928-0987(17)30253-1
DOI: doi: 10.1016/j.ejps.2017.05.025
Reference: PHASCI 4039
To appear in: European Journal of Pharmaceutical Sciences
Received date: 10 May 2017
Revised date: ###REVISEDDATE###
Accepted date: 11 May 2017

Please cite this article as: Johannes Kast, Yichao Yu, Christoph N. Seubert, Virginia E.
Wotring, Hartmut Derendorf , Drugs in space: Pharmacokinetics and pharmacodynamics
in astronauts, European Journal of Pharmaceutical Sciences (2017), doi: 10.1016/
j.ejps.2017.05.025

This is a PDF file of an unedited manuscript that has been accepted for publication. As
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 ACCEPTED MANUSCRIPT

Submission Type: Mini Review

Title:
Drugs in Space: Pharmacokinetics and Pharmacodynamics in Astronauts

Author names and affiliations:

Johannes Kasta, Yichao Yua, Christoph N. Seubertb, Virginia E. Wotringc,d,
Hartmut Derendorfa,*

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a
Department of Pharmaceutics, University of Florida, Gainesville, FL, 1345 Center

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Drive, PO Box 100494, Gainesville, FL 32610, USA
*Corresponding: Department of Pharmaceutics, University of Florida, 1345 Center Drive,

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PO Box 100494, Gainesville, FL 32610, USA, 001-(352) 273-7856, [email protected]
b
Department of Anesthesiology, University of Florida, Gainesville, FL, 1600 SW Archer
Road, PO Box 100254, Gainesville, FL 32610, USA [email protected]

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c
Center for Space Medicine and dDepartment of Pharmacology, Baylor College of
Medicine, 1 Baylor Plaza, Houston, TX 77030, USA, [email protected]
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Table of Contents
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1. Introduction
2. Impact of Spaceflight on the Human Body
2.1 Cardiocirculatory - Fluid Shifts
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2.2 Musculoskeletal - Muscle and Bone Loss

2.3 Effects on the Immune System
2.4 Gastrointestinal Changes
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2.5 Metabolic Changes

3. Medication Use During Spaceflight
4. Pharmacokinetics in Space
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4.1 Inflight Studies

4.2 Ground-based Studies in Simulated Microgravity
5. Pharmacodynamics in Space
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5.1 Pharmacodynamic Measures During Spaceflight

6. Pharmacokinetic/Pharmacodynamic Studies in Simulated Microgravity
7. Drug Stability in Space
8. Potential Impacts of Spaceflight on Drug Efficacy and Safety: Bacterial Infections
9. Summary
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1. Introduction
President Barack Obama recently reiterated the goal of sending humans to Mars and
returning them back to Earth safely by the 2030s (Obama, 2016; Siceloff, 2010). To
achieve this goal successfully, it is critical to understand the impact of the spaceflight
environment on the human body and develop countermeasures. Future space missions
will last longer than ever before and immediate evacuation is not feasible in most of the
cases. Thus crew members will need to work more autonomously and rely on
medications and medical procedures onboard the spacecraft to treat medical issues on

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future deep space exploration missions (Komorowski et al., 2016). Therefore, it is
crucial that medical procedures can be performed as necessary and administered

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medications are safe and efficacious onboard the spacecraft. Spaceflight is known to
impact almost every organ system in the human body (Huang et al., 2009). These

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physiological changes could in return lead to changes in pharmacokinetic (what the body
does to the drug) and/or pharmacodynamic (what the drug does to the body) properties of
medications taken during spaceflight. If those changes occur during spaceflight and are

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not accounted for, drug efficacy and safety could be impacted substantially, thereby
threatening the health of the crew. AN
2. Impact of Spaceflight on the Human Body

Physiological changes are observed as a consequence of exposure to the microgravity

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environment. Duration of these effects can vary widely, ranging from fast resolution
within the first days of the mission or shortly after returning to Earth, up to several years,
with some permanent effects that never resolve completely (Williams et al., 2009).
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2.1 Cardiocirculatory - Fluid Shifts

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One of the physiological impacts that appears even before launch, are fluid shifts, driven
when astronauts sit for hours in a supine or leg elevated position. The phenomenon
continues once the astronauts are exposed to the microgravity environment. The arterial,
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venous and microcirculatory blood pressure gradients are no longer present which causes
a fluid shift from the lower to the upper parts of the body (Hargens and Richardson,
2009) and a decrease in blood volume, initially exacerbated by the effects of space
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motion sickness. These fluid shifts may impact the pharmacokinetics of drugs, thus have
the potential to alter overall drug safety and efficacy.

