PHARMACOTHERAPEUTICS IN SPACE Lakshmi Putcha, Ph.D., FCP NASA Johnson Space Center

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PHARMACOTHERAPEUTICS
IN SPACE
Lakshmi Putcha, Ph.D., FCP
NASA Johnson Space Center
GOAL
Deliver Safe and effective diagnostic
and pharmacological intervention
products, procedures, and strategies
to support successful space medical
operations
Autonomous Medical
Care Concerns
ISS
(1 yr)
Moon
(30 d)
Mars
(30 m)
Monitoring and Prevention
2
2
1
Clinical
Major Illness & Trauma
2
1
1
AMC
Clinical
Pharmacology of Space Medicine
Delivery
2
2
1
23
AMC
Clinical
Return to Gravity/Rehabilitation
3
2
1
24
AMC
Clinical
Medical Informatics Technologies
and Decision Support Systems
3
2
1
22
AMC
Clinical
Ambulatory Care
3
3
2
25
AMC
Clinical
Medical Skill Training and
Maintenance
3
2
2
Risk #
Theme
Discipline
19
AMC
Clinical
20
AMC
21
Risk Title
Spaceflight Challenges
Environmental extremes
Internal conditions will impact pharmaceutical storage and use
Time and distance
Clinical care and monitoring of medicinals will be impacted
Physiological responses to microgravity
Bone, muscle, and cardiovascular changes; neurovestibular
alterations; decreased immune function; variations in endocrine
system
Psychological considerations
Changes in light/dark cycles, isolation, confined environment
Risk Factors
• GI, hepatic and renal physiology changes
• Pharmacokinetic/ pharmacodynamic
alterations and therapeutic implications
• Adverse drug reactions
• Stability and shelf-life of pharmaceuticals
• Terrestrial drug dosages and delivery routes
in a microgravity environment
Initiating Events
Pharmacotherapeutics Mission Impacts
•Crew illness
•Trauma/Injury/
Surgery
•Treatment failure
Overarching Concerns
Inadequate Knowledge/
Experience Base
• Unstable drugs
• Altered PK/PD
•Infection
•Cumulative
organ pathology
Unknown
Efficacy
Stability Adequacy
Crew Health/Illness
•Formulary Adequacy
•Pharmaceutical stability
•Efficacy
•PK/PD database
Near term requirements
Risks
Consequences
Improper treatment
Improper treatment
(based on unvalidated,
(based on unvalidated,
anecdotal reports)
anecdotal reports)
Crew Health, Safety &
Mission Impact
Overdose
Overdose
(exacerbation, obtundation)
(exacerbation, obtundation)
Inadequate treatment for
Inadequate treatment for
•Infection
•Infection
•organ systems
•organ systems
•Bone/muscle augmentation
•Bone/muscle augmentation
•Inadequate
treatment
•adverse events
•crew illness/
injury
•treatment failure
Unique adverse events
Drug interactions
Altered therapeutic index/window
Altered therapeutic index/window
Hypersensitivity
Hypersensitivity
•Evidence Based Medicine
•Medication debriefs analysis for
•Use
•Efficacy
•Side effects
•Standardized clinical efficacy test regimen
•Stable pharmaceuticals
•Shielding technologies
•Novel dosage forms
•Therapeutic adjustment per organ funciton
•Crew selection & training
Near Future requirements
Loss of Mission
Objectives
Mission
Failure
•Evidence Based treatment
•Mitigation of risk due to
•treatment failure
• adverse event
•Therapeutic cocktails
•Innovative clinical-care
systems
Moon/Mars requirements
Illness/
injury/
death
Pharmacotherapeutics for
Space Exploration
Major areas of emphases include
Pharmaceutical stability
of dosages forms
Evidence Based Medical practice
- PK/PD changes
- Therapeutic monitoring
- Systematic evaluation
Enabling technologies
for drug treatment, monitoring &
management
.
Research Objectives
Assess, manage and mitigate pharmacotherapeutic
risks that may limit astronauts’ ability to survive
and/or function during prolonged space flight.
