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Therapeutic Drug monitoring (TDM)...pptx
- 1. MD Seminar Dr. AnishaMathew 1
- 2. A patient withcongestive heart failure has been successfully treated with digoxin for several years, but recently developed renal failure. Laboratory records indicate semi-annual peak digoxin concentrations that have all been within the therapeutic range. A serum specimen was collected upon admission. Although the digoxin concentration is elevated, the physician indicates the patient is not exhibiting signs or symptoms of toxicity Case study 2
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- 4. Contents • Definition • Indication •Basic concepts • Why TDM? • Provision of TDM • Drugs which require monitoring • Issues with TDM • Summary 4
- 5. Definition Drug monitoring Process ofstudying effects of a chemical substance administered to an individual Therapeutic Drug monitoring: Process used to measure blood drug levels so that the most effective dosage is maintained and toxicity prevented 5
- 6. Introduction • Measurement ofplasma concentration involving analysis, assessment, and evaluation of circulating concentrations of drugs in serum, plasma, or whole blood • Clinical laboratory measurement with appropriate medical interpretation • Individualize therapeutic regimens for optimal patient benefit 6
- 7. Basic Concepts to TDM Pharmacokinetics Pharmacodynamics Mechanism ofaction Drug Half life Therapeutic range 7
- 8. Pharmacokinetics What body does toa drug? Mathematica description of physiological disposition of xenobiotics or endogenous chemicals Indicated by Absorption Distribution Metabolism Excretion 8
- 9. Pharmacokinetics • All ofthese are dependent on: • Disease state • Distribution • Co-medication • Age • Sex • Amount of drug absorbed relative to quantity given is referred to as its bioavailability 9
- 10. Pharmacokinetics- Absorption • Most directroute of administering a drug is intravenous delivery • Frequently delivered via oral administration • Pass from gastrointestinal tract into vascular system • Compound must dissociate from its dosing formulation into digestive fluids 10
- 11. Pharmacokinetics-Drug Distribution 11 •Spreads throughout the systemic circulation and into various tissues • Distribution of a drug to a particular site in body depends on numerous factor • Molecular size, • Degree of ionization, • Lipid solubility, • Extent of protein binding • Body composition
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- 13. Therapeutic Range/Window Therapeutic range/therapeutic window is concentration range of drug in plasma where drug has been shown to be efficacious without causing toxic effects in most people 13
- 14. Drug Metabolism • Biotransformationof a compound, whether endogenous or exogenous • Many drug metabolites are active (must be considered) • Metabolic enzymes are expressed body, with largest concentrations in oLiver oGastrointestinal tract oKidneys • Most drugs undergo first pass metabolism • Biochemical pathway responsible for metabolism: Hepatic mixed function oxidase (MFO) system 14
- 15. Drug Elimination • Plasmafree fraction of a parent drug or its metabolites is subject to glomerular filtration, renal secretion, or both • If there is no reabsorption, elimination rate directly relates to GFR • Drugs are eliminated through hepatic metabolism, renal filtration, or a combination of both • Most often occur as a first-order process indicating an exponential rate of loss 15
- 16. Protein Binding • Mostdrugs bind to Proteins in plasma (e.g. bilirubin) • Acidic drug bind to albumin while basic bind to glycoproteins • Proportion: 0%-100% • Effects of changes of protein binding esp. during interpretation • Free fraction of a drug change within an individual over time e.g. pregnancy or withdrawal of drugs • Highly abnormal binding proteins concentration in plasma • Pathological states 16