2.2 Musculoskeletal - Muscle and Bone Loss

Life without gravity results in a remodeling of the musculoskeletal system. Both, muscle
mass and muscle strength are diminished during spaceflight as a result of a reduction in
workload on the muscle in a microgravity environment, which exerts less force on the
body than Earth’s gravity. Although astronauts exercise for 2 hours a day 6 days a week,
muscle loss still persists after they return back to Earth (Buckey, 2006). The experienced
muscle losses could impact the distribution of drugs. Historically, bone loss was observed
during spaceflight despite the daily exercise program that astronauts perform (Lang et al.,
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2004; Sibonga et al., 2007; Smith et al., 2005). However, recent advances in exercise and
nutrition have shown that astronauts can return from 6 month spaceflight missions
without significant losses of bone mass (Smith et al., 2012).

2.3 Effects on the Immune System

Negative effects on biochemical measures of the immune system have been observed in
astronauts during and after spaceflight. The human immune system can be dysregulated
by the microgravity environment, physiological stress, isolation, radiation, disrupted
circadian rhythms and other flight-associated factors (Williams et al., 2009). Recent in-

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flight studies indicated a change in leukocyte distribution, a reduction in T cell function,

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and altered cytokine production profiles during flight (Crucian et al., 2013; Crucian et al.,
2008). Of note, most of these immunity alterations were observed in low earth orbital

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flights of short duration. For longer space missions, the prolonged immune system
alterations may potentially cause adverse events and even malignant diseases.

2.4. Gastrointestinal Changes

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Alternations in gastric emptying and intestinal transit rate may result in inefficient
absorption of orally administered drugs. In microgravity, particle size discrimination of
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stomach and little dependence on density could influence gastric emptying (Amidon et
al., 1991). It can also be altered by space motion sickness through the inhibition of gastric
motility (Graebe et al., 2004; Stewart et al., 1994). The exposure to microgravity is
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highly possible to increase the intestinal transit rate due to the decrease of the
dimensionless ratio of gravitational forces to viscous forces (Graebe et al., 2004). These
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variations in gastric emptying and intestinal transit may ultimately lead to variability in
drug and/or its metabolites.

2.5 Metabolic Changes

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Several enzyme systems and transporters play an important role in drug metabolism. It
has been shown that the activity of a variety of enzymes is altered in animals exposed to
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spaceflight and simulated microgravity, suggesting that xenobiotic metabolism in humans

may also be altered by spaceflight (Graebe et al., 2004). Several studies showed that the
activities of some intestinal digestive enzymes and hydroxymethylglutaryl-coenzyme A
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reductase increased during spaceflights (Groza et al., 1987; Groza et al., 1983; Moskaleva
et al., 2015), while comparable studies demonstrated a decrease of microsomal
cytochrome P450 in rats subjected to spaceflights (Merrill et al., 1990). Recently, it was
also demonstrated that spaceflight may increase hepatic triglyceride storage, altering lipid
metabolic hemostasis (Jonscher et al., 2016). In addition, genetic expression of ATP-
binding cassette transporters (Vaquer et al., 2014) and activity of certain transmembrane
proteins and ion channels (Goldermann and Hanke, 2001) have been found to change in
real and simulated microgravity conditions. These changes could lead to clinically
significant metabolic disorders and potentially dangerous undesired pharmacological
effects during spaceflight.
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3. Medication Use During Spaceflight

The medical complaints caused by physiological changes or other factors may require
pharmacotherapy during spaceflight missions. On 94% of all flights, astronauts reported
taking at least one medication (Putcha et al., 1999). Among the most common complaints
during space missions are sleep problems, space motion sickness, pain (headache, joint
pain, back pain and muscle pain), allergies and sinus congestion (Putcha et al., 1999;
Wotring, 2015).
Difficulty falling asleep caused by disruptions in circadian rhythm and work stress

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lead to frequent intake of sleep promoting drugs during space missions. More than 70%
of crew members reported the use of a sleep aids on both space shuttle missions and

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International Space Station missions with multiple doses observed on 17% of the nights
when sleep aids were taken (Barger et al., 2014; Wotring, 2015). The relatively large

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number of multiple dose administrations of sleep promoting drugs in the same night
might indicate a lack of efficacy after administration of the first dose.
Other frequently taken drug classes during International Space Missions include

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congestion and allergy treatments, pain relievers, rash treatments, motion sickness
prophylaxis and treatment, and alertness aids, with 21%-55% of crewmembers reporting
their use (Wotring, 2015). Many of these medications are also likely to be used on longer
exploration missions, but there is a lack of experimental evidence regarding alterations in
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their pharmacokinetics or pharmacodynamics in the unusual environment of a spaceflight
mission.
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4. Pharmacokinetics in Space
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Due to the physiological changes that occur during spaceflight, such as fluid shifts, fluid
loss, muscle loss and cardiovascular adaptation, the absorption, distribution, metabolism
and excretion of drugs might be different in space. The possible impact of those changes
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on the pharmacokinetic and pharmacodynamic properties of drugs is summarized in

Figure 1. Despite more than fifty years of manned spaceflight, little data are available on
pharmacokinetics in space. Table 1 summarizes the results of pharmacokinetic studies
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conducted during spaceflight as well as in ground-based models.

