How to set up a TDM unit dr. Shakeeb Dhorajiwala
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A brief presentation about the abovementioned title, it covers historical aspects, about the process of therapeutic drug monitoring, its indications, criteria, team involved and so on and so forth.
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How to set up a TDM unit dr. Shakeeb Dhorajiwala
- 1. How to set up a TDM unit Dr. Shakeeb Dhorajiwala DM resident- 1st year Department of Clinical Pharmacology
- 3. Historical aspect 1960: development of TDM principles 1970: automation of lab methods 1980: widespread expansion 28-01-2021 1. Patsalos PN et. al. Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia, 49(7):1239–1276, 2008 3 World: Buchthal & Svensmark1 TDM in India: mid and late1980 Earlier effective dose establishment- Trial & error method
- 4. 28-01-2021 4
- 5. Clinical case (1/2) • An elderly male Mr. XYZ was apparently alright 2 months back when he experienced doubling of vision at his work place which compelled him to return home. He felt dizzy and developed speech difficulty, gait disturbance (ataxic gait) subsequently. The symptoms were severe to start with and remained static. Gait disturbance has debilitated the patient to the extent that he is now wheel-chair bound. • Past h/o: i) neuro-surgery was done 2 years back and since then he’s put on phenytoin 100 mg tds till now. • ii) B/l THR 6 months back • No h/o BA, DM, HTN, TB 28-01-2021 5
- 6. Case (2/2) • Personal h/o: sleep, appetite, bladder: unaffected, chronically constipated, chronic alcoholic and tobacco chewer but now abstaining. • Drug h/o: i) tab. Eptoin 100 mg tds x 2 years • ii) tab. Diclogem sos • Provisional diagnosis: 28-01-2021 6
- 7. Therapeutic Drug Monitoring (TDM) Defn2: clinical practice involving: • -Assays & clinical interpretation of drugs and active metabolites in biological fluid • -Optimize therapeutic effect • -Minimize ADR (adverse drug reaction) Role of TDM: • Decrease Pk/Pd variability • Individualization of therapy 28-01-2021 2. Maiti R. Post-graduate topics in Pharmacology.Paras Medical books<, ed.3, Hyderabad: 2020 https://www.google.co.in/search?q=therapeutic+drug+monitoring+graph&tbm=isch&ved=2ahUKEwiLt6Ohz4vuAhWzxHMBHR4hBZMQ2- 7
- 8. Pre-requisites for TDM 1. Availability of analytical methods Immunoassays Chromatography Gas Liquid 2. Good correlation plasma levels and effect 28-01-2021 8
- 9. Indications for TDM 1. Narrow TI 2. compliance: to identify Non-responders (drug conc.<drug dose) Non-compliant (drug conc.<<drug dose) Fast- metabolizers 3. Therapeutic effect difficult to monitor 4. High Pk variability 28-01-2021 9
- 10. Drug examples Antiepileptics e.g. Phenytoin, Valproic acid Anti-arrhythmics e.g. Digoxin, Lignocaine Antibiotics e.g. Gentamycin, amikacin Anti-neoplastic e.g. Methotrexate Anti-mania e.g. Lithium Bronchodilators e.g. Theophylline Immunosuppress ants: Cyclosporine 28-01-2021 10
- 11. Ideal Method Distinguish between unchanged drug and metabolite Sensitive Specific- Unaffected by other drugs Reproducible results Short turn-around time 28-01-2021 12
- 12. Sample collection Most drugs: serum/ plasma Cyclosporin A: whole blood Infants: capillary blood 28-01-2021 13