- 17. Main Pharmacokinetic Parameters •Bioavailability • Volume of distribution and distribution phases. • Clearance • Half-life • Protein binding of drug 17
- 18. Pharmacodynamics • Action ofdrug on body • Optimum dosage can be arrived at by commencing treatment with a standard dose • Modifying this as necessary in light of the observer response • Effect also depends on drugs competing for same receptor • Genetic conditions/ Tolerance status for drug 18
- 19. Factors influencing pharmacokinetics andDynamics • Correlation between plasma concentration and pharmacological effect provides the rationale for the use of concentration measurement in therapeutic drug monitoring 19
- 20. Pharmacodynamic monitoring • Studyof biological effect of a drug at target site • Mostly applied to area of immunosuppressive therapy and cancer therapy • Eg: Effects of cyclosporin and tacrolimus assessed by direct measurement of calcineurin phosphatase activity • Disadvantage: Assays involved are often complex and time consuming 20
- 21. Role of Biomarkers •Biochemical measurement used to determine efficacy, extent of toxicity or individual pharmacodynamics • Marker of toxicity more then pharmacodynamics • Eg: Red cell 6-thioguanine nucleotide concentrations • Integrate biomarker monitoring~ Define therapeutic ranges • Eg: 21
- 22. Pharmacogenetics • Study ofgenetic influences on drug metabolism and application of drugs to enhance safety and/or efficacy • Pharmacogenetic polymorphism is defined as existence in a population of 2 or more alleles at same locus resulting in phenotypes in respect to effect of drug • Administration of test dose and integrating information • Eg: CYP3A4 isoforms • Clinical application • Anticoagulation (Warfarin-CYP2CA) • Oncology/immunosuppression (DPD gene mutations) • Psychiatry (COMT genotying) • Epilepsy etc. 22
- 23. Why therapeutic Drug monitoring? Analysis, assessment, and evaluationof circulating concentrations of drugs Certain drugs have a narrow therapeutic range Not all patients have the same response at similar doses Effective and safe drug therapy in individual patient using serum drug concentration 23
- 24. Criteria for clinicallyuseful TDM • Absence of good clinical marker of drug effect • Poor correlation between dose and clinical effect • Good correlation between plasma drug concentration and clinical effect • Narrow concentration interval between therapeutic and toxic effects 24
- 25. Criteria for effectivedrug monitoring 25 • Appropriate clinical question • Accurate patient information • Appropriate sample • Accurate analysis • Relevant clinical interpretation • Effective action taken
- 26. Appropriate clinical question •Effective therapy • Dosage sufficient • Avoiding toxicity • Steady state concentration • Pharmacokinetic interactions 26
- 27. Accurate patient information • Specificforms to be designed for good TDM 27
- 28. Appropriate sample • Mostpreferred: Blood sample • Serum Vs. Plasma • Depending on drug (Cyclosporin concentration in RBC) • Avoid hemolysis • Protein bound Vs. Free bound • Urine, Saliva etc. • Timing: Need a baseline and drug dependent 28
- 29. Specimen for TDMother blood • Urine: Benzodiazepines • Sweat: Cocaine & Heroin • Saliva: Marijuana, Cocaine, Alcohol • Breath: Alcohol 29
- 30. Saliva, Upcoming TDMSpecimen • Non-invasive • Concentration of a drug in saliva is proportional to the concentration of unbound drug in plasma • Easier in children and neonates • Limitations: • Discrepancies in plasma/salivary ratios • Salivary flow may be reduced in patients taking anti cholinergic drugs • High interferences 30
- 31. TDM drugs todone in saliva • Phenytoin • Carbamazepine • Primidone • Ethosuximide • Phenobarbital • Lamotrigine • Levetiracetam • Oxcarbazepine • Tacrolimus • Cyclosporin • Digoxin • Lithium • TCA inhibitors 31