Aims:
• Assessment of efficacy of existing countermeasures
and effects of microgravity on PK/PD and efficacy
(interdisciplinary)
• Development of advanced instrumentation and
methodologies
• ISS-based data collection on physiological and
pharmacological variables
Number of Doses
Medication Use Profiles
150
Pain
SMS
Sleep
Decon
% of Total Flights
Shuttle Pharmaceuticals
100
Flight Frequencies
20
10
0
2
4
6
8 10 12 14 16 17
Mission Duration (days)
50
0
0
2
4
6
Mission Day
8
10
0
E
VA
Sl
ee
p
SM
S
Na
us
ea
C
on
ge
sti
on
H
ea
da
ch
In
e
di
ge
st
io
n
Ba
ck
ac
he
Pr
op
hy
la
ct
ic
Percent of All Doses
Incidence & Interventions
40
30
20
10
Percent Data Recorded
Post-flight Assessment
100
80
60
40
20
0
y
rit
ve
s
Se
ct
fe
Ef
eid
S y
ac
fic
f
n
Ef
tio
ca
di
In
e
od
M
e
os
D
ET
M
MET: mission elapsed time
Pharmacotherapeutic
Profile
Pharmacokinetic Changes in
Space
ƒ
Design, develop and
validate noninvasive
monitoring technologies
and strategies
ƒ
Develop simple, highly
sensitive and reliable
analytical techniques for
drugs and biomarkers
ƒ
Identify and validate
ground-based analogs for
PK/PD evaluations and
interpretations
Gastrointestinal Transit
Time
Mean GI transit time as measured by lactulose:
ABR and Space flight
ABR subjects(n=3)
140
Astronauts(n=2)
Time (min)
120
100
80
60
40
20
0
P re
Da y 2
Da y 28-30
Da y 54-58
Test days
Da y 88
P o s tDa y 6-7
Reference Database
Create, compile, and
maintain a comprehensive
space pharmacokinetic,
pharmacodynamic and
therapeutic reference
database
ƒ
Conduct ground-based analog
studies
ƒ
Develop optimal sampling and
PK/PD models of operationscritical pharmaceuticals and
chronobiotics
Pharmacodynamic
Changes
Therapeutic Implications of:
10
5
8
4
6
3
PMZ
4
2
¾ Acute changes
Ratio of SSS
PMZ (ng/ml)
Salivary promethazine (PMZ) levels &
Stanford Sleepiness Score (SSS)
¾ Chronic changes
¾ Gender differences
1
2
SSS
0
0
0
10
20
30
40
¾ Physiologic vs. PK/PD
50
Time (h)
interactions
Plasma Concentration Profiles of Promethazine
¾ Drug-drug interactions
30
Male
Female
PMZ (ng/ml)
25
20
15
10
5
0
0
10
20
30
Time (hour)
40
50
60
Significant Findings
Limited information on inflight drug utilization and therapeutic
benefits of medications used
Data suggest that drug dynamics
may be altered
Altered pharmacokinetics (PK)
Altered gastrointestinal motility and
gastrointestinal microbial status
Changes in sleep patterns and
melatonin levels
Suboptimal light conditions
Clinical assessment
Altered pharmcodynamics (PD)
Frequent use of hypnotics/sedatives
Oral drug treatment may be
ineffective or less effective
(anecdotal reports)
Light Intensity Spectrum
During 24 hours
Inflight
Preflight
>0 lux
>500 lux
>1,000 lux
>2,000 lux
>5,000 lux
>10,000 lux
>15,000 lux
PK Parameters of APAP
Bioavailability
APAP Absorption in Flight
Absorption
40
Distribution
30
Metabolism
20
pre
during
35
post
25
15
Elimination
10
5
0
mg/L
mgh/L
h-1
Cmax
AUC
ka
PK parameters affected by
spaceflight
Clearance
APAP Cl/F (L/h)
35
30
Glomerular filtration
20
L/h
renal and hepatic blood
flow
25
15
10
enzymes of drug
metabolism
(cytochromes, etc.)
5
0
pre
during
post
Volume of distribution
APAP Vz/F (L)
Total and vascular body
water
120
100
80
L
drug binding proteins
drug transporter proteins
(tubular secretion, blood
brain barrier)
60
40
20
0
pre
during
post
Significant Findings
• In-flight drug utilization and therapeutic benefit have been
poorly documented
• Sufficient data suggest that drug dynamics may be altered in a
microgravity environment:
Ê
Physiologic
Changes
Ê
Ê
Ê
Ê
Ê
Gastrointestinal motility significantly reduced (Shuttle
and Mir-18 data)
Bacterial flora/GI physiology perturbed during longduration flights (Mir-18 data and Russian experience)
Inflight hepatic metabolism altered in flight (Mir-18 data)
Inflight sleep decrements and fatigue commonly occur
(Shuttle data)
Inflight melatonin levels elevated (Shuttle data)
Light conditions are suboptimal (Shuttle data)
Significant Findings
(continued)
Pharmacokinetic
Alterations
Clinical
Assessment
Ê
Absorption/bioavailability of solid
oral dosage forms is slow and
variable (Shuttle data)
Ê
Prolonged and frequent use of
hypnotics/sedatives - may influence
crew performance (Shuttle data)
Ê
Promethazine effects may be reduced
(Shuttle data)
Ê
Oral drug treatment may be ineffective
or less effective (anecdotal reports)
Pharmaceutical Stability
Altered physiochemical properties