4.1 Inflight Studies

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In 1983, 22 years after the first human spaceflight, Pool and Nicogossian showed that
some orally administered medications taken during flight were not as effective as
expected (Pool and Nicogossian, 1983). Until today, only three clinical studies have
measured the pharmacokinetics of drugs during spaceflight, all using salivary samples.
The National Aeronautics and Space Administration (NASA) conducted two inflight
studies in the 1980s. One study investigated the pharmacokinetics of acetaminophen
after two 325 mg tablets were administered orally to five crewmembers on three different
missions (Cintron et al., 1987b) and another one the pharmacokinetics of a 0.4-mg dose
of oral scopolamine combined with 5 mg dextroamphetamine in 12 crew members
(Cintron et al., 1987a).
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Data obtained from the acetaminophen study showed a significant difference

between preflight and in-flight salivary levels of acetaminophen, especially in the
absorption phase. When compared with the pre-flight control, a pronounced increase of
peak concentrations was observed in two out of five crewmembers after 2 days of flight.
However, data from two crewmembers on day 4 of the mission indicated a significant
decrease in the absorption rate. These differences may be due to changes in
gastrointestinal transit time or an early equilibrium on day 4 of physiological adaptation
to weightlessness (Cintron et al., 1987b). In the scopolamine/dextroamphetamine study,
concentration-time curves were shown to be erratic and space profiles exhibited higher
inter-individual variability as compared to those of preflight data obtained from the

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ground-based controls (Cintron et al., 1987a).

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In the most recent inflight study, the investigators examined the pharmacokinetic
properties of acetaminophen in two dosage forms under long-term space flight conditions

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(Kovachevich et al., 2009). Five crewmembers took a tablet and five took a capsule of
500 mg acetaminophen. Compared with ground control, the relative bioavailability from
tablets increased substantially, whereas the rate of drug absorption decreased
significantly under microgravity conditions. For capsules, absorption time decreased

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whereas the half-elimination time, mean residence time, and the volume of distribution
increased. No significant change of bioavailability was observed during spaceflight
compared to ground conditions for capsules. Besides these studies, no other inflight
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pharmacokinetic data has been reported. This lack of ability to gather data firsthand has
led to the development of models simulating the physiological changes observed during
weightlessness.
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4.2 Ground-based Studies in Simulated Microgravity

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Water immersion and head-down bed rest (HDBR) are the most frequently used
experimental models to simulate responses to microgravity (Gandia et al., 2005). Water
immersion may potentially cause skin maceration for long term studies, thus most
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simulated weightlessness experiments have been performed in HDBR.

To study the influence of simulated weightlessness on drug absorption, Gandia et
al. conducted a 3-month -6º HDBR study with acetaminophen used as a gastric emptying
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probe. Increased maximum concentrations (Cmax) and decreased time to maximum

concentration (tmax) were observed in both plasma and saliva, indicating rapid drug
absorption due to faster gastric emptying or increased intestinal blood flow in the
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simulated microgravity condition (Gandia et al., 2003). However, these results were
contradictory with the results of two previous studies where no variation in absorption
rate was found in a supine position (Renwick et al., 1992; Rumble et al., 1991). In
another study, Gandia et. al investigated the pharmacokinetic behavior of promethazine
in simulated weightlessness and observed a significant increase in the bioavailability by
30%, which may have resulted from prolonged contact time with the intestinal wall in the
bed-rest position (Gandia et al., 2006). Recently, faster onset of action of ibuprofen
resulting from increased dissolution and absorption rate was noted by Idkaidek and
Arafat under simulated microgravity conditions (Idkaidek and Arafat, 2011).
Ground-based models provide the best available means to simulate most
physiological effects of spaceflight. However, sometimes the results obtained with the
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same drug probe differ from those observed inflight, as is the case for acetaminophen.
The discrepancies between real microgravity and models simulating weightlessness
might be explained by differences in the physical features that cause different local and
systemic hemodynamic states (Regnard et al., 2001) as well as gastrointestinal
adaptations like changes in transit time due to space motion sickness. Thus, it is critical
to obtain more accurate knowledge of the physiological features in microgravity and
devise a higher-fidelity ground-based model to predict the pharmacokinetic variation
during spaceflight.

