1. THERAPEITIC DRUG MONITORING

2. Introduction Therapeutic drug monitoring (TDM) is a tool that can guide the clinician to provide effective and safe drug therapy in the individual patient. measuring drug concentrations and clinical interpretation (Ahmed S. Ali1,* et,al. 2013) It is unnecessary to employ TDM for the majority of medications (Ju-Seop Kang, et,al, 2009 ) The goal - customize medication doses

3. Cont… Therapeutic index (therapeutic ratio) In animal studies - TI = LD50/ED50 In clinical practice - between the ED50 and TD50 The larger the TI, the safer the drug is narrow TI - steep concentration–response relationship Therapeutic window is a range of doses producing MEC and MTC (Juan Tamargo, and et.al 2015)

4. Con..

5. BASIC PRINCIPLES OF THERAPEUTIC DRUG MONITORING Decision to request Drug level Biological Sample Laboratory measurement Result communication by Laboratory Clinical interpretation Therapeutic management

6. Criteria for TDM The drug in question has a narrow therapeutic range A direct relationship exists between the drug /drug metabolite levels and the pharmacological effects The therapeutic effect cannot be readily assessed by the clinical observation Large individual variability Availability of appropriate analytic techniques (C.Suthakaran and C.Adithan *. Health Administrator Vol : XIX Number 1: 22-26)

7. MAJOR INDICATIONS FOR TDM Low therapeutic index Poorly defined clinical end point Non compliance Therapeutic failure Drugs with saturable metabolism Wide variation in the metabolism of drugs Major organ failure Prevention of adverse drug effects For diagnosis of suspected toxicity & determining drug abuse (C. Suthakaran and C.Adithan *. Health Administrator Vol : XIX Number 1: 22-26, Australian Prescriber Volume 31 | number 2 | pp. 42, April 2008)

8. TDM is unnecessary when Clinical outcome is unrelated either to dose or to plasma concentration Dosage need not be individualized The pharmacological effects can be clinically quantified When concentration effect relationship remains un- established Drugs with wide therapeutic range such as beta blockers and calcium channel blockers Hit and run drugs: Omeprazole, MAO inhibitors, Reserpine

9. Common drugs required for TDM and their therapeutic range The most commonly monitored drugs are Cardio active drugs Antibiotics Antiepileptic drugs Bronchodilators Immunosuppressants Cytotoxic drugs Analgesics and Antidepressants and antipsychotics. (Ahmed Shaker Ali, 2013)

10. The following tables show Drugs suitable for therapeutic drug monitoring with their therapeutic range (Australian prescriber| Volume 31 | NUM BER 2 | APRIL 2008)

12. TIMING OF SAMPLE COLLECTION The timing of sample collection is an important part of TDM but not given attention. The best sampling time is in the pre-dose or through phase just prior to a maintenance dose (after Css) Peak plasma concentrations are helpful in evaluating the dose of antibiotics used to treat severe, life-threatening infections – For Iv infusion peak concen. Is at 30 min after infusion ceased. – bolus injection, samples should be taken at least 1 h post- dosage to avoid overlapping the distribution phase (C. Suthakaran and C.Adithan * Health Administrator Vol : XIX Number 1: 22-26, Australian prescriber| Volume 31 | NUM BER 2 | APRIL 2008)

13. OPTIMAL SAMPLING TIME In most cases blood samples should not be collected until a steady-state However, drug concentrations may be determined earlier if toxicity is suspected.

14. Sampling time for some drugs (Fiona Davidson, Guidelines for Therapeutic Drug Monitoring Version NO: 6 )

15. ANALYTICAL METHODOLOGY The fundamental procedures necessary for the quantification are: recovery from body fluids, tissues, and organs separation from the biological components, identification of the species concerned finally quantification.

16. The analytical methodology employed should ideally: Distinguish b/n compounds of similar structure unchanged drug and metabolites. Detect small amounts Be simple enough to use as a routine assay and Be unaffected by other drugs administered simultaneously (C. Suthakaran and C.Adithan * THERAPEUTIC DRUG MONITORING) and (https://www.slideshare.net/tulasiraman/therapeu tic-23896317)

17. There are many analytical methods Spectrophotometry and Fluorimetry Thin layer chromatography (TLC) HPLC and GLS Radio immuno assay (RIA) Enzyme Immuno assay (C. Suthakaran and C.Adithan * THERAPEUTIC DRUG MONITORING) and (https://www.slideshare.net/tulasiraman/therapeutic-23896317)