- 32. Accurate Analysis Purpose required •On-site analysis in clinics • Urgent analysis • Batch analysis, single drug • Batch analysis, Multi-drug • Single analysis with metabolite patterns Most appropriate method • Point of case immunoassay • Optical immunoassays • Optical immunoassays, HPLC, Gas Chromatography, Mass Spectrometry (MS) • HPLC, Gas chromatography (GS) • HPLC, MS or LC/MS 32
- 33. Current techniques toassess TDM • HPLC: High Pressure Liquid Chromatography is a common analytical method used to measure therapeutic drug levels. Eg: Bupropion • GC/MS and LC/MS: Gas-liquid chromatography is a separation method using very high temperatures to cause sample vaporization. molecules separated on the basis of molecular weight therefore establishes a “fingerprint” for identification • RIA: Radioimmunoassay not commonly used any longer due to waste disposal issues • EIA or enzyme immunoassay: Most of drug testing today is performed using homogeneous EIA techniques in a single step. Eg: Digitoxin • Chemiluminescence: This is a chemical reaction that emits energy in the form of light. Most common is enzyme-amplified. Eg: Phenobarbital, Valproic acid 33
- 34. Newer techniques toassess TDM • PETINIA: An immunoturbidimetric method that is used today for TDM testing is PETINIA or Particle Enhanced Turbidimetric Inhibition Immunoassay. This method uses the creation of light scattering particles to measure drug levels • EMIT (Enzyme Multiplied Immunoassay Technique): competition for target analyte antibody binding sites. Eg: Methotrexate • FPIA (Fluorescence Polarization Immunoassay): fluorescent molecule as label • ACMIA: Affinity Chrome-Mediated Immunoassay. ACMIA is a technique to measure drug concentrations in which free and drug-bound antibody enzyme conjugates are separated using magnetic (chrome) particles • CEDIA: Cloned Enzyme Donor Immunoassay. CEDIA employs a recombinant DNA technology 34
- 35. Relevant clinical interpretation •Target ranges to be set • Therapeutic ranges to be set to patient response and not to be inflexible • Therapeutic decisions not to solely rely on serum drug concentrations • Treat Patient, not drug concentration 35
- 36. Effective action taken •Patient symptomology • Drug concentration based on therapeutic window and response • Adverse effects • Achievement of steady state concentration • Drug taken time to be known 36
- 37. Drugs being monitored • Lithium •Phenytoin • Tacrolimus • Digoxin • Aminoglycosides • Theophylline • Methotrexate • Cyclosporin 37
- 38. Lithium This Photo byUnknown Author is licensed under CC BY-SA • Treatment of Bi-polar disorder • Mechanism of action: unknown • Half life: 20-40 hours depending on treatment duration • Narrow therapeutic window; Highly nephrotoxic • Dosage: Slow release preparations~ 12hourly • Elimination: Kidneys • Effective concentrations: ~1.2mmol/L (acute mania) • Method of estimation: Fluorimetry and spectrophotometry, ISE 38
- 39. Lithium This Photo byUnknown Author is licensed under CC BY-SA Plasma concentration response relationship • ˃ 0.4 mmol/L: Little therapeutic effect • 0.4 to 1 mmol/L: Optimum range for prophylaxis of mania • 0.8 to 1.2 mmol/L: Optimum range for acute mania • 1.2 to 1.5 mmol/L: Causes possible renal impairment • 1.5 to 3 mmol/L: Renal impairment, weakness, drowsiness, thirst and diarrhoea • 3 to 5 mmol/L: Confusion, spasticity, convulsions, coma and death 39
- 40. Lithium This Photo byUnknown Author is licensed under CC BY-SA • Problems faced with estimation being done here • No history of patient • Sample type unknown • No monitoring being reported • Lack of involvement and participation 40
- 41. Phenytoin • Antiepileptic Drug •Mechanism of action: voltage-dependent block of voltage gated sodium channels • Long half life • Elimination: Kidneys • Effective concentrations: 5-20mg/L (20-80 µmol/L) • Timing: from time of administration to 6-7 days • Method of estimation: HPLC This Photo by Unknown Author is licensed under CC BY-SA 41