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5. Pharmacodynamics in Space

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Very limited data are available to assess the effect of the spaceflight environment on
pharmacodynamics. Evaluating pharmacodynamic changes caused by microgravity is

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difficult since the drug effect over time for a given dose is dependent on both, the
pharmacokinetic and pharmacodynamic characteristics. Loss of plasma volume may alter
drug-receptor interaction in hypovolemic situations, thus potentially affecting clinical

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response of medications (Klockowski and Levy, 1988). Microgravity can also alter the
function of some specific ion channels by decreasing the channel’s probability to be
open, but the effects of these changes in microgravity are still to be studied (Goldermann
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and Hanke, 2001). The cardiovascular system is largely affected by the exposure to
microgravity, leading to modifications in the pharmacological effect of antihypertensives
and diuretics (Graebe et al., 2004). Overall, this area is vastly unexplored and more
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studies are needed to understand the mechanisms involved.

5.1 Pharmacodynamic Measures During Spaceflight

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As previously discussed, sleep promoting drugs are commonly taken by astronauts during
their missions. To determine the pharmacodynamic effects of those drugs during space
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missions, a suitable biomarker or surrogate should be determined. Electroencephalogram

(EEG) provides an objective and non-invasive approach to measure the changes in brain
neuronal activity produced by internal or external stimuli. It is known that EEG is well-
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suited for utilization as a surrogate measure to establish

pharmacokinetic/pharmacodynamic relationships of benzodiazepines (Mandema et al.,
1991), anesthetics (Doenicke et al., 1997) and opioids (Groenendaal et al., 2008). The
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most common EEG parameters used to characterize the central nervous system effects of
pharmacological agents include total duration, rate of occurrence, and peak amplitude
(Bewernitz and Derendorf, 2012). An ongoing study will investigate pharmacokinetic and
pharmacodynamic responses of medications during spaceflight, using EEG to measure
the pharmacodynamic effect of a sleeping aid targeting the GABAA-benzodiazepine
receptor complex. This study will provide insights into the differences in drug effects
observed in spaceflight and ground application.
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6. Pharmacokinetic/Pharmacodynamic Studies in Simulated

Microgravity
Previous studies from our lab evaluated the effect of simulated microgravity on the
pharmacokinetics and pharmacodynamics of ciprofloxacin and propofol. Schuck et al.
compared the pharmacokinetics of ciprofloxacin after a single 250-mg oral dose in
normal gravity and 3-day HDBR. Though plasma concentrations of ciprofloxacin were
almost identical in both conditions, slightly lower tissue penetration was noticed in
simulated microgravity. Figure 2 shows the total plasma and free interstitial

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concentrations in normal and simulated microgravity (Schuck et al., 2005). Compared
with the antimicrobial effect of ciprofloxacin under normal gravity, Escherichia coli grew

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faster and showed increased concentrations in the stationary phase in simulated
microgravity, while no differences were observed for Streptococcus pneumoniae between

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the two conditions. The results suggest that a generalization about the pharmacodynamic
response of antibiotics in microgravity is not possible (Schuck, 2004).
Similarly, a study with propofol was conducted in healthy volunteers to evaluate

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the pharmacokinetic/pharmacodynamic profile of the anesthetic in simulated
microgravity (2-day HDBR) and normal gravity. Plasma samples were collected during
and after anesthesia, and the therapeutic response of propofol was monitored by the
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sedation score and the bispectral index, an EEG-derived measure for the state of
anesthesia. The study showed only a minor impact of simulated microgravity on the
pharmacokinetic/pharmacodynamic profile of propofol and clinically equivalent
anesthesia was achieved in both conditions (Figure 3). This preliminary study indicated
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that the adaptation to microgravity does not raise any novel safety concerns and propofol
can still be considered as an ideal general anesthetic during space missions (Seubert,
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2007). Unfortunately, to our knowledge, no inflight pharmacokinetic/pharmacodynamic

study has been performed up to date, so that a translation of these results to an inflight
situation is difficult.
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7. Drug Stability in Space

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Aside from the potential impacts on drug efficacy and safety resulting from differences in
pharmacokinetic and/or pharmacodynamic properties of medications, altered drug
stability in the microgravity environment represents another risk factor that could
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influence medication efficacy during space missions.

After storage for 28 months on the International Space Station, four out of 14
solid dosage form medications failed to meet the United States Pharmacopeia (USP)
dissolution requirements when stored in space as compared to two ground controls that
failed to meet the requirements. Furthermore, six medications underwent changes in their
physical characteristics (weight, physical appearance, color, odor, and texture) as
compared to two observed changes in the ground controls (Du et al., 2011). Another
study by Wotring that investigated degradation products and chemical potency found that
eight of nine medications met USP requirements for the API and could not find any
uncommon degradation products (Wotring, 2016).
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8. Potential Impacts of Spaceflight on Drug Efficacy and Safety:

Bacterial Infections
During the space shuttle program between 1989 and 1998 alone, 26 infections were
reported in American astronauts (Taylor, 2015). 29 % of reported notable
immunological-related medical events in International Space Station crew members were
related to infectious disease (Crucian et al., 2016). The risk of complications caused by
bacteria seems to be of special concern during space missions since a combination of
factors might increase susceptibly to, and severity of infections. Figure 4 illustrates how

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severity of infections could be impacted by multiple factors.
First, as described previously, the reduced immune function among crew in space

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could increase the opportunity for bacteria to cause infection and could decrease the
capacity of the immune system to eradicate infections. Second, some antibiotics may be

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more prone to drug degradation in space than others. In a pilot study (n=1), the antibiotic
combinations of sulfamethoxazole/trimethoprim and amoxicillin/clavulanate showed
faster degradation profiles in space as compared to ground controls (Du et al., 2011),

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however, this result is inconclusive due to small sample size. Third, the isolated,
confined spaceflight environment is likely to affect bacterial physiology and potentially
susceptibility to antimicrobials, which might lead to increased antibiotic resistance. It is
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known that bacteria replicate faster in the microgravity environment and that higher
radiation levels experienced in space could lead to increased mutation rates (Taylor,
2015). Finally, if potential pharmacokinetic and/or pharmacodynamic changes would
further negatively impact the efficacy of medications, astronauts could be in severe
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danger if suffering from an infection.

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9. Summary

It seems likely that the numerous physiological changes occur during spaceflight will
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affect the pharmacokinetic and pharmacodynamic properties of medications. In addition,

reduced drug stability in space, alterations in immune response, and differences in
physiology of human pathogens (bacteria, viruses, fungi) might further complicate
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pharmacotherapy in space. At this point, it is difficult to assess the interplay of these

factors and to evaluate their clinical impact. Clearly, more research needs to be done to
better understand medication efficacy and safety during spaceflight and how to optimize
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drug therapy for astronauts.

Acknowledgments
This work was partly supported by the National Space Biomedical Research Institute
NCC 9-58. The research underlying figure 3 was supported by NASA Grant
NNJ04HF74G to Christoph N Seubert.
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References

Amidon, G.L., DeBrincat, G.A., Najib, N., 1991. Effects of gravity on gastric emptying,
intestinal transit, and drug absorption. J Clin Pharmacol 31, 968-973.
Barger, L.K., Flynn-Evans, E.E., Kubey, A., Walsh, L., Ronda, J.M., Wang, W., Wright, K.P.,
Jr., Czeisler, C.A., 2014. Prevalence of sleep deficiency and use of hypnotic drugs in astronauts
before, during, and after spaceflight: an observational study. The Lancet. Neurology 13, 904-912.
Bewernitz, M., Derendorf, H., 2012. Electroencephalogram-based pharmacodynamic measures:

T
a review. Int J Clin Pharmacol Ther 50, 162-184.
Buckey, J.C., 2006. Muscle loss: approach to maintaining strength, in: Space physiology. Oxford

IP
University Press, New York, pp. 77-100.
Cintron, N.M., Putcha, L., Chen, Y.M., Vanderploeg, J.M., 1987a. Inflight salivary

CR
pharmacokinetics of scopolamine and dextroamphetamine. Results of the Life Science DSOs
Conducted Aboard the Space Shuttle 1981-1986. NASA, 25-29.
Cintron, N.M., Putcha, L., J.M., V., 1987b. Inflight pharmacokinetics of acetaminophen in

US
saliva. Results of the Life Science DSOs Conducted Aboard the Space Shuttle 1981-1986.
NASA, 19-23.
Crucian, B., Babiak-Vazquez, A., Johnston, S., Pierson, D.L., Ott, C.M., Sams, C., 2016.
AN
Incidence of clinical symptoms during long-duration orbital spaceflight. International journal of
general medicine 9, 383-391.
Crucian, B., Stowe, R., Mehta, S., Uchakin, P., Quiriarte, H., Pierson, D., Sams, C., 2013.
M

Immune system dysregulation occurs during short duration spaceflight on board the space
shuttle. J Clin Immunol 33, 456-465.
Crucian, B.E., Stowe, R.P., Pierson, D.L., Sams, C.F., 2008. Immune system dysregulation
ED

following short- vs long-duration spaceflight. Aviation, space, and environmental medicine 79,
835-843.
Doenicke, A.W., Roizen, M.F., Rau, J., O'Connor, M., Kugler, J., Klotz, U., Babl, J., 1997.
PT

Pharmacokinetics and pharmacodynamics of propofol in a new solvent. Anesth Analg 85, 1399-
1403.
Du, B., Daniels, V.R., Vaksman, Z., Boyd, J.L., Crady, C., Putcha, L., 2011. Evaluation of
CE

physical and chemical changes in pharmaceuticals flown on space missions. AAPS J 13, 299-
308.
Gandia, P., Bareille, M.P., Saivin, S., Le-Traon, A.P., Lavit, M., Guell, A., Houin, G., 2003.
AC