18. fluorimetry

19. Spectrophotometry

22. INTERPRETATION Drug concentrations need to be interpreted in the context of the individual patient without rigid adherence to a target range. – Other factors that affect the concentration effect relationship should be considered For example, the serum potassium should be noted when interpreting digoxin concentrations as toxicity can occur at a therapeutic concentration if there is hypokalemia (C. Suthakaran and C.Adithan * THERAPEUTIC DRUG MONITORING), (Australian Prescriber| Volume 31 | NUM BER 2 | APRIL 2008 43)

23. Cont… Most drug assays measure total drug conc (bound and unbound drug), but only the unbound drug interacts with its receptor to produce a response. The unbound fraction may be affected by factors such as serum albumin concentration, displacement by an interacting drug and renal failure. New filtration devices (equilibrium dialysis, ultrafiltration, and ultracentrifugation)- measure free unbound drug levels in serum. The free concentrations are independent of changes in plasma binding and are the pharmacologically active concentration (C. Suthakaran and C.Adithan * THERAPEUTIC DRUG MONITORING), (Australian Prescriber| Volume 31 | NUM BER 2 | APRIL 2008 43)

24. FACTORS TO BE CONSIDERED DURING TDM Dosage regimen Active metabolite – e.g. imipramine is biotransformed to the active metabolite – desipramine. Effect of disease states – Acute or chronic disease alters drug clearance patterns

25. USE OF SALIVA IN DRUG MONITORING concentration of a drug in saliva is proportional to the concentration of the unbound rather than to the total of bound and unbound drugs in plasma The practice of measuring drugs in saliva is appealing because it is non- invasive. Limitations active secretion: Li binding to salivary proteins: phenytoin binding to oral cell debris: propranolol Drugs that affect salivary flow may ↑ or ↓ estimation – anti-cholinergic drugs – Preparations that stimulate salivary flow

26. COST EFFECTIVENESS: The measurement of drug levels in body fluids must be cost effective. The cost is determined by the summing equipment, personnel, supply and overhead expenditure for a given period of time and dividing that amount by the number of assays performed in the same time interval (C. Suthakaran and C.Adithan * Health Administrator Vol : XIX Number 1: 22-26)

27. MAJOR CAUSES OF UNEXPECTED SERUM CONCENTRATION IN PATIENTS Non compliance In appropriate dosage Malabsorbation poor bioabilibility Drug interaction Hepatic and renal disease Altered protein binding and genetic factors differences in drug formulations patient genetic variation

28. Cont… If these factors cannot be eliminated, a dosage adjustment is required. For drugs with linear kinetics the following formulae may be used (C. Suthakaran and C.Adithan * THERAPEUTIC DRUG MONITORING Health Administrator Vol : XIX Number 1: 22-26) and (Ju-Seop Kang andet.al 2009)

29. CLINICAL USEFULNESS OF TDM maximize efficacy, avoid toxicity, identify therapeutic failure, facilitate adjustment of dosage, identify poisoning, drug toxicity and drug abuse. (C. Suthakaran and C.Adithan * Health Administrator Vol : XIX Number 1: 22-26) LIMITATIONS OF TDM PROCESS Problems on scientific accuracy of the drug assays Laboratory variability in reporting Limited accessibility and the validity of suggested target ranges (C. Suthakaran and C.Adithan * Health Administrator Vol : XIX Number 1: 22-26)

30. Discussion questions Q. Do warfarin require TDM? Answer yes of course, because Warfarin has a narrow therapeutic range, so TDM or INR monitoring is necessary to avoid complications from both over-dosage (which increases the risk of bleeding) and under-dosage (which may result in clots) Warfarin needs special monitoring because it's efficacy and safe use is based on the patients INR http://webcache.googleusercontent.com/search? q=cache:http://inronline.net/179-2/

31. Cont… The typical INR goal is a value of 2.0 - 3.0, although this range can vary based on the indication and specific patient characteristics. INR monitoring is used in the initiation of warfarin at a weekly rate in order to determine the correct dosage for the individual patient. Additionally, a patient's INR level should be monitored monthly once their levels are stable. The TDM service is able to effectively monitor INR levels to make sure that the patient is within the therapeutic range and make appropriate dose adjustments to ensure that patients remain in target range. https://sites.google.com/site/section4tdmservice/home/dr ug-two/drug-two---need

32. Q2.TDM does not required when an effect of a drug is clinically observed and quantified.why? Express with examples

33. Answer TDM is based on the principle that for some drugs there is a close relationship between the plasma level of the drug and its clinical effect. If such a relationship does not exit TDM is of little value. Like any diagnostic test, the measurement of plasma level is justified only when the information provided is of potential therapeutic benefit. The clinical value of plasma level monitoring depends on how precisely the treatment outcome can be defined.

