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TDM Group 06.pptx
- 2. TherapeuticDrug Monitoring Presented To: Mam Sumbul Presented By: Mahnoor Pervaiz Roll No: 19021560-025C Course Code: Bch-453 Course Title: Toxicology Group No: O6 Department Of Biochemistry University Of Gujrat
- 3. Presentationlayout: Introduction TDM: definition, goals & objectives Criteria for TDM Indications Factors affecting TDM TDM process Analytical methods Samples & timing Clinical interpretation Common drugs requiring TDM Clinical usefulness Problems Limitations Conclusion
- 4. Whatis TDM? (Therapeutic drugmonitoring) “TDM is the measurement of drug concentrations usually in blood/ plasma that facilitates adjustment of dosage to produce a desired response”
- 5. Whytdm? Therapeutic drug monitoring can guide the clinician to provide effective & safe drug therapy in the individual patient using serum drug concentration.
- 6. Whyshoulddrug levelbemonitored? Narrow therapeutic range Upper limit: drug toxic Lower limit: drug ineffective Same response to similar doses
- 8. Monitoringofdrug therapy: Monitoring of drug therapy can be done by Therapeutic outcome using clinical end points Pharmacodynamic measures using surrogates markers Pharmacokinetic measures using TDM
- 9. Monitoringofdrug therapy: Therapeutic outcome: • Therapeutic events • Anti-convulsant-seizure frequency • Angina pectoris-attacks Pharmacodynamic measures: • Surrogate markers • Arterial BP- hypertension • Blood glucose- diabetes • INR-oral anticoagulants Pharmacokinetic measures: • TDM
- 10. TDM:Definition “The clinical laboratory measurement of chemical parameter that, with appropriate medical interpretation, will directly influence drug prescribing procedures by combining knowledge of pharmaceutics, pharmacokinetics, & pharmacodynamics”
- 11. GOALSOFTDM: Ensure that given drug dosage produces Max. therapeutic benefit Min. toxic adverse effects Drug-appropriate conc.-site of action-produces benefits
- 12. TDM:Objectives Appropriate dosing of drug Chances of drug toxicity Economic convenience Reduce patient variability Accumulation of drug in body Dose-response relationship
- 13. Sourcesofvariability indrugresponse: Pharmacokinetic variability- variation in dose & plasma conc. Pharmacodynamic variability- variation in drug conc. at receptor level & response • Bioavailability • Plasma protein binding • Volume of distribution • Clearance Pharmacokinetic variables • Genetic polymorphism • Enzyme inhibitors • Enzyme inducers • Drug interactions • Drug tolerance Pharmacodynamic variables
- 14. Therapeutic range/window: “Conc. range of drug in plasma where drug has been shown to be efficacious without causing toxic effects in most people” Min. Effective Conc. (MEC) Max. Therapeutic Conc./ Minimum Toxic Conc. (MTC)
- 18. Therapeutic Drug Monitoring forAll Diseases??? PlasmaconcentrationBestmonitoring methodology Notusedforalldiseases……why? Reasons: 1. Checkplasmaconc.needbloodsample 2. Instrumentationexpensive (HPLC, Spectrophotometry) 3. Needexpertstooperate 4. Notavailableeverywhere
- 19. Criteria for Therapeutic Drug Monitoring: 1. Effectof drugcannotbe monitored Not used for: Anti-HTN Anti diabetic Anti coagulant
- 20. Criteria for Therapeutic Drug Monitoring: 2-NarrowTherapeuticIndex Margin of safety Can administer only 10-20mg Response starts Shows toxicity
- 23. Drugs which don’t need Therapeutic Drug Monitoring: Drugswithwidetherapeuticrange• Hitandrundrugs:omeprazole,MAOinhibitors Pharmacologicaleffects canbeclinicallyquantified/monitoredby clinicalendpoints,e.g.,BP,HR,cardiacrhythm,bloodsugar,blood cholesterolandtriglycerides,urinevolume,bodytemperature, inflammation,pain,headache,etc. Drugswhoseserumconcentrationsdonotcorrelatewith therapeuticortoxiceffects. Drugsusedtotreatlesscomplicatedornonlifethreatening diseases Drugfollowinglinearkinetics(lesscomplicatedpharmacokinetics)
- 24. Indications for Therapeutic Drug Monitoring: Low therapeutic index Poorly defined clinical end point Drugs with saturable metabolism Drugs having wide distribution in the body Wide variation in the metabolism of drugs Major organ failure Prevention of adverse drug effects Suspected toxicity Inadequate therapeutic response (Therapeutic failure)