- 13. Can TDM be done arbitrarily? At steady state conc.- reflects levels at receptor site • Loading dose to expedite process e.g. digoxin (t1/2: 36 h) In case of toxicity: ASAP • e.g. Salicylates, lithium For short-acting drugs: both trough and peak levels large difference • e.g. gentamicin (P – 30 mins and T-3 hrs) Long-acting trough/peak small difference • e.g. phenobarbitone, amiodarone (t1/2: 60 d) Errors in timing errors in interpretation of the results3 28-01-2021 3. Kang JS, Lee MH. Overview of Therapeutic Drug Monitoring. Korean J Int Med. 2009; 24(1): 1-10 14
- 14. Reporting Format Specify technique used Conc. expressed in mass/molar units State conc. range of drug Clinically co-relatable • e.g. therapeutic range of digoxin is lower in hypokalaemia 28-01-2021 15
- 15. Functions of TDM centre[2] Selection of dosage regimen Evaluate pt’s response Assays of drug conc. Pk evaluation of drug Readjust dosage regimen Formula for adjusted dose: New dose= Previous dose x Css desired Css measured Monitor sr. conc. 28-01-2021 16
- 16. Is TDM really useful? Useful Narrow TI drugs Poorly defined clinical endpoints Drugs with saturable kinetics major organ failure ADR prevention Determine drug regimen Compliance testing Unnecessary 28-01-2021 17 Wide TI • e.g. CCBs, beta blockers Clinical outcome unrelated to dose/ plasma conc. Pharmacological effect- not quantifiable
- 17. TDM Process (1/2) TDM team- Multi- disciplinary • Clinical pharmacologist • Analytical scientist • Clinical pharmacist Our role as clinical pharmacologist: • To advise (v) about: • Dose adjustment using nomograms • Non-responsiveness • Compliance • Use AEDs in pregnancy • Identify and manage ADRs 28-01-2021 18
- 18. TDM Process- 7 steps4 (2/2) Step VII: Therapeutic management Step VI: Clinical interpretation Step V: Results Step IV: Lab measurement Step III: The request Step II: Sampling Step I: Decision to request 28-01-2021 4. Basalingappa S, Sharma A, Amarnath S. Basic Concepts of Therapeutic Drug Monitoring. International Journal of Current Pharmaceutical Review and Research 2014-15, 5(4), 70-75 19
- 19. Nomograms (1/2) Defn: Dose charts used to determine dosage regimen in patients on drugs following non-linear kinetics based on: • Pt’s demography • Pk of drugs • Drug plasma levels • Creatinine clearance Quick dosage regimen adjustment according to: • age • weight • physiological states 28-01-2021 20
- 20. Nomograms (2/2) 28-01-2021 https://s.docworkspace.com/d/ALDRHA6fprJbwY61kuedFA 21 Frequently used in place of pk calculations Designed for a particular drug and named after scientist designing it. Eg. i) Rambeck nomogram for phenytoin ii) Siersback-Nielson nomogram: estimate creatinine clearance based on: Age Weight Sr. creatinine
- 21. Common Methods (1/5) Spectrophotometry Thin layer chromatography HPLC -Immunoassays • Radio- • Enzyme- 28-01-2021 22
- 26. Enzyme Linked Immuno-sorbent Assay(5b/5) 28-01-2021 27
- 27. Budget: A Rough Estimate Chromaster HPLC – nearly 4 million INR AB SCIEX API 2000 QTRAP LCMS MS System- 3.3 lakh INR* UFLC shimadzu- 3.3 million INR* Area required : 300 sq. ft- 9 million INR Other Criteria: • Temp criteria: Requires cool ambience • Technician • Refrigerators for sample storage • Waste disposal cost Rough estimate: 20 million INR(set-up cost) + annual maintenance charges (3 million INR) 28-01-2021 *https://www.google.co.in/search?sxsrf=ALeKk01Xiz5- GwKsv9xHkbasNlrPubMmg:1611509424659&q=AB+SCIEX+API+2000+QTRAP+LC+MS+MS+System+cost&spell=1&sa=X&ved=2ahUKEwi89ru2jLXuAhUegdgFHc64DtQQBSgAegQIAxA1&biw=1 366&bih=663 28
