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Therapeutic drug monitoring

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Overview of Therapeutic Drug Monitoring (TDM) process

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Therapeutic drug monitoring

  1. 1. Dr. Arun Sharma Therapeutic Drug Monitoring (TDM)
  2. 2. Overview • TDM Introduction • Historical aspects • TDM in India • Criteria for TDM • Indications for TDM • The TDM Process • Clinical significance of TDM • Limitations • Pharmacoeconomic aspects of TDM • Conclusion 2
  3. 3. TDM : Introduction • Therapeutic drug monitoring (TDM) is the clinical practice of measuring specific drugs at designated intervals to maintain a constant concentration in a patient’s bloodstream, thereby optimizing individual dosage regimens. • In other words, TDM refers to the individualization of drug dosage by maintaining plasma or blood drug concentrations within a targeted therapeutic range or window. 3
  4. 4. • Therapeutic drug monitoring involves not only measuring drug concentrations, but also the clinical interpretation of the result. • The goal of this process is to individualize therapeutic regimens for optimal patient benefit. • By combining knowledge of pharmaceutics, pharmacokinetics and pharmacodynamics, TDM enables the assessment of the efficacy and safety of a particular medication in a variety of clinical settings. 4
  5. 5. • 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. • Another assumption is that drug metabolism varies from patient to patient. • When a precise therapeutic end point is difficult to define, monitoring of drug levels may be of considerable therapeutic assistance. • Routine monitoring is however not advocated for most drugs. • Only clinically meaningful tests should be performed. 5
  6. 6. • Therapeutic drug monitoring aims to promote optimum drug treatment by maintaining serum drug concentration within a ‘Therapeutic Range’. 6
  7. 7. TDM : History • The science of Therapeutic Drug Monitoring grew out of the recognition that: – Certain drugs have a narrow therapeutic range. – In concentrations above the upper limit of the range, the drug can be toxic. – In concentrations below the lower limit of the range, the drug can be ineffective. – Not all patients have the same response at similar doses. 7
  8. 8. • These findings led to the development of Clinical Pharmacology departments. • However, not everyone embraced TDM testing. Some believed that TDM testing provided little or no value. • Studies were initiated to determine the clinical value of TDM testing, and in certain instances clear clinical value was demonstrated. • Today there are over 20 therapeutic drugs which are routinely monitored. 8
  9. 9. TDM in India • TDM was introduced in India in mid 1980s and last 20 years have seen its growth. • TDM in India exists in mainly 2 settings: –In Large teaching hospitals through Dept. of Clinical Pharmacology. –In Private sector (Biochemistry Labs, dedicated CPU units in Corporate hospitals like Apollo) 9
  10. 10. Criteria for TDM 1) An appropriate analytical test for drug and active metabolites must exist. 2) Drug should have a narrow therapeutic range. 3) Patients not showing adequate clinical response to a drug despite being on adequate dose. 4) The therapeutic effect can not be readily assessed by the clinical observation (e.g. anticonvulsants, anti arrythimcs, antidepressants etc.) 5) Large individual variability in steady state plasma concentration exits at any given dose 10
  11. 11. • There are several classes of drugs commonly monitored to ensure correct blood concentration, including the following: – Antiepileptics (Phenytoin, Valproic acid etc.) – Antiarrythmics (Digitalis, lignocaine etc.) – Antibiotics (Gentamycin, amikacin, tobramycin) – Antineoplastics (Methotrexate) – Antimanics (Lithium) – Bronchodilators (Theophylline) – Immunosuppressives (Cyclosporine) 11
  12. 12. Indications for TDM • While there may be specific individual circumstances for TDM, most indications can be summarized as follows: 1. Low therapeutic index. 2. Poorly defined clinical end point. 3. Non compliance. 4. Therapeutic failure. 5. Drugs with saturable metabolism. 6. Wide variation in the metabolism of drugs. 7. For diagnosis of suspected toxicity & determining drug abuse. 12
  13. 13. Indications for TDM 8. Drugs with steep dose response curve (small increase in dose can result in a marked increase in desired/undesired response e.g. theophylline) 9. When another drug alter the relationship between dose & plasma concentration e.g. plasma concentration of lithium is increased by thiazide. 10. Renal disease (alters the relationship between dose & the plasma concentration. Important in case of digoxin, lithium & aminoglycoside antibiotics.) 13
