How do the pharmacokinetics of drugs change in astronauts in space?

KEYWORDS:

• Astronaut
• cytochrome P450
• International Space Station
• microgravity
• pharmacokinetics
• space travel
• spaceflight

1. Introduction

By the beginning of 2020, over 560 individuals have flown in space, with duration ranging from 15 min to 437 days. Among these were seven ‘space tourists’, some with known medical problems, who typically spent over a week onboard the International Space Station (ISS) [1,2]. As we enter a new era of commercialized spaceflights, more individuals will be able to travel to low Earth orbit or even to deep space.

Space travel imposes multiple challenges to the human body due to microgravity, radiation, confinement, isolation, changes in circadian rhythm, and stress. The effect depends on the duration of the mission and its destination and varies with the phase of the spaceflight. During the first days of flight, participants may develop space motion sickness. Fluids shift to the central compartment of the body and the head with subsequent changes in the concentration of albumin and other plasma components and in renal metabolism. Within a few days, fluid redistribution is compensated by diuresis and loss of plasma and extracellular fluid volume. Longer stays in space have many physiological consequences, including loss of bone mineralization and muscle strength, reduced cardiovascular capacity, alterations in immune function and in the microbiome, and neuro-ocular symptoms [1,2]. Those changes can prompt medication consumption while potentially altering drug handling by the body, as was recently reviewed in more detail [2]. The present editorial adds recent examples of the complexities of drug treatment in space, comparatively summarizes the available pharmacokinetic parameters in astronauts, and highlights fields of knowledge and lack thereof.

2. Medication usage in space

Medications have been used during space missions to prevent or treat conditions associated with spaceflight and for the management of preexisting illness or ordinary medical complaints. In a recent survey of drug use that was completed by six crewmembers during flight, there were 20.6 ± 8.4 entries per subject per flight week [3]. Indications for drug use in space have included space motion sickness, sleep deficiency, headache, backache, muscle or joint pain, bone resorption, congestion, and hypersensitivity reactions [2]. Most recently, enoxaparin and apixaban were used for treating jugular venous thrombosis in an astronaut onboard the ISS [4]. The efficacy and safety of these treatments are largely unknown, and it has been suggested that some medications may be less effective than expected [5]. However, in addition to pharmacokinetics and pharmacodynamics, the nature of disease itself (e.g. motion sickness and hypercoagulability) might differ in space.

3. Effects of spaceflight on pharmacokinetics: rigidly defined areas of doubt and uncertainty

Current knowledge on spaceflight-associated changes in pharmacokinetics is limited and is based on sporadic evidence. Five studies evaluated drug pharmacokinetics in crewmembers during orbital spaceflight, all relying on the measurement of drug concentrations in saliva (Table 1). Common to the four studied compounds (acetaminophen, scopolamine, promethazine, and antipyrine) is hepatic metabolism as a major route of elimination, though by different drug-metabolizing enzymes. Several limitations complicate the interpretation of the data from these studies. First, measuring drug concentrations in saliva could increase variability and introduce error, given that the saliva:blood ratios in space are unknown. Second, most studies were limited by small subject numbers and variation in mission day, sampling time, route of administration, formulation, food consumption, and lack of data on within-subject variability on the ground. Third, parameters related to the experimental setting were only partially described. In the studies conducted by Lakshmi Putcha’s group, acetaminophen was likely combined with scopolamine and dexamphetamine (and vice versa), possibly by some crew members but not others, and few pharmacokinetic parameters were reported [6–8]. The paper by Kovachevich et al. describes a more comprehensive pharmacokinetic analysis but does not indicate the mission day of the study, which additionally could have varied between participants [9]. Accordingly, the results of these studies are inconsistent and often conflicting, with considerable differences between and within individuals in concentration–time curves and in pharmacokinetic parameters. Unfortunately, only one study clearly presented the volume of distribution and half life data. Despite those limitations, a theme common to all individuals and studies was an apparent trend toward altered drug disposition during spaceflight compared to measurements on Earth.

Table 1. Spaceflight-induced pharmacokinetic changes in humans.