Failure to meet USP requirements of drug
quality/content
Reduced release/absorption Æ reduced Sensitivity (ISS & SOMS) by heat, light, or humidity
therapeutic activity
Storage conditions
Potential altered stability causes
30
35
Humidity
„ Example: Augmentin tablets
Proposed radiation-induced effects:
„ Gamma and nucleon
„ Photo-/thermo-labile (ground) Æ radiolabile (space)
„ Reduction in therapeutic content
„ Exposure may generate potentially
toxic species
Low
Medium
High
35
Pharmaceutical Stability
Initial findings
Differences in the chemical stability of antibiotics tablets after
flight
Treatment maybe impacted in space with these formulations
Limitations
Limited samples – could not perform assessment of
degradation kinetics
Limited dedicated resources – compromised time-critical
sample analysis postflight
Recommendation for follow-on efforts
Assess stability of spaceflight and ground samples with same
lot number and adequate sample size
Examine more batches from similar flight conditions for
kinetic analysis
Enhance the assessment of radiation conditions seen in flight
on medication stability and shelf-life
Critical Issues
ƒ Therapeutic adjustments for pharmacokinetic,
pharmacodynamic alterations
ƒ Extended shelf-life pharmaceuticals
ƒ GI, hepatic and renal function modulators
ƒ Adverse drug interactions assessment
ƒ Adjusted terrestrial drug dosages and delivery
routes for microgravity environment
ƒ Training for management of fatigue and
neurocognitive drug synergistic effects and
chronotherapeutic adjustments
Current Activities
ƒ Inflight therapeutic effectiveness monitoring
ƒ Therapeutic trends from Shuttle-Mir data
ƒ State-of-the-art therapeutic/pharmaceutical
information data base
ƒ Alertness enhancement/fatigue-reduction
countermeasures strategies
→ Pharmaceuticals
→ Enhancement tools
→ Training
ƒ Pharmaceutical stability
→ Optimization of existing formulary
→ Cutting-edge pharmaceutical
technologies
Intranasal Formulations
Development
¾ Intranasal formulations
Quick onset
Enhanced bioavailability
Better therapeutic index
adjustments
More effective route for
motion sickness treatment
Formulation Development
¾ Acute treatment regimens
Motion
Sickness
Agents
Radioprot
ectant
Nonsurgical
Therapeutic
s
Cardiova
scular
Drugs
Antibiotics
Immunoenhancers
¾ Chronic treatment
regimens
¾ Fast delivery and
sustained-release delivery
systems
¾ Smart dispensing
Musculo-skeletal
Drugs
Osteoporo
sis
Medicatio
ns
Endocri
ne
Drugs
technologies and
extended shelf-life
pharmaceuticals
Promethazine Encapsulation via
Spinning Disk Atomization
PMZ Microspheres produced
by hot melt processing
Micro/Nanotechnology
Non-obtrusive therapeutic monitoring sensors
Microelectromechanical systems (MEMS)
Portable medical monitoring technologies
Ingestible biomedical sensors
Nanotechnology facilitates the design of miniaturized
medical monitoring and treatment devices
Lab-on-a-Chip Technology
• Microsampling
• Biological fluids
• Environmental samples
• Microprocessing
• PCR
• Sample separation
• Cell-sort
• Microanalysis
• Drug & Metabolites
Fluoresce
nce
Detection
Waste
Outlet
SP
E
Separation
Channel
Sample
Inlet
Diagnostic Tools
New endoscopic
technology - Pillcam®
Monitor small bowel
pathophysiology
Measure intestinal
transit time
Acknowledgements
Pharmacotherapeutics Laboratory
™
™
™
™
™
™
™
™
™
™
™
Kurt Berens, B.A.
Jason L. Boyd, Ph.D.
Cammille Crady, B.S.
Hrilina Das, MPH
Jianping Du, Ph.D.
Karalee Gatlin, Pharm.D.
Joseph Gutheinz
Vinodbala Shah, M.S.
Zalman Vaksman, M.S.
Zuwei Wang, Ph.D. and
Extra-mural Collaborators and Students
Progress is not a leap in the dark,
but a succession of logical steps.
Robert Goddard
2005
PhaseI I
Phase
Identify risks &
estimate uncertainties
2010
2015
2020
PhaseIIII
Phase
2025
Phase
PhaseIIIIII
Enabling knowledge Standardize drug therapy evaluation Dose individualization
drug stability testing
drug use/efficacy DB
PK/PD database
Countermeasures
shielding
novel therapeutics
dose individualization
stable formulary
Space Station
Return to the Moon
Mars
Applications: Novel dosage forms, therapies, & diagnostic tools,
clinical intervention products
This approach allows for the identification of inflight pharmacotherapeutic
risks, enhancement of medical care, and facilitation of state-of-the-art
intervention strategies and technologies for risk mitigation of space
exploration.
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