- 25. Indications for Therapeutic Drug Monitoring: Compliance concerns (non compliance) e.g. in epileptics Dosage change Change in patient’s clinical state Change in co-medications (quinidine decreases digoxin clearance) Manifestations of toxicity and disease state are similar (Nausea & vomiting occur in both digitalis toxicity & congestive heart failure)
- 27. Factors affecting the TDM Factors Physiological factors Pathological factors Other factors Many factors are affecting TDM such as:
- 29. Pathological factors affecting the TDM Diseases cause individual variation in drug response Factors Renal failure Liver failure Diarrhea Vomiting inflammatory bowl disease GIT diseases Inflammation
- 30. Others factors affecting theTDM Patient’s demographic Dosage regimen and duration of therapy Alcohol and tobacco use Medicine or sampling errors Laboratory errors Patient compliance Individual capacity to distribute, metabolize and discrete the drug Altered protein binding
- 31. Process ofTDM
- 33. Refrences: Burton, M. E. (2006). Applied pharmacokinetics & pharmacodynamics: principles of therapeutic drug monitoring, LippincottWilliams &Wilkins. Rousselot, P., et al. (2015). Personalized daily doses of imatinib by therapeutic drug monitoring increase the rates of molecular responses in patients with chronic myeloid leukemia. Final results of the randomized OPTIM imatinib study, American Society of HematologyWashington, DC. Soola,A. H., et al. (2022). "Evaluation of the factors affecting triage decision-making among emergency department nurses and emergency medical technicians in Iran: a study based on Benner’s theory." BMC Emergency Medicine 22(1): 1-9. https://slideplayer.com/slide/12736698/ https://bmcemergmed.biomedcentral.com/articles/10.1186/s1287 3-022-00729
- 34. Therapeutic drug monitoring 19021560-037 CONTENT: • Analytical Methodology • Sample Collection
- 35. ANALYTICAL Methodology TDM 35 The fundamental procedures necessary for the quantification of the drug in the body are: – recovery from body fluids, tissues, and organs – separation from the biological components – quantification.
- 36. Introduction The analytical methodology employed should ideally: – distinguish between compounds of similar structure – unchanged drug and metabolites – detect small amounts – be simple enough to use as a routine assay – be unaffected by other drugs administered simultaneously TDM 36
- 37. 1. Colorimetry 2. UV- spectrometry 3. Fluorescence spectrometry 4. Chromatography Gas chromatography Mass spectrophotometry HPLC HPTLC 5. Capillary electrophoresis Laboratory Measureme nts:
- 38. Immunoassay : Immunoassay – RIA: Radio immunoassay – Enzyme Immunoassay – ELISA: Enzyme linked immunoassay – EMIT: Enzyme multiplies immunotechnique – FPIA: Fluorescence polarization immunoassay 38
- 39. Free drug monitoring: Development of new filtration devices: (equilibrium dialysis, ultrafiltration, ultracentrifugation) has made it possible to measure free unbound drug levels in serum. – Advantage: The free concentration is independent of changes in plasma binding and is the pharmacologically active concentration. – Disadvantage: It is time consuming, expensive and therapeutic ranges do not yet exist for many drugs. 39
- 40. Tdm 40 Samples: Plasma or Serum is used for drug assays: • Whole blood: used for drugs such as cyclosporin, tacrolimus, sirolimus
- 42. Guidelines for sampling time: • Short half life drugs: – pre dose sampling • Long half life drugs: – at any point in the dosing interval • One vs Two samples Drugs with a short half-life: peak and trough concentrations will be very different from one another – both samples to be obtained Peak and trough concentrations will not differ substantially for drugs whose half-life is much longer than the dosing interval – single sample is sufficient • 42