Drug	Dosage form	Day of flight	Number of participant	Cmax	Tmax	AUC	Volume of distribution	Half-life	Reference
Acetaminophen^a	Tablets (fasting)	2	2	↑	↓				[7]
		3	2	↑	↑
		4	2	↓	↑	↓?
Acetaminophen	Tablets (fasting) Capsules (fasting)		5	↓	↑	↑	↓	↑	[9]
			5	↓	↓*	↑^b	↑*	↑*
Scopolamine	Capsules (combined with dextroamphetamine)	0–1	2	↓	↑				[6]
		1–2	1	↑	↔
		2–-3	1	↑	↓
Promethazine	I.M. injection, oral tablet, or rectal suppository	1	9	↓	↑	↓		↑	[10]
Antipyrine	Oral (fed state)		2			↓↑^c			[11]

*Statistically significant difference.

^aThe study was later extended to 12 participants from 7 different flights (with similar results), but the numbers of participants on each study day were not reported [8].

^bAUC_0-∞.

^cInferred from reported reduction in oral clearance.

Given the difficulties of studies in astronauts, terrestrial human bedrest and rodent analog models have been used to simulate the effects of spaceflight on drug disposition. While these models can mimic microgravity-induced fluid shifts, they do not account for many of the other features of spaceflight [5]. Several studies compared the liver size and expression or activity of drug-metabolizing enzymes between rodents flown to space and ground controls. The majority of these studies demonstrated smaller microsomal protein or cytochrome P450 content and reduced activity of glutathione S-transferase (GST). Significantly lower GST activity can predispose cells to oxidative damage and affect the metabolism of leukotrienes, prostaglandins, and medications. This can lead to accumulation of drugs or their metabolites, including N-acetyl-p-benzoquinone imine (NAPQI), the hepatotoxic metabolite of acetaminophen [12].

Changes in the expression of individual CYP450 enzymes were not consistent. For instance, the effect of spaceflight on murine Cyp2d26 expression ranged from no change to a statistically significant, 1.5-fold increase [2]. Limitations of the experiments in animal models resemble those of studies which involved astronauts but additionally include differences in species and maintenance conditions as well as delays in post-flight recovery of the animals. Yet the alterations in the expression of drug-metabolizing enzymes imply that drug elimination, prodrug activation, or formation of toxic metabolites can all differ in space.

Compared to macro ADME parameters, even less is known about processes that affect the cellular kinetics of drugs. Microgravity-induced alterations in membrane fluidity can affect drug diffusion across membranes and the activity of uptake and efflux transporters. The only drug transporter whose functional activity in microgravity was reported is MRP2, which was shown to be less active during a parabolic flight [2]. However, spaceflight can induce changes in transporter expression. The protein levels of the solute carrier organic anion transporter family, member 1b2 (Slco1b2), were 1.7-fold higher in livers from mice which were flown on a biosatellite for 30 days than in re-adapted mice. In microorganisms, ABC transporter genes were upregulated [13,14] in space, and expression of P-glycoprotein (P-gp) increased 2.3-fold in slowly-growing human fibroblasts [15]. Such changes in P-gp function could impact the efficacy or toxicity of the above-mentioned apixaban.

Modified pharmacokinetics in microgravity may result from both physical and physiological factors. The former were suggested to play a significant role in drug absorption, e.g., by altering the distribution of aerosols within the airways and the more random positioning of oral dosage forms within the stomach (instead of floating or sinking) [2]. Physiological factors that can directly affect absorption include delayed gastric emptying due to space motion sickness (and medications taken to treat it) and altered gut microbiome [2,5]. Altered blood flow to tissues can translate to changes in each of the ADME parameters. Dehydration and fluctuations in serum albumin levels can affect drug volume of distribution and excretion. Moreover, shifts in global and local cerebral fluid distribution and blood flow may affect drug distribution within brain tissue thus potentially modulating drug efficacy or cerebral adverse effect (e.g. those related to the cerebellum) [2,4]. An additional space-related factor that should be taken into account is altered immune function that was previously shown to contribute to pharmacokinetic variability [2].

In the absence of clear evidence, many fundamental pharmacokinetic assumptions need to be questioned. For instance, we do not know whether only unbound drug distributes to tissues, if flow-limited elimination of drugs becomes intrinsic clearance-limited or vice versa, and whether transporter-based processes are equally important in space. These challenges, together with the paucity of essential pharmacodynamic data, make astronauts an ‘orphan’ population with respect to drug efficacy and safety.