Influence of simulated weightlessness on the oral pharmacokinetics of acetaminophen as a

gastric emptying probe in man: a plasma and a saliva study. Journal of clinical pharmacology 43,
1235-1243.
Gandia, P., Saivin, S., Houin, G., 2005. The influence of weightlessness on pharmacokinetics.
Fundamental & clinical pharmacology 19, 625-636.
Gandia, P., Saivin, S., Le-Traon, A.P., Guell, A., Houin, G., 2006. Influence of simulated
weightlessness on the intramuscular and oral pharmacokinetics of promethazine in 12 human
volunteers. Journal of clinical pharmacology 46, 1008-1016.
Goldermann, M., Hanke, W., 2001. Ion channel are sensitive to gravity changes. Microgravity
Sci Technol 13, 35-38.
 ACCEPTED MANUSCRIPT

Graebe, A., Schuck, E.L., Lensing, P., Putcha, L., Derendorf, H., 2004. Physiological,
pharmacokinetic, and pharmacodynamic changes in space. Journal of clinical pharmacology 44,
837-853.
Groenendaal, D., Freijer, J., Rosier, A., de Mik, D., Nicholls, G., Hersey, A., Ayrton, A.D.,
Danhof, M., de Lange, E.C., 2008. Pharmacokinetic/pharmacodynamic modelling of the EEG
effects of opioids: the role of complex biophase distribution kinetics. Eur J Pharm Sci 34, 149-
163.
Groza, P., Bordeianu, A., Boca, A., 1987. The digestive tract of rat after flight in the biosatellite
Cosmos 1667. Physiologie 24, 187-190.
Groza, P., Ursea, N., Vasilescu, F., Munteanu, A., Lungu, D., Bolocan, N., 1983. Changes in

T
some digestive enzymes after a seven-day orbital flight. Physiologie 20, 27-33.

IP
Hargens, A.R., Richardson, S., 2009. Cardiovascular adaptations, fluid shifts, and
countermeasures related to space flight. Respiratory physiology & neurobiology 169 Suppl 1,

CR
S30-33.
Huang, Y., Dai, Z.Q., Ling, S.K., Zhang, H.Y., Wan, Y.M., Li, Y.H., 2009. Gravity, a regulation
factor in the differentiation of rat bone marrow mesenchymal stem cells. Journal of biomedical
science 16, 87.

US
Idkaidek, N., Arafat, T., 2011. Effect of microgravity on the pharmacokinetics of Ibuprofen in
humans. J Clin Pharmacol 51, 1685-1689.
Jonscher, K.R., Alfonso-Garcia, A., Suhalim, J.L., Orlicky, D.J., Potma, E.O., Ferguson, V.L.,
AN
Bouxsein, M.L., Bateman, T.A., Stodieck, L.S., Levi, M., Friedman, J.E., Gridley, D.S., Pecaut,
M.J., 2016. Spaceflight Activates Lipotoxic Pathways in Mouse Liver. PLoS One 11, e0152877.
Klockowski, P.M., Levy, G., 1988. Kinetics of drug action in disease states. XXV. Effect of
M

experimental hypovolemia on the pharmacodynamics and pharmacokinetics of

desmethyldiazepam. J Pharmacol Exp Ther 245, 508-512.
ED

Komorowski, M., Fleming, S., Kirkpatrick, A.W., 2016. Fundamentals of Anesthesiology for
Spaceflight. Journal of cardiothoracic and vascular anesthesia 30, 781-790.
Kovachevich, I.V., Kondratenko, S.N., Starodubtsev, A.K., Repenkova, L.G., 2009.
Pharmacokinetics of acetaminophen administered in tablets and capsules under long-term space
PT

flight conditions. Pharm Chem J 43, 130-133.

Lang, T., LeBlanc, A., Evans, H., Lu, Y., Genant, H., Yu, A., 2004. Cortical and trabecular bone
mineral loss from the spine and hip in long-duration spaceflight. Journal of bone and mineral
CE

research : the official journal of the American Society for Bone and Mineral Research 19, 1006-
1012.
Mandema, J.W., Sansom, L.N., Dios-Vieitez, M.C., Hollander-Jansen, M., Danhof, M., 1991.
AC

