Pharmacoenvironmentology Current Research Tool in Pharmacovigilance

1. Pharmacoenvironmentology Current Research Tool in Pharmacovigilance Syed Ziaur Rahman, MD Assistant Professor Dept. of Pharmacology Jawaharlal Nehru Medical College, AMU, Aligarh, India PhD Candidate School of Medicine University of Western Sydney, Australia

2. Introduction INTRODUCTION • Living in an environment that is polluted not only by chemicals, toxins, pesticides & emissions, but also with heavy metals & pharmaceutical substances. • With growing technological advances, newer & more effective drugs manufactured & are used on an ever-growing scale for people with various medical conditions. • Demand for more pharmaceutical products is destroying countless species of animals & plants, placing the public at risk, & supporting disappearance of rain forests around the globe - loss of rainforests - changes in global climate. The whole ecosystem is being changed. Entry of chemicals into acquatic environment is a more serious concern today. • Drugs lead double lives! Once APIs in administered medications have completed their intended purposes, they can take on renewed lives in environment. These pharmaceuticals enter into environment through various routes causing harmful effects. • Healthcare can itself be a cause of environmental damage as well as its remediator. • To date little is known in medical literature regarding causes, extent, risks of or solutions for drugs as pollutants.

3. CURRENT FOCUS • Earlier epidemiological work was focused on environmental factors such as toxins, chemicals, & pollutants, however, we now conceptualize environment as everything that is extrinsic to individual. This may includes surroundings, drugs, diet, exercise & family structure. • Human health & ecology may well turn out to be more intimately related than we ever imagined. • Scientists are now working in different directions such as understandingof gene-environment interactions, drug-environment interactions and toxin-environment interactions. • Still, closer collaboration between environmental sciences & medical communities is needed to address that gap.

4. * Pharmacovigilance. * With advancing research facilities in the field of ecology and environment, many of the adverse effects of these drugs on the environment have come to light. * A number of findings related to rising levels of some drugs and their adverse effects on the flora and fauna has necessitated some action by regulatory agencies like the FDA & the EU. * Still, there lacks a substantial protocol for prospective monitoring of drug concentrations in environment & the evident adverse effects.

5. Vicious cycle of never ending Medication in the Environment

6. ENTRY PATHS

9. CURRENT RESEARCH • Widespread concern about and research into the effect of PPCPs has largely occurred since the 1990s. • Until this time, PPCPs were largely ignored because of their relative solubility and containment in waterways compared to conventional pollutants like agrochemicals, industrial chemicals, and industrial waste and byproducts. Current research on PPCPs aims to answer these questions: • What is the impact of exposure to low levels of PPCPs over time? • What is the impact of exposure to mixtures of chemicals? • Are the impacts acute (short-term) or chronic (long-term)? • Are certain populations, such as the elderly, very young, or immuno-compromised, more vulnerable to the impacts of these compounds?

10. GUIDELINES • Although, FDA & EU have set some cut-off limit for environmental concentration of drugs • There is little concern & research to find AEs on environment, of particular drugs given at therapeutic doses. • In CTs, where many limitations like that of limited size, narrow population, narrow indications & short duration are observed, we also found that evaluation of drugs on environment is practiced very minimally.

11. History • The issue of the potential impact of pharmaceuticals on environmental, is emerging one, but not new. • US FDA has regulated pharmaceuticals in the environment (PiE) since 1977 through the environmental review process for NDAs. • In Europe, guidelines for ERAs have been available in draft since 1996, with the most recent draft issued in June 2006. • ESA

12. Guidelines outlines… • The RA procedure for new active pharmaceutical substances, excipients and their metabolites. • Potential ERs that are a consequence of people use, storage & disposal of medicines. • Recommendations appropriate precautionary and safety measures to limit the product’s environmental impact.

13. Underlying principle used in the EU & USFDA is same.

14. BASIC PRINCIPLE Environmental Concentration Guidelines

15. US FDA PROTOCOLS • Three tiered approach Tier 1- Acute testing one species Tier 2- Acute testing three or more species Tier 3- Chronic testing If expected introduction concentration = or >1ppb then ERA is required EMEA RISK PROTOCOL 1. Phase 1 –Estimation of exposure to environment 2. Phase 2 –Environment fate and effects analysis

16. Doesn’t cover • Risk posed by synthesis or manufacture of drugs. • Drugs already on the market • No actual testing is conducted after a drug is marketed • to see if the environmental concentration was estimated correctly • to periodically check its exposure & fate analysis • Post marketing surveillance of therapeutic drugs entering into environment – Pharmacoenvironmentology

17. Limitations • Not retroactive i.e. only for new drugs. • Laboratory testing & modelling cannot completely represent environment. • Definitions are broad, often leading to confusion, & legal loopholes. • Drug interactions - additive or synergism not taken into account. • Sales taken to be uniform in all geographical regions & seasons. • Further, how drugs that pose risks will be handled, apart from the addition of labels & proper disposal of drugs. But even if future legislation require ERA of drugs already on the market, the big question is who should do the testing since the originator of a drug is often no longer the main manufacturer moreover monitoring may be difficult for drugs already on market for years.