- 43. Timing of Sample Collection: The timing of blood collection is an important part of therapeutic drug monitoring Blood sample should be collected once the drug concentration have attained steady state. Absorption is variable after oral drug administration and blood samples should be collected in elimination phase rather than absorption / distribution phases. • Trough conc : – when a drug is administered by multiple oral doses, commonly used for anti-convulsant drugs – should be obtained just prior to the next dose at steady-state conditions • Peak conc. : – useful for some antibiotics given IV – Peak should be determined after drug absorption (generally 2-4 hours for oral administration, 0.5-1 hour for IM, SC route) 43
- 44. Clinical Interpretati on For therapeutic drug monitoring The information required to allow interpretation of the result should include:- • Patient -Age, weight, sex, height, smoker status • Clinical – clinical status (renal -serum creatinine; cardiac -cardiac output; liver function etc. • Other drug therapy • Relevant disease states • Time of the sample collection • Time of the last dose • Dosage regimen • Indication for drug monitoring e.g. .lack of effect, routine monitoring, suspected toxicity 44
- 45. DRUG IN SERUMCONC: Lower than anticipated: • Patient non compliance • Error in dosage regimen • Rapid elimination • Timing of sample • Steady state not reached • Change in hepatic blood flow • Induction of metabolizing enzymes • Poor bioavailability • Increased plasma protein binding • Enlarged apparent volume of distribution 45 Higher than anticipated: • Error in dosage regimen • Increased bioavailability (hepatic disease) • Slow elimination • Inhibition of metabolizing enzymes • Decreased plasma protein
- 46. HowCAN we make drug monitoring easier… MOST APPROPRIATE SAMPLE: Urine is the most commonly used specimen for drug testing because of ease of collection.Other advantages to using urine for drug testing are the relatively high concentrations of many drugs and metabolites in urine 46 FAVORABLE ANALYTICAL METHOD: chromatographic methods such as liquid chromatography–tandem mass chromatography is the ability to simultaneously analyze multiple drugs in a single assay and methods typically provide higher specificity for identification of the drug.
- 48. TDM: Clinical Applications To confirm adequate serum concentrations where clinical response is inadequate: TDM can be used to assess the appropriateness of dosing regimen to maintain the minimum concentration required to exhibit efficacy To avoid drug toxicity: maintaining within therapeutic range To individualize dosing of some drug with an unpredictable dose-response curve. To assess medical compliance To help predict a patient dose requirements
- 49. TDM: Clinical Interpretation Patient- Age, weight, sex, height, smoker status Clinical Status Other drug therapy Time of sample collection Time of last dose Dosage Regimen
- 53. Drugs commonly Monitored: Cardio Active Drugs: Digoxin Quinidine, Digitoxin Antibiotics: Gentamycin, Tobramycin Antidepressants: Lithium and tricyclic antidepressants Antiepileptic Drugs: Phenytoin, Phenobarbitone Bronchodilators: Theophylline Cancer chemotherapy: Methotrexate Immunosuppressives: Cyclosporine
- 54. TDM: Clinical Usefulness Short Hospital Stay Better disease control Dose adjustment Dose guidelines Individualized dose requirements Avoidance of unnecessary medication
- 55. TDM: Problems Physician sometime do not understand the principles, benefits and limitations of TDM services Inappropriate Sampling Time Do not state the indication of TDM Insufficient Patient history and other necessity data
- 57. AimsOfTGM
- 58. How to design a study to evaluate therapeutic drug monitoring in infection disease
- 60. Limitations Interference from other drugs Lack of training and skills Cost involved Individual variability Analytical variability Timing of samples Limited availability Clinical expertise
- 61. Conclusion Therapeutic drug monitoring is required for a small fraction of drugs used in pharmacotherapy,but for these drugs such monitoring is essential in order to achieve maximum efficacy of the drug as well as to avoid drug toxicity.
- 62. Thank you