4. Pharmacogenetics in astronauts and space travelers

Preemptive pharmacogenetic typing of astronauts, e.g. for selected CYP isoforms and drug transporters, has been suggested as means for supporting individualization of pharmacological treatment [16]. However, no findings from such studies are currently available. The contribution of genetics by itself to pharmacokinetic variability in space is unknown. Environmental factors might be pronounced especially during the first days after launch (as was reported for acetaminophen [8]) and initially after return to Earth, which may also encompass the entire duration of touristic flights. For longer stays in space, the ISS offers more uniform environment in terms of nutrition, temperature, and fitness. Notably, the ISS has hosted astronauts of many nations, including the United States, Russia, China, India, Japan, Brazil, Israel, and the United Arab Emirates. Current pharmacogenetic data which guide treatment in some ethnic populations do not apply to others, and can even lead to under- or overestimation of the dose. Astronauts additionally vary in gender and age. The youngest astronaut, Gherman Titov, was 25 years when he was launched as the second human in orbit, and John Glen was 77 years old when he flew aboard the Space Shuttle for his second mission [17]. Current astronauts are not that young or that old, but the age of space tourists and their medical background are likely to be variable. This does not rule out the importance of gaining pharmacogenetic data and connecting it to outcomes in future studies in space.

5. Expert opinion

Despite decades of drug use by astronauts during space missions, data on drug disposition under microgravity conditions are scarce and inconsistent. The few available reports suggest that spaceflight might affect drug absorption, distribution, and elimination, with high between- and within-subject variability. No major adverse drug effects on astronauts in space have been reported so far. Yet associations between drug use and changes in performance of crewmembers cannot be ruled out and might be detected in future analyses. Moreover, with expansion of spaceflight to deep space, larger exposure to galactic cosmic radiation may become an additional variable with yet unknown effects on human physiology that could increase drug use while altering their disposition. Despite those risks, randomized, controlled pharmacokinetic studies in astronauts in space do not seem to be prioritized. For instance, a search for the terms astronaut and microgravity in ClinicalTrials.gov (March 2020) yielded 35 and 34 entries, respectively, of which one related to drug efficacy. NASA’s Human Research Roadmap [18] does not include pharmacokinetics-related studies other than a completed but yet unpublished analysis of hepatic drug-metabolizing enzymes in mice. In the absence of new pharmacokinetic studies in astronauts, publication of the missing raw data and derived pharmacokinetic parameters of older studies (e.g. changes in oral clearance) is desirable. The accumulating ‘real-world’ data on drug use and effectiveness onboard the ISS can provide a basis for artificial intelligence-based tool for treatment personalization. In addition, outliers within the astronaut population can provide valuable data on factors that contribute to pharmacokinetic and pharmacodynamic variability.

Ideally, pharmacokinetics in astronauts would become more predictable with increased mechanistic understanding of the physiological changes that occur during spaceflight and upon return to Earth. An important tool for such studies are microphysiological (organ-on-a-chip) systems that have already been flown to space [19]. Although such systems do not capture complexities of the entire organism, they can provide important data for in vitro-to-in vivo extrapolations. Unmanned, remote-controlled minilabs are emerging as means for conducting such studies without the need of astronaut intervention. Such platforms can be launched to the ISS or be operated onboard satellites or unmanned shuttles [20]. Eventually, lessons gained from these studies might apply to Earth as well, as was previously demonstrated for other space-based knowledge and technologies.

Rare opportunities for serial blood sampling from astronauts, e.g. NASA’s Twin Study or the case of anticoagulant treatment onboard the ISS, should be utilized for measuring drug concentrations. Drugs are commonly used by astronauts, and pharmacokinetic studies are important for dosage adjustment. The recent incident of anticoagulant use onboard the ISS reminds us that medical emergencies can occur in space, and that the medical team’s base of knowledge for decision-making should be as broad as possible.

Declaration of Interest

S Eyal is on a sabbatical leave at SpacePharma, Israel, from 1 July 2019. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript except for those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.