34. When therapeutic outcome can be objectively and replicably quantified, such as during antithrombotic therapy with coumarin derivatives,little additional information is gained by plasma levels. On the other hand when a precise therapeutic and point is difficult to define, monitoring of drug levels may be of considerable therapeutic assistance. http://webcache.googleusercontent.com/search? q=cache:http://medind.nic.in/haa/t06/i1/haat07i 1p22.pdf

35. In which case clinical quantification is usfeul, theophyline or Aminophyline? And why? Three different forms of theophylline are available. Aminophylline is the ethylenediamine salt of theophylline, and anhydrous aminophylline contains about 85% theophylline while aminophylline dihydrate contains about 80% theophylline. Oxtriphylline is the choline salt of theophylline and contains about 65% theophylline. Theophylline serum concentration monitoring is mandatory in patients receiving the drug. If a patient is experiencing clinical signs or symptoms that could be due to a theophylline adverse effect, a theophylline serum concentration should be obtained at that time to rule out drug- induced toxicity.(applied clinical pharmacokinetics 2 nd edtion)

36. Cont… Therapeutic range - 5-2 g/ml Time to steady state: 36 hours (average). Toxicity - manifest as tachyarrythmias, vomiting & convulsions. PK problems - Bioavailability varies widely between preparations. 90% eliminated by the liver & 10% unchanged in the urine (reversed ratio in neonates) i.e. No adjustment for renal failure required but dose in presence of impaired hepatocellular function. Whenever possible establish drug level before administering IV and if in doubt do not give bolus loading dose. Drawing levels: Oral solution or immediate release tablet: 1-2 hours after administration. Extended-release tablet: 4-12 hours after administration. Injection: 30 minutes after completion of the intravenous loading dose; a second measurement should be obtained after one expected half-life- 4 hours in children age 1 to 9 years and 8 hours in nonsmoking adults.(therapeutic drug monitoring slide share)

37. Q4.Does paracetamol PRN base require TDM? Drug assays are costly, so the reason for monitoring and the additional information to be gained (if any) should be carefully considered. For some drugs, therapeutic drug monitoring helps to increase efficacy (vancomycin), to decrease toxicity (paracetamol) and to assist diagnosis (salicylates). Routine monitoring is not advocated for most drugs. Only clinically meaningful tests should be performed If suspected toxicity is due to paracetamol even if in PRN base adminstration,quantification of APAP, APAP-glucuronide, APAP-sulfate, APAP-cysteine, APAP-glutathione, APAP- mercapturate, and protein-derived APAP-cysteine in human plasma by ultraperformance liquid chromatography-electrospray ionization-tandem mass spectrometry should be carried out and monitored https://www.nps.org.au/australian-prescriber/articles/therapeutic-drug- monitoring-which-drugs-why-when-and-how-to-do-it https://www.nps.org.au/australian-prescriber/articles/therapeutic-drug- monitoring-which-drugs-why-when-and-how-to-do-it https://journals.lww.com/drugmonitoring/Abstract/2017/04000/Quantific ation_of_Acetaminophen_and_Its.11.aspx

38. What are hit and ran drugs? Do they need tdm? ‘Hit and run drugs’ (whose effect lasts much longer than the drug itself), in other words,the medications whose action is irreversible is called "hit and run drugs" e.g.— reserpine, guanethidine, MAO inhibitors, omeprazole. In this case monitoring of plasma concentration is of no value. The duration of action of the drug may be longer than the actual stay of the drug in the body due to this „hit and run‟ effect as in case of Reserpine and Omeprazole. (essentials of medical pharmacology 7 th ed) http://nishurs.blogspot.com/2011/04/hit-and-run- drugs.html

39. Cont… The pharmacodynamic actions of „hit and run‟ drugs may be due to some irreversible or permanent changes in the enzymes or cellular functions as with aspirin, MAOIs and cortisone. The „hit and run‟ effect may be responsible for some ADR or may even be the reason for a lesser risk of a particular ADR. E.g. DDVAP and atypical antipsychotics. The „hit and run‟ effect may be seen with the parent compound but may not be seen with the metabolite e.g. selegiline. e. „Hit and run‟ effect of some drugs (cocaine) may cause euphorogenic effects. The „hit and run‟ effect may be responsible for the “post antibiotic effect” as with aminoglycosides. International Journal of Medical and Health Sciences Journal Home Page: http://www.ijmhs.net ISSN:2277- 4505

40. Is tdm required for drugs having delayed side effect? Q. how can dose adjustment both slow and fast acetylators carried out?