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 Design, develop and validate noninvasive monitoring technologies and strategies Develop simple, highly sensitive and reliable analytical techniques for drugs and biomarkers 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 Conduct ground-based analog studies 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 Therapeutic adjustments for pharmacokinetic, pharmacodynamic alterations Extended shelf-life pharmaceuticals GI, hepatic and renal function modulators Adverse drug interactions assessment Adjusted terrestrial drug dosages and delivery routes for microgravity environment Training for management of fatigue and neurocognitive drug synergistic effects and chronotherapeutic adjustments Current Activities Inflight therapeutic effectiveness monitoring Therapeutic trends from Shuttle-Mir data State-of-the-art therapeutic/pharmaceutical information data base Alertness enhancement/fatigue-reduction countermeasures strategies → Pharmaceuticals → Enhancement tools → Training 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.