Pharmacokinetic-pharmacodynamic modeling of the electroencephalographic effects of

benzodiazepines. Correlation with receptor binding and anticonvulsant activity. J Pharmacol Exp
Ther 257, 472-478.
Merrill, A.H., Jr., Hoel, M., Wang, E., Mullins, R.E., Hargrove, J.L., Jones, D.P., Popova, I.A.,
1990. Altered carbohydrate, lipid, and xenobiotic metabolism by liver from rats flown on
Cosmos 1887. FASEB J 4, 95-100.
Moskaleva, N., Moysa, A., Novikova, S., Tikhonova, O., Zgoda, V., Archakov, A., 2015.
Spaceflight Effects on Cytochrome P450 Content in Mouse Liver. PLoS One 10, e0142374.
Obama, B., 2016. America will take the giant leap to Mars.
http://www.cnn.com/2016/10/11/opinions/america-will-take-giant-leap-to-mars-barack-
obama/index.html (accessed 10.13.16).
 ACCEPTED MANUSCRIPT

Pool, S.L., Nicogossian, A., 1983. Biomedical results of the Space Shuttle orbital flight test
program. Aviat Space Environ Med 54, S41-49.
Putcha, L., Berens, K.L., Marshburn, T.H., Ortega, H.J., Billica, R.D., 1999. Pharmaceutical use
by U.S. astronauts on space shuttle missions. Aviation, space, and environmental medicine 70,
705-708.
Regnard, J., Heer, M., Drummer, C., Norsk, P., 2001. Validity of microgravity simulation
models on earth. Am J Kidney Dis 38, 668-674.
Renwick, A.G., Ahsan, C.H., Challenor, V.F., Daniels, R., Macklin, B.S., Waller, D.G., George,
C.F., 1992. The influence of posture on the pharmacokinetics of orally administered nifedipine.
Br J Clin Pharmacol 34, 332-336.

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Rumble, R.H., Roberts, M.S., Denton, M.J., 1991. Effects of posture and sleep on the

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pharmacokinetics of paracetamol (acetaminophen) and its metabolites. Clin Pharmacokinet 20,
167-173.

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Schuck, E.L., 2004. Pharmacokinetics and Pharmacodynamics of Ciprofloxacin in Simulated
Microgravity., PhD Thesis. Gainesville FL, USA. Department of Pharmaceutics, Univeristy of
Florida. .
Schuck, E.L., Grant, M., Derendorf, H., 2005. Effect of simulated microgravity on the

US
disposition and tissue penetration of ciprofloxacin in healthy volunteers. J Clin Pharmacol 45,
822-831.
Seubert, C.N., 2007. Effects of Simulated Microgravity on the Anesthetic Properties of Propofol
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(NNJ04HF74G).
https://lsda.jsc.nasa.gov/lsda_data/dataset_inv_data/NNJ04HF74G__2340957670.pdf_BRC_NN
J04HF74G_2011_234_100857.pdf (accessed 11.17.16).
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Sibonga, J.D., Cavanagh, P.R., Lang, T.F., LeBlanc, A.D., Schneider, V.S., Shackelford, L.C.,
Smith, S.M., Vico, L., 2007. Adaptation of the Skeletal System During Long-Duration
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Spaceflight. Clinical Reviews in Bone and Mineral Metabolism 5, 249-261.

Siceloff, S., 2010. President Outlines Exploration Goals, Promise.
http://www.nasa.gov/about/obamaspeechfeature.html (accessed 10.13.16).
Smith, S.M., Heer, M.A., Shackelford, L.C., Sibonga, J.D., Ploutz-Snyder, L., Zwart, S.R., 2012.
PT

Benefits for bone from resistance exercise and nutrition in long-duration spaceflight: Evidence
from biochemistry and densitometry. Journal of bone and mineral research : the official journal
of the American Society for Bone and Mineral Research 27, 1896-1906.
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Smith, S.M., Wastney, M.E., O'Brien, K.O., Morukov, B.V., Larina, I.M., Abrams, S.A., Davis-
Street, J.E., Oganov, V., Shackelford, L.C., 2005. Bone markers, calcium metabolism, and
calcium kinetics during extended-duration space flight on the mir space station. Journal of bone
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and mineral research : the official journal of the American Society for Bone and Mineral
Research 20, 208-218.
Stewart, J.J., Wood, M.J., Wood, C.D., Mims, M.E., 1994. Effects of motion sickness and
antimotion sickness drugs on gastric function. J Clin Pharmacol 34, 635-643.
Taylor, P.W., 2015. Impact of space flight on bacterial virulence and antibiotic susceptibility.
Infect Drug Resist 8, 249-262.
Vaquer, S., Cuyas, E., Rabadan, A., Gonzalez, A., Fenollosa, F., de la Torre, R., 2014. Active
transmembrane drug transport in microgravity: a validation study using an ABC transporter
model. F1000Res 3, 201.
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Williams, D., Kuipers, A., Mukai, C., Thirsk, R., 2009. Acclimation during space flight: effects
on human physiology. CMAJ : Canadian Medical Association journal = journal de l'Association
medicale canadienne 180, 1317-1323.
Wotring, V.E., 2015. Medication use by U.S. crewmembers on the International Space Station.
FASEB journal : official publication of the Federation of American Societies for Experimental
Biology 29, 4417-4423.
Wotring, V.E., 2016. Chemical Potency and Degradation Products of Medications Stored Over
550 Earth Days at the International Space Station. The AAPS journal 18, 210-216.

