Factors affecting therapeutic drug monitoring
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Factors affecting therapeutic drug monitoring






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Factors affecting therapeutic drug monitoring Factors affecting therapeutic drug monitoring Presentation Transcript

  • INTRODUCTION Therapeutic drug monitoring (TDM) is generallydefined as the clinical laboratory measurementof a chemical parameter that, with appropriatemedical interpretation, will directly influencedrug prescribing procedures by combiningknowledge ofpharmaceutics, pharmacokinetics, andpharmacodynamics.September 28, 20122
  • CLINICAL USEFULNESS OF TDM1. Maximize efficacy of drug2. Avoiding toxicity3. Identifying therapeutic failure4. Facilitating dose adjustment5. Facilitating therapeutic effectsSeptember 28, 20123
  • Factors Affecting TDM1. Patient demographics2. Patient Compliance3. Individuals capacity toabsorb/distribute/metabolize/excretethe drug4. Genetic factorsSeptember 28, 20124
  • Factors Affecting TDM…5. Concomitant disease, Tropical diseaseand nutritional deficiencies6. Alternative system of medicine7. Ethnic differences and extrapolation ofthe normal rangeSeptember 28, 20125
  • Factors Affecting TDM…8. Alcohol & Tobacco use9. Quality of medication and genericformulation10. Control of drug assay11. Medication or sampling errors12. Laboratory errors13. Cost effectivenessSeptember 28, 20126
  • 1. Patient demographics Age, sex and lean body weight areparticularly important for renally cleareddrugs as knowledge of these allowscalculation of creatinine clearance. Ethnicity may be an importantconsideration for TDM of some hepaticallycleared drugs.September 28, 20127
  • 2. Patient Compliance If the concentration of the drug is lowerthan expected, the possibility of noncompliance should be considered beforea dose increase is recommended.September 28, 20128
  • 3. Individuals capacity toabsorb/distribute/metabolize/excrete the drugAbsorption:The rate of absorption and extent of absorptionare dependent on various factors such as: Drug formulation Manufacturer Route of administration Intra-individual variations Another aspect of absorption isbioavailability. This is the fraction of theadministered dose that reaches the systemiccirculation. Bioavailability is 100% for IV injection.September 28, 20129
  • Distribution:(Vd) = dose/plasma concentrationThe absolute bioavailability of a drug, whenadministered by an extra vascular route, isusually less than one (i.e. F<1). For example if a drug has a half life of fourhours, four hours after the initial dose, 50%of the drug will be removed. Eight hours after the initial dose, half of theremaining drug (25% of total) will beremoved, for a total of 75% having beenremoved at that time, and so on.September 28, 201210
  •  Half-life information is used to determinethe correct drug dose required to attainthe desired therapeutic range.September 28, 201211
  • Metabolism: In addition, drug metabolites can beeither protein bound (inactive) or free(active). The drug dosage will depend on how thedrug metabolizes. Factors that impact drug metabolismincludesgenetics, environment, nutrition, and age.September 28, 201212
  • Excretion: Drug excretion from the body occursthrough the kidneys, or fluids excretedthrough the lungs, GI or skin. Renal dysfunction reduces drugclearance and may contribute to drugaccumulation and increased risk ofadverse drug effects.September 28, 201213
  • Some other causes Age: In general, drugs metabolized moreslowly in foetal, neonatal, and geriatricpopulations Physical properties of the drug(hydrophobicity, pKa, solubility) If the drug is administered in a fed orfasted state Gastric emptying rateSeptember 28, 201214
  •  Interactions with other drugs (e.g.antacids, alcohol, nicotine) Interactions with other foods (e.g.grapefruit juice, pomello, cranberry juice)September 28, 201215
  • Enzyme induction/inhibition by otherdrugs/foods:- Enzyme induction (increase rate ofmetabolism). e.g.Phenytoin, barbiturates, carbamazepine,glutethimide, primidone, rifampicininduces CYP1A2, CYP2C9, CYP2C19 andCYP3A4, , which is involved in a drugsmetabolism may reduce the drugsactivitySeptember 28, 201216
  • Enzyme inhibition (decrease rate ofmetabolism), resulting in ↑ drugactivity, e.g. Protease inhibitors, Nitrogenmustard, Mtx, Cidenafil Citrate Prolonging the action of variousdrugs, includingchloramphenicol, cimetidine, disulfiram(Antabuse), isoniazid, methyldopa, metronidazole, phenylbutazone Grape fruit juice inhibits CYP3A --> highernifedipine concentrationsSeptember 28, 201217
  •  Individual Variation in MetabolicDifferences Phenotypic differences, inter hepaticcirculation, diet, gender.September 28, 201218
  • 4. Genetic factors It plays an as yet poorly defined role intherapeutic drug monitoring, as is thecase of the poor ability of some racialgroups to acetylated drugsSeptember 28, 201219
  • 5. Concomitantdisease, Tropical disease andnutritional deficienciesThis includes diseases highly prevalent indeveloping countries such as Infections, Diarrhoea, Worm infestations, Tuberculosis, Nutritional deficiencies, plus a Higher proportion of patients with diabetesand AIDSSeptember 28, 201220
  •  Nutritional deficiencies are oftensubclinical and escape detection andthey have been shown to affect drugpharmacokinetics.September 28, 201221
  • 6. Alternative system ofmedicineSeptember 28, 201222 India is unique in having atleast three systems ofmedicine coexisting with‘western’ medicine(allopathy);ayurveda, homeopathy andunani. A patient with a history ofgeneralized tonic-clonic (GTC)seizures, well controlled andwith plasma phenytoin levelswithin the therapeuticrange, presented with suddenloss of seizure control.
  •  History revealed that he was taking‘shakhapushpi’ and plasma analysisshowed that his phenytoin level haddropped. Interaction with conