Antonsen, Erik L.

Bayuse, Tina M.

Blue, Rebecca S.

Cory, Wendy C.

Daniels, Vernie R.

Wotring, Virgina

English

NASA Technical Reports Server

National Aeronautics and Space AdministrationNational Aeronautics and Sp ce Administration
Limitations in Understanding Use, 
Stability, and Effectiveness of 
Medications during Spaceflight
Tina M. Bayuse, PharmD, RPh
Rebecca S. Blue, MD, MPH
Vernie R. Daniels, RPh
Wendy Cory, PhD
Virginia Wotring, PhD
Erik L. Antonsen, MD, PhD
https://ntrs.nasa.gov/search.jsp?R=20200001663 2020-03-28T19:13:33+00:00Z
Overview
This presentation will discuss our current understanding of:
• Medication usage during spaceflight
• Medication effectiveness in the space environment
• Medication stability in the space environment
We will further discuss opportunities for improved scientific 
understanding and research for future exploration spaceflight
2
Medication Usage
Subjective Efficacy
3
Retrospective Medication Use Evaluation
• Johnson Space Center Pharmacy Team conducted a review 
of inflight medication use data of:
– Sleepers/Stimulants
– Rash/Allergy
– Headache/Congestion
– NSAIDS
• Original Plan: Expedition 1 to 40
• After Review, Re-scope to include Expeditions 21 to 40 as a 
result of the way the data was captured (21-40 through more 
standard reporting)
4
ISS Medication Usage
• Historically, we have 
had poor capture of 
medication usage 
data (which meds, 
effectiveness or 
response, side 
effects, etc)
• Data presented are 
AVERAGE reports 
per crewmember
• Short trial (5 
subject) Dose-
Tracker project: 
data shows a 20-60x 
increase in data 
points Supplemental Data: LSAH, Dose Tracker
Reported Subjective Efficacy
Bayuse- On Orbit MUE Summary
• PMC tool doesn’t 
‘ask’ to capture this 
information.
• Whether or not the 
crewmember 
thought the 
medication worked 
is self-reported
• Claim that we ‘don’t 
have a problem’ is 
artificial - we don’t 
have good data to 
support that claim
Supplemental Data: 
LSAH, Dose Tracker
Reported Subjective Efficacy
Dose Tracker Data –unpublished Wotring/Smith
• Perceived efficacy was reported for 32 medications by 1- 3 
subjects. 
• Most medications were considered partially effective. 
• Two subjects evaluated efficacy in both flight and Earth 
environments: 
– one found valacyclovir to provide “complete relief, but required 
continued dosing” in both situations, and 
– another found zaleplon to provide complete relief in a single dose, 
both flight and ground. 
• One subject reported the absence of side effects during both 
flight and ground use for 8 medications. 
7
Efficacy
• Potential reasons for lack of efficacy
– Pharmacokinetics (PK) / Pharmacodynamic (PD) 
changes
– Stability of medication
8
Pharmaceutical Stability
Shelf Life and Radiation
Pharmaceutical Stability
• Loss of drug stability caused by any alteration of physical
or chemical properties can result in: 
- changed:
• Appearance
• Dosage form physical attributes and uniformity
• Potency
• Excipient composition
- or promoted:
• Excipient-active ingredient interactions
• Toxic degradation
Pharmaceutical Stability
• To test for stability:
– Concentration of Active Pharmaceutical Ingredient (API)
o Acceptable ± limits defined by US Pharmacopoeia
– API Release Characteristics
o Dissolution (e.g. tablets, capsules) / Diffusion (e.g. ointments, creams)
– Presence of degradation products
o Some known / toxic products have USP-determined limits
– Visible alteration of physical appearance
Average Manufacturer Expiration Dates
Terrestrial Evidence: Shelf-Life
DRUG
DOSAGE 
FORM
LOTS TESTED MEAN EXT 
(mo.)
EXT. RANGE 
(mo.)
Amoxicillin Tablet* 21 23 21-23
Bupivicaine Inj. Solution 3 88 79-95
Ceftriaxone Inj. Powder 4 60 44-69
Ciprofloxacin Tablet 242 55 12-142
Cimetidine Tablet 5 67 59-75
Dexamethasone Inj. Solution 7 61 24-93
Diphenhydramine Inj. Solution 12 76 33-126
Doxycycline Capsule 13 50 37-66
Guaifenesin ER Tablet 7 85 39-122
Ketamine Inj. Solution 6 64 42-87