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Tables
Table 1: Pharmacokinetic studies performed in simulated weightlessness and spaceflight.
P.O.: by oral administration, I.V.: intravenous administration, BCS: Biopharmaceutical Classification System
Drug BCS Drug probe Study Observed Pharmacokinetics Type Duration
Class

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Acetaminophen
P.O.
III, IV Absorption rate Cintron et al., 1987b

Kovachevich et al., 2009

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Increase in the absorption rate after 2 days of flight;
decrease in the absorption rate after 4 days of flight

R
Decrease in absorption rate for tablets during long-
Spaceflight

Spaceflight
Short-term

Long-term

S C
term spaceflight; increase in absorption rate for
capsules during long-term spaceflight
Rumble et al., 1991
position

N U
No variation of absorption rate in the supine Bedrest 6 hours

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Renwick et al., 1992 No variation of absorption rate in the supine Bedrest 4 hours
position (right decubitus); decrease in absorption

Gandia et al., 2003 M rate in the supine position (left decubitus)

Increase in absorption rate with -6º bedrest Bedrest 3 month

Promethazine I, III Absorption rate

E D
Gandia et al., 2006 No variation of absorption rate with -6º bedrest Bedrest 2 days
P.O.
Ibuprofen P.O. II Absorption rate
P T
Idkaidek and Arafat, 2011 Increase in absorption rate with -6º bedrest Bedrest 1 day

Ciprofloxacin
P.O.
III

C E
Distribution Schuck et al., 2005 Slightly lower tissue penetration with -6º bedrest Bedrest 3 days

Propofol I.V.

Lidocaine I.V.
II

I A C
Liver metabolism

Liver metabolism
Seubert et al., 2007

Kates et al., 1980

Slightly reduced clearance with -6º bedrest

No variation of clearance in the supine position

Bedrest

Bedrest
2 days

7 days

Saivin et al., 1995 Increase in clearance with -6º bedrest Bedrest 4 days

Penicillin I.V. I, III Kidney elimination Kates et al., 1980 No variation of clearance in the supine position Bedrest 7 days
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Rumble et al., 1986 No variation of clearance in the supine position Bedrest 4 hours

P T
R I
S C
N U
A
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P T
C E
A C
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Figures

Figure 1: Potential physiological effects of the spaceflight environment on pharmacokinetics and

pharmacodynamics of drugs.

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Figure 2: Total plasma (•) and free interstitial (■) concentrations of ciprofloxacin in Earth’s
gravity (top) and simulated microgravity (bottom). Experimental points represent the means of 6
subjects. Vertical bars represent the standard deviation of the mean. Figure adapted from
(Schuck et al., 2005).

Earth’s Gravity

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Figure 3: Sedation Score and Bispectral Index (an electroencephalographic measure of cortical
anesthetic drug effect) during propofol anesthesia in simulated microgravity and in normal
gravity (control) (n=8).

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Figure 4: Factors that could increase susceptibility to, and severity of infections in space.
MIC: minimum inhibitory concentration, Cmax: maximum drug concentration after
administration, AUC: area under the curve, PK/PD: Pharmacokinetic/Pharmacodynamic

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Abstract

Space agencies are working intensely to push the current boundaries of human spaceflight by

sending astronauts deeper into space than ever before, including missions to Mars and asteroids.

Spaceflight alters human physiology due to fluid shifts, muscle and bone loss, immune system

dysregulation, and changes in the gastrointestinal tract and metabolic enzymes. These alterations

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may change the pharmacokinetics and/or pharmacodynamics of medications used by astronauts

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and subsequently might impact drug efficacy and safety. Most commonly, medications are

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administered during space missions to treat sleep disturbances, allergies, space motion sickness,

pain, and sinus congestion. These medications are administered under the assumption that they

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act in a similar way as on Earth, an assumption that has not been investigated systematically yet.
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Few inflight pharmacokinetic data have been published, and pharmacodynamic and

pharmacokinetic/pharmacodynamic studies during spaceflight are also lacking. Therefore, bed-

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rest models are often used to simulate physiological changes observed during microgravity. In
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addition to pharmacokinetic/pharmacodynamic changes, decreased drug and formulation

stability in space could also influence efficacy and safety of medications. These changes along
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with physiological and the resulting pharmacokinetic and pharmacodynamic changes must to be
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considered to determine their ultimate impact on medication efficacy and safety during

spaceflight.
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Graphical Abstract:

Figure 1: Potential physiological effects of the spaceflight environment on pharmacokinetics and

pharmacodynamics of drugs.

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