  14. 14. • TDM is unnecessary when: 1) Clinical outcome is unrelated either to dose or to plasma concentration. 2) dosage need not be individualized. 3) the pharmacological effects can be clinically. quantified (BP, HR, Blood sugar, urine volume etc.) 4) when concentration effect relationship remains unestablished. 5) drugs with wide therapeutic range such as beta blockers and calcium channel blockers. 6) Hit and run drugs e.g. Omeprazole. 14
  15. 15. The TDM Process TDM is a multidisciplinary function and requires collaboration and good communication between scientists, clinicians, nurses and pharmacologists. 1) Decision to request Drug level: Decision will be based on proper reasons: – Suspected toxicity. – Lack of response/compliance. – To asses therapy following change in dosage. – Change in clinical state of patient. – Potential drug interactions due to concomitant medications. 15
  16. 16. 2) The Biological Sample: • After decision is made, biological sample is collected for to provide measurement. • Serum or plasma samples are usually collected for TDM. • Serum separator tubes should be avoided as lipophilic drugs can dissolve in gel barrier. • Blood sample should be collected once the drug concentration have attained steady state (SS) (at- least 5 half lives at the current dosage regimen). • Levels approximating SS may be reached earlier if a loading dose has been administered (drugs with long half lives e.g. digoxin). 16
  17. 17. • However, drugs with long half-lives should be monitored before SS is achieved to ensure that individuals with impaired metabolism or renal excretion are not in the risk of developing toxicity at the initial dosage prescribed. • If toxicity is suspected the concentration should be measured as soon as possible. • Immediate assay is required if there is a poor therapeutic control as in atrial fibrillation, when loading dose would be useful. 17
  18. 18. • Blood samples should be collected in elimination phase rather than absorption / distribution phases. • Usually blood samples are collected at the end of the dosage interval (Trough). • For antibiotics given intravenously, Peak concentrations (30 minutes after cessation of i.v. infusion) are also measured. • Usually drug concentrations are monitored in venous blood, serum or plasma and it is important that the appropriate matrix is assayed. 18
  19. 19. • In general serum or plasma concentrations are comparable but the blood collecting tube used is important as few anticoagulants used are inappropriate to few drugs and analytical procedures. • Whole blood must be sampled for few drugs like, Cyclosporine A, that distributes between plasma and erythrocytes. • In infants, capillary blood may be collected for TDM. • Despite extensive research examined the utility of saliva measurements other biological fluids are not routinely sampled. 19
  20. 20. • Errors in the timing of sampling are likely responsible for the greatest number of errors in interpreting the results. • Examples: – Lithium: 12 hr sample is most precise. – Digoxin: Make measurements at least 6 hrs after a dose to avoid inappropriate high levels. – Carbamazepine: Its half life is as long as 48 hrs following a single dose. So a thorough concen- tration taken just after a dose together with a peak level three hrs later is ideal 20
  21. 21. 3) The Request: • Following details must be effectively communicated to members of TDM team with a drug assay request: – Timing of sample – Dosage regimen – Patient demographics (age, sex, ethnicity etc.) – Co-medications, if any – Indication for monitoring – PK and therapeutic range of drug 21
  22. 22. • When a drug which is commonly measured for TDM is suspected of causing toxicity, it is very important for requesting clinicians to clearly communicate the expectation of a high concentration and need for a rapid feedback of results. 4) Laboratory measurement: • A quality drug assay should be performed within a clinically useful time frame. • The assay procedure should be a validated one 22
  23. 23. • Wherever possible assay procedure should be evaluated with an external quality assurance program. • Senior laboratory staff should verify the assay results in light of clinical request. • Ideally the results of the assay should be available to the clinician before the next dose is given. • Commercial kits can be used wherever possible and found economical, but these kits are not available for all the drugs require TDM. 23
  24. 24. • The analytical methodology employed should ideally: 1) Distinguish between compounds of similar structure – unchanged drug and metabolites 2) Detect small amounts 3) Be simple enough to use as a routine assay 4) Be unaffected by other drugs administered simultaneously. • Various analytical techniques available are Spectrophotometry and Fluorimetry, Thin layer chromatography (TLC), HPLC and GLC, Radio Immuno assay(RIA), Enzyme Immuno assay, Fluorescence polarization Immunoassay (FPIA) 24