Meperidine Inj. Solution 6 89 32-128
Morphine Inj. Solution 13 89 35-119
Naloxone Inj. Solution 10 77 60-95
Phenytoin Inj. Solution 5 63 29-100
Promethazine Inj. Solution 9 51 28-73
Acetaminophen** Tablet - - 336-480
Caffiene** Tablet - - 336-480
Caffiene† Tablet - - 336-480
Hydrocodone* Tablet - - 336-480
Doxycycline Tablet 3 179 144-204
Amoxicillin Tablet 2 138 132-144
FD
A 
SL
EP
Ca
nt
re
ll 
20
12
M
at
to
20
13
• Table: Medications flown 
in ISS formulary that have 
been tested by various 
terrestrial studies on 
shelf-life extension
– FDA SLEP Program
– Cantrell 2012
– Matto 2013
• Some drugs found to be 
stable under SLEP 
terrestrial analysis have 
demonstrated instability or 
alterations in flown studies 
(Du et. al. 2011, Wotring
2016)
Stability Evidence: Flown Studies
References
Du et al. 2011
Zwart et al. 2009
Chuong et al. 2011
Wotring 2016
Unpublished:
Cory 2017
Wu 2016
Altered 
Medication
Unaltered 
Medication
* Drug tested only for Vit B API
** Drug would fail by today’s API standard
† drug had unidentified degradant product
• Risk of Radiation:
– High-intensity electromagnetic radiation:
o May cause significant loss of API – can reduce therapeutic effect
o May initiate formation of degradation products
– Is radiation contributing to the alterations observed in 
spaceflight? Or are other environmental factors?
Pharmaceutical Stability: Radiation
Photolability
Reference Doses (GCR, SPE)
Conclusions
and
Recommendations
Conclusions
1. We have insufficient data collection to understand medication usage, side 
effects, and effectiveness in spaceflight today 
2. Our current understanding of pharmaceutical stability suggests that most 
medications do not have sufficient labeled shelf life to last for planetary 
exploration missions
3. To provide safe and effective medications for exploration spaceflight, we need 
to balance resources available with a standard of acceptable scientific 
evidence sufficient to characterize the risk
Recommendations
1. Crew tracking of pharmaceutical usage, effectiveness, and side 
effects should be encouraged and streamlined
2. Support pilot research projects regarding initial characterization 
of the stability issues that may be encountered in flight should be 
encouraged to build a foundational database from which the need 
for future, more detailed investigations can be evaluated. 
3. NASA and industry / academic partners should actively pursue 
spaceflight exposures of medications to characterize with the best 
available evidence the environmental impact on pharmaceuticals 
in upcoming missions.  
QUESTIONS?
National Aeronautics and Space AdministrationNational Aeronautics and Sp ce Administration
BACKUP SLIDES
Back to Presentation
Spaceflight Evidence – Pharmaceutical Stability
• Du B, Daniels VR, Vaksman Z, Boyd JL, Crady C, Putcha L. Evaluation 
of physical and chemical changes in pharmaceuticals flown on space 
missions. AAPS J 2011; 13:299–308. 
• Chuong MC, Prasad D, Leduc B, Du B, Putcha L. Stability of vitamin B 
complex in multivitamin and multimineral supplement tablets after space 
flight. J Pharm Biomed Anal 2011; 55:1197–200. 
• Wotring VE. Chemical Potency and Degradation Products of Medications 
Stored Over 550 Earth Days at the International Space Station. AAPS J 
2016; 18:210–6. 
• Cory, W, James, V, Lamas, A, Mangiaracina, K, Moon, J. Analysis of 
degradation of pharmaceuticals stored on the International Space 
Station. 2017; presented at the HRP Investigator’s Workshop, Galveston, 
TX.
• Wu and Chow, Degradation Analysis of Medications from ISS Using LC-
MS/MS Assays – NSBRI RFA‐15‐01 First Award Fellowship, Final 
Report, Submitted by 11/29/16
Back to 
Presentation
Back to Presentation
• Beyond LEO, the most important sources of space 
radiation consist of galactic cosmic rays (GCR), and 
Solar Particle Events (SPE).
• GCR
• Dose-rates ~0.3 mGy / day from GCR
• SPE
• Modeled intravehicular dose-rates: 0 – 2800 mGy / hr during 