- 42. Phenytoin • Narrow therapeuticwindow • Highly protein-bound; drug-drug interactions, drug- disease interactions • Non-linear pharmacokinetics even within the therapeutic range Approximately 90% of phenytoin is bound to albumin and must be corrected according to albumin levels: This Photo by Unknown Author is licensed under CC BY-SA 42
- 43. Phenytoin • When takenin doses >20mg/L Neurotoxicity (Concentration dependent):Far gaze nystagmus Gastrointestinal: Nausea, vomiting, Anorexia • Doses >30mg/L: 45º lateral gaze nystagmus and ataxia • Doses >40mg/L: Decreased mentation • Doses >100mg/L: Death This Photo by Unknown Author is licensed under CC BY-SA 43
- 44. Tacrolimus • Immunosuppressants- Calcineurinphosphastase inhibitor • Prevent graft rejection • Metabolism: CYP3A in liver • EDTA whole blood preferred • Not nephrotoxic but causes vascular renal constriction • Monitoring very important in hepatic dysfunction • Preferred to used in combined therapy • Target concentrations: 5-15μg/L • Methods of estimation: Immunoassays or LC-MS preferred 44 This Photo by Unknown Author is licensed under CC BY-SA
- 45. Digoxin • Cardiac Glycosides •Mechanism of action: Inhibition of Na+, K+ ATPase pump • Long term patients: production of additional pump • Long half-life (20-60 hours) • Dose: Once daily • Elimination: Kidneys • Effective plasma concentration : 0.5-2.0 μg/L (0.6-2.6 nmol/L) • Heart failure: 0.5-1.0 μg/L (0.6-1.3 nmol/L) • Timing of blood sampling: 6hour post dose • Method of estimation: liquid chromatography-tandem mass spectrometry (LC/MS) This Photo by Unknown Author is licensed under CC BY-SA 45
- 46. Digoxin • Plasma concentration–response relationship • 0.5µg/L: No therapeutic effect • 0.7 µg/L: some ↑ in force of contraction of heart • 0.8- 2 µg/L: Optimum therapeutic range • 2 -2.5 µg/L: ↑ risk of toxicity although tolerated in some patients • ˃ 2.5 µcg/L: Gastrointestinal, cardiovascular and CNS toxicity including death • Rule out Digoxin like interfering substances (DLS) This Photo by Unknown Author is licensed under CC BY-SA 46
- 47. Aminoglycosides • Amikacin, Gentamycin,Tobramycin • Mechanism of action: bind to receptors on the 30S subunit of bacterial ribosomes inducing misreading of genetic code • Dose: once a day • Elimination: Kidneys • Method of Estimation: X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) • Exhibit significant systemic toxicity • Nephrotoxicity (Reversible): cause a viscous cycle • Ototoxicity: Mild-reversible, but if left untreated, Irreversible This Photo by Unknown Author is licensed under CC BY-SA 47
- 48. Theophylline • Bronchodilator • Half-life:3-13 hours; Sustained release-12-24 hour intervals • Narrow therapeutic range and wide pharmacokinetic variability • Elimination: Liver vis cytochrome p450 • Concentration: Adults-10-20mg/L (55-110 µmol/L) Neonates 5-15mg/L (25-80 µmol/L) • Caffeine replacing Theophylline in treatment of neonatal apnoea • Method of estimation: Gas liquid chromatography, HPLC, radioimmunoassay and enzyme immunoassay (EIA) This Photo by Unknown Author is licensed under CC BY-SA 48
- 49. Theophylline • PK problems- Bioavailability varies widely between preparations. • 90% eliminated by the liver & 10% unchanged in the urine • Dose to be calculated in presence of impaired hepatocellular function • Toxicity - manifest as tachy-arrythmias, vomiting & convulsions • Mild: Nausea, Headache, Jitteriness • Serious: Tremor, agitation, insomnia, diarrhoea, palpitations, seizures, cardiac arrythmias • TDM of great assistance in patients receiving intravenous therapy of theophylline This Photo by Unknown Author is licensed under CC BY-SA 49