  25. 25. 5) Result communication by Laboratory: • The assay results should be communicated as quickly as possible once it is verified by the senior laboratory personnel (preferably within 24 hr). • The drug concentrations measured are generally reported in mass or molar units . • To relate concentration back to dose, mass units are preferable. • The result should clearly state the therapeutic concentration range for the drug assayed. 25
  26. 26. 6) Clinical interpretation: • Clinical interpretation can ‘add value’ and convert ‘therapeutic measurement service’ into ‘therapeutic drug monitoring service’. • Just relating a drug concentration to a published therapeutic range is not an adequate interpret- ation. • Concentration must always be interpreted in the light of clinical response, individual patient demographics and dosage regimen used. • Therapeutic ranges are available but should only be used as a guide. 26
  27. 27. • Dosage prediction by using several softwares help in individualizing dosage regimen. • Special situations:  Serum Concentrations Lower than Anticipated: (Patient compliance, error in dosage regimen, wrong drug product, poor bioavailability).  Serum Concentrations Higher than Anticipated: (Patient compliance, error in dosage regimen, poor metabolizer, high plasma protein bounding).  Serum Concentration Correct but Patient Does Not Respond to Therapy: (Altered receptor sensitivity eg, tolerance, drug interactions at receptor ) 27
  28. 28. 7) Therapeutic management: • The clinician caring for a patient will modify a drug dosage regimen in light of all available information • Physicians usually accept and implement recommendations of TDM team. • Hence, member of the TDM team with appropriate clinical expertise should be available to conduct a successful TDM 28
  29. 29. Clinical significance of TDM 1. Maximizes efficacy 2. Avoids toxicity 3. Identifies therapeutic failure – Non compliance, subtherapeutic dose 4. Facilitates adjustment of dosage New dose = Old dose X Desired Css/Old Css 5. Facilitates the therapeutic effect of drug by achieving target drug concentration 6. Identify poisoning, drug toxicity and drug abuse
  30. 30. 30 Limitations of TDM Process
  31. 31. TDM: Pharmacoeconomics • The measurement of drug levels in body fluids must be cost effective. • Mungall et al showed that therapeutic drug monitoring service offered substantial benefits like fewer adverse reactions, shorter intensive care unit stay and shorter overall hospital stay. • Resources consumed by TDM are likely to be regained by positive outcomes • Thus, TDM is an appropriate candidate for an economic outcomes evaluation. 31
  32. 32. FREE DRUG MONITORING (FDM) • Development of new filtration devices (equil- ibrium dialysis, ultrafiltration, ultracentri- fugation) has made it possible to measure free unbound drug levels in serum. • The advantages are that the free concentrations is independent of changes in plasma binding and is the pharmacologically active concentration. • The disadvantages are that it is time consuming, expensive and therapeutic ranges do not yet exist for many drugs. 32
  33. 33. Conclusion • TDM may be useful for establishing initial dosing and monitoring certain medications. • TDM can not compensate for error in diagnosis, poor choice of drugs, errors in dispensing and dosages, errors in sampling, non compliance etc. • However, when used in combination with good clinical observation, it can lead to optimal drug therapy with minimal side effects. 33
  34. 34. • TDM data provides the clinician with greater insight into the factors determining the patients response to drug therapy. • It can help to distinguish a noncompliant patient and a patient who is a true non-responder. • Thus, TDM is a useful adjunct in treating many patients provided the potential pit falls and problems are considered. ****** 34
  35. 35. References  Therapeutic drug monitoring in a developing country: an overview N J Gogtay, N A Kshirsagar, S S Dalvi Br J Clin Pharmacol. 1999 November; 48(5): 649–654. doi: 10.1046/j.1365-2125.1999.00088.x PMCID: PMC2014358 Web link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014358/  Therapeutic Drug Monitoring (TDM) - An Educational Guide Web link: http://www.medical.siemens.com/siemens/en_GLOBAL/gg_diag_FBAs/files/ products_disease_states/TDM/TDM_Guide_FINAL.pdf  Therapeutic drug monitoring D.J. Birkett, Professor of Clinical Pharmacology, Flinders University of South Australia, Adelaide Web link: http://www.australianprescriber.com/magazine/20/1/9/11  Overview of Therapeutic Drug Monitoring .Ju-Seop Kang and Min-Ho Lee.. Korean Journal of Internal Medicine Vol. 24, No. 1, March 2009. pg 1-8 35

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