large SPE in interplanetary space
Pharmaceutical Stability: Radiation
Back to Presentation
• 2004: European pharmacopoeia identified more than 250 
drugs and adjuvants considered to be photochemically
unstable (photolabile)
• In 2009, Hospital Pharmacy published a list of US approved 
oral medications, and injections in 2014 considered to be 
photolabile.
– Of the medications included in the 2017 ISS medication kit 
formulary:
• 35.6% of the oral medications were included on the list of oral 
photolabile drugs
• 88% of the injection medications were included on the list of injection 
photolabile drugs
Pharmaceutical Stability: Radiation
Back to Presentation
Back to Presentation
Limitations of Terrestrial Radiation Research
• Dose – cumulative mission dose delivered over a matter of minutes
• Dose-rate – Significantly higher dose-rate in terrestrial studies or radiostability
analyses
• Altered energy delivery = altered chemical reactions, short-term dosing = no propagation 
of reaction over time; may alter free-radical generation or exhaustion
• Type of exposure – single ion does not emulate the complexity of the space 
environment or the varied energy transfers of different ions
• Intravehicular / intrapackaging – added spallation (scatter) ions may alter chemistry 
or reactivity of exposed drugs
• Hydrolysis vs. Direct – historically focused on water-based drugs re: increased 
production of free radical (oxygen species). 
• Direct impact to solid/powder drug lattice may trap free radicals, directly catalyze 
chemical reaction, or alter excipient structure
Back to Presentation
Back to Presentation
Medication Use Evaluation – LSAH Data
Data: Expeditions 1 through 40 
(~107.5 months)
• 43 unique crewmembers (7 women, 
36 men)
• 790 total reported medication uses
Data: Expeditions 21 through 40 
(63.5 months)
• 20 unique crewmembers (5 women, 
15 men)
• 462 total reported medication uses
Bayuse- On Orbit MUE Summary
Back to presentation
Pharmacotherapeutics: Adverse Effects
0.0%
0
0.0%
0
0.0%
0
0.0%
0
2.4%
3
1.4%
1
0
25
50
75
100
125
Hypnotic Stimulant Rash/Allergy Headache Congestion NSAID
N
u
m
b
er
 o
f 
R
ep
o
rt
s
Category
Reports with an Adverse Effect for Exp 21-40 
Bayuse- On Orbit MUE Summary
• PMC tool doesn’t 
‘ask’ to capture 
this information.
• Adverse effects 
self-reported
• A Zero in this 
graph does not 
mean that there 
weren’t adverse 
effects, only 
means there is 
no 
Back to presentation
Potential Drug-Drug Interactions
Bayuse- On Orbit MUE Summary
• Potential DDI
• Medications taken 
concurrently during the 
reporting period
• 28 of the 29 due to 2 
sleepers reported use 
within the same 
reporting period.
• Interactions between 
different classes of drugs
• Underestimated: the fidelity of 
data doesn’t support this level 
of review
• Multiple days of possible 
interactions within each 
reporting period
• Lack of dosing specificity as 
a contributing factor (i.e., 
timing of drugs taken during 
the reporting period) 
Back to presentation
Dose Tracker Insights
• Dose Tracker pilot project: 
• Collected data on 6 crewmembers during ISS missions
• As of February 2017, DT collected over 224 weeks of medication 
usage data 
• 128 weeks inflight, 96 weeks on the ground
• >5800 recorded medication entries (3049 inflight, 2717 ground)
• Average of 961 entries per subject (453 inflight, 508 ground). 
• Inflight average of 453 medication entries per subject
• 20x increase over average 23.1 / CM reported Exp 21-40
• 60x increase over average 7.6 / CM reported Exp 1-20
• 49 reports of no medication use in a given week of data collection
• POSITIVE confirmation of no medication use
• Previous efforts rely on possibly incorrect assumption that no report = 
no medication use
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Limitations in Understanding Use, Stability, and Effectiveness of Medications During Spaceflight

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