- 50. Methotrexate • Chemotherapy/ Immunosuppressant •Mechanism of action: Inhibitor of folic acid metabolism • Half life: 6-12hours • Used in high dose • Rationale: Short exposure period, kill rapid dividing cell sparing slow normal growing cells • In case of longer exposure period, leucovorin given • Method of Estimation: HPLC, fluorescence detection, radioimmunoassay, dihydrofolate reductase inhibition assay • Require monitoring of liver function (Hepatotoxic) • N-terminal propeptide of collagen type III (Hepatic fibrosis) This Photo by Unknown Author is licensed under CC BY-SA 50
- 51. Cyclosporin • Immunosuppressant: Graftrejections • Mechanism of action: Inhibit Calcineurin phosphatase and limit T-cell action • Nephrotoxic/ balance risk of undertreatment • not a useful marker for prediction of acute rejection • Half life: 5-18 hours • High lipophilic so EDTA sample preferred • Elimination: Liver via CYP3A (Multiple metabolites) • Method of estimation: Immunoassays and LC/MS This Photo by Unknown Author is licensed under CC BY-SA 51
- 52. Cyclosporin • Cyclosporine bloodlevels determination : 2-3 days then monthly after 3 months • Target of TDM: avoidance of nephrotoxicity and too high immunosuppression This Photo by Unknown Author is licensed under CC BY-SA 52
- 53. Circumstantial drug monitoringbut not practiced • Amiodarone • Anti-retoviral drugs • β-Blockers • Caffeine • Chloramphenicol • Clozapine • Disopyramide • Flecainide • Valproate • Flucytosine • Methadone • Morphine • Mycophenolic acid • Olanzapine • Phenobarbital • Procainamide • Teicoplanin • Tricyclic antidepressants • Vancomycin 53
- 54. Drugs with lowvalue of monitoring • Analgesic: Aspirin • Psychiatrical Drugs: SSRIs • Anti-neoplastics (Except Methotraxate) • Opiate/Opiods: Methadone • Anticonvulsants: Oxacarbazepine Primidone Valproate Newer Anti-convulsant 54
- 55. Drugs with Moderate-Highvalue of Monitoring • Antiarrhythmics: Amiodarone, Diopyramide, Flecainide, Procainamide • Anticonvulsants: Carbamazepine, Ethosuximide, Phenobarbital • Psychiatrical drugs: Haloperidol • Antimicrobial: Vancomycin,Chloramphenicol, Antifungals • Antitubercular drugs • Anti-retroviral • Immunosuppressants: Sirolimus, Tacrolimus, Mycophenolic acid • Opiate/Opioids: Morphine 55
- 56. Provision of therapeutic drug Monitoring Staff Turn aroundtime Point of case testing Reporting Units Quality assurance Continuing education 56
- 57. Challenges in TherapeuticDrug Monitoring • Quality drug assay should be performed within a time frame that is clinically useful • Biological sample is collected to provide a clinically meaningful measurement • Properly timed blood specimens • Absorption is variable after oral administration • Factors such as slow absorption can significantly delay peak concentrations • Plasma samples should be drawn at trough • Both the parent drug and the metabolites must be measured • Not possible in routine monitoring • Clinical features that may affect the relationship between concentration and clinical effects • Cost effectiveness and infrastructure 57
- 58. Summary • TDM ismonitoring of plasma concentration of drug for individualization of dose in patients • Mainly indicated for drugs having narrow therapeutic index, or to check compliance and titration of dose • Most common drugs to undergo TDM are anticonvulsants, lithium, digoxin, gentamicin • HPLC, LC/MS are most common techniques used for TDM • There are several issues pertaining to TDM 58
- 59. References • Blameris TL.TherapeuticDrug Monitoring. In: Clinical Chemistry. 8th ed. Philedelphia: Wolters Kluwers; 2018. p. 1508–52 • Snozek CLH, Mcmillin GA. Therapeutic Drug Monitoring. In: Teitz's textbook of clinical chemistry and molecular diagnosis. 7th ed. Missouri: Elseiver's; 2015. p. 562–84 • Marshal WJ. Therapeutic drug monitoring and chemical aspects of toxicology. In: Marshal's textbook of Clinical Chemistry. 7th ed. British Library:Elseiver’s ; 2012 • Hallworth M. Therapeutic drug monitoring. In: Marshal’s textbook of Medical Biochemistry. 3rd ed. British Library:Elseiver’s 2015. 767-86 59
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