18. What is Schedule Y • Regulation and guidelines for permission to import and / or manufacture of new drugs for sale or to undertake clinical trials • It has outlined extensive study criteria in line with the globally accepted formats such as ICH and US FDA guidelines • REFER TO RULES 122A, 122B, 122D, 122DA, 122DAA and 122E NO Environmental risk assessment in Schedule Y

19. Precautionary & Safety Measures • The purpose of ERA is not to ban drugs, but to enable to use that is most environmentally friendly when there are alternatives with similar therapeutic effects. • An indication of potential risks presented by medicinal product for the environment on Product label. • Guidance for patient use, product storage and disposal. • Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

20. Drawbacks of present testing methods to study the effects and fate of drugs on environment • More importance is given either to drugs or heavy metals as such but and not its metabolite, which are actually major products excreted in the environment. • Laboratory testing and modeling cannot completely represent the environment. • No study design to study effect of drug and its metabolite after ingesting the second generation contaminated material. • Even no test for the compound they form after interaction with chemicals present in soil

21. Proposed Model for varifying the impact of Therapeutic Drugs on Terrestrial Environment using Laboratory Animals

22. Materials & Methods

23. Animals • Inclusion criteria: • Accessible • Long survived • Experimentally feasible • Herbivorous • Tolerant to environmental pollution i.e. should not die at therapeutic doses of the test drug given. • Exclusion criteria: • Sensitive to the drug

24. Plants • Inclusion criteria:- • Short life (Herbs / Shrubs) • Full cycle known • Parts of the plants easily distinguishable • Can be grown under laboratory conditions • Has following parts  flower, leaves, fruits, seeds, roots • Exclusion criteria:- • Long life cycle

25. Drug • Essential Medicines • Excreted unchanged and / or as a metabolite • Low toxicity to vital organs • Soil • Suitable soil for plant cultivation, e.g. for pea it has to be slightly acidic in nature with temperature above 100c

26. Proposed Model • Step 1: Herbivorous animal given test drug for one month • Step 2: Urine and excreta of test animals collected on each day for one month. • Step 3: Refuse is mixed with soil. Small fast growing herbs and shrubs would be cultivated. Therapeutic Drugs consumption Soil analyzed Excreta and urine collected on soil for 1 month Parts analyzed

27. Toxicological analysis of organs • Step 4: Parts of the plants would be fed to another group of test animals for at least 10 days. • Step 5: Toxicological studies of animals’ organs • Step 6: Seedlings and Plantation for second generation on normal soil. • For above test trial, there would be a control test trial with similar plants and animals. The steps 1-6 would be repeated without giving test drug Plant Fed Animals Drugs contaminated plants Parts analyzed Seedlings & Plantations

28. Analysis • Drug concentration (ppm) in the following specimens • Soil (Mixed with Animals’ Urine and Excreta) at step 2 • Plants (Grown on contaminated soil) at step 3 • Animals (For toxicological studies on organs including blood examination) at step 5 • Productivity (for plants) • Plants analysed for % proteins, carbohydrate & minerals • Compaired with control group

29. Limitation of the model: • Only one food chain is being examined. • One environmental condition i.e. terrestrial environmental condition is being used.

30. Discussion • Predicted environment concentration (PEC) of therapeutic drugs is calculated in Clinical Trials studies. • *When a human or animal is given a drug orally, it may either be fully or poorly absorbed from the gastrointestinal tract. Clearly, unabsorbed drug will pass into the environment along with faeces. *When humans or animals are given drugs parenterally or orally, the drug may be metabolized to a greater or lesser extent and excreted into the environment (including in exhaled air) as parent drug or metabolites, or as a mixture of both. *Once they are excreted into the environment, they enter food chains and concentrate as they move upward into larger predators. Genomic & Physiological Indicators of Effects of Pharmaceuticals on Aquatic Organisms are studied in details, however, no appropriate model for varifying the impact of therapeutic drugs entering into the terrestrial environment is ever suggested and worked upon • To improve models for testing the impact of the drugs on environment and incorporate them in the animal phase of clinical trials of drugs

31. Further reading…………… An Introduction to Environmental Pharmacology 2008 Eds. S. Z. Rahman, M. Shahid & V. Gupta Ibn Sînâ Academy of Medieval Medicine & Sciences, Aligarh, India

32. Acknowledgement…………… Prof. Rahat Ali Khan Dr. Varun Gupta Dr. Misbahuddin Dr. Syed ShariqNaeem