- 28. Pros of Setting up TDM Facility Determinant of dose of formulation5 • e.g. phenytoin 30 mg Improvise standard dose recommendation • e.g. standard paediatric dose of phenytoin (10–15 mg kg−1) was found to yield suboptimal plasma levels6 Clinical malpractice viz prescribing irrational and dangerous combinations can picked up • e.g. Ca2+ tabs+phenytoin, proconvulsant anti-bacterials to epileptics 28-01-2021 5. Kshirsagar NA, Joshi MV, Shah PU, Dalvi SS. Need for25 mg tablets of phenytoin. J Assoc Phys Ind 1991; 39: 395–396 6. Rane CT, Gogtay NJ, Kadam VS, Powar HS, Dalvi SS, Kshirsagar NA. Subtherapeutic levels of phenytoin with standard doses in infants: need to review dosage schedule. Br J Clin Pharmacol 1999; 48: 465–466 https://www.google.co.in/search?q=phenytoin+formulations&sxsrf=ALeKk02fAo2ltz4JtxrFrAbwH9taXRBBJA:1610686026422&source=lnms&tbm=isch&sa=X&ved=2ahUKEwjr- MuDkZ3uAhVPzzgGHfi7ArAQ_AUoAXoECAIQAw&biw=1517&bih=736#imgrc=cRla8zNznFCFyM 29
- 29. Limitations[2] Limited no. of drugs Doubtful scientific accuracy of assays • Active metabolites carbamazepine-10,11-epoxide therapeutic response not routinely measured Variability in reporting • ideal laboratory turnaround time<dosing interval • due to cost, tested in batches lengthen turnaround time Limited access 28-01-2021 Maiti R. Post-graduate topics in Pharmacology. Paras Medical books, ed.3, Hyderabad: 2020 30
- 30. What future holds for TDM (1/2)[7] potential to improve patient outcomes and drastically reduce healthcare costs sensor-based approaches not yet fully explored • E.g. i) LC with sensors • ii) UPLC-MS: simultaneous quantification of multiple anti-microbials from different samples Orbitrap technology: high mass resolution measurements over wider concentration ranges 28-01-2021 7. Ates HC et al. On-Site Therapeutic Drug Monitoring. Trends in Biotechnology, November 2020, Vol. 38, No. 11 31
- 31. Future of TDM (2/2) Biosensor: analytical device converts biological response quantifiable signal via molecular recognition using bioreceptors Microneedles 28-01-2021 7. Ates HC et al. On-Site Therapeutic Drug Monitoring. Trends in Biotechnology, November 2020, Vol. 38, No. 11 32
- 32. Challenges encountered in developing countries Alternative systems of medicine Paucity of quality control (QC) measures- lab accreditation/ external QC Financial : Set-up pays to overseas QC programmes 28-01-2021 33
- 33. Conclusion A useful adjunct tool for clinicians provides greater insight into factors determining patients’ response to drug therapy helps tailor drug dose and regimen as per clinical condition of patient leads to drug optimization TDM cannot compensate for error in: •diagnosis •poor choice of drugs •errors in dispensing medication •non compliance However, when used in combination with good clinical observation, it can lead to optimal drug therapy with minimal side effects. 28-01-2021 34
- 34. Acknowledgements Dr. Nithya Gogtay Dr. Bhaskar Krishnamurthy Hina Khimsuriya Swati More 28-01-2021 35
- 35. 28-01-2021 36
Editor's Notes
- Trough levels: drug in elimination phase- least variable point in the dosing interval is just before the next dose is due digoxin monitoring should not be performed within six hours of a dose, because it will still be undergoing distribution and so plasma concentrations will be erroneously high
- Better alternative: FPIA (fluorescence polarization) and EMIT (enzyme mediated)– expensive Chromaster
- Proconvulsant anti-bacterials: mefloquine, (epileptogenic) ciprofloxacin- enzyme inhibition
- Intrinsic limitation of HPLC: high turn around time, cost
- LC with sensors: low cost, short turn-around time
- Kem uses overseas QC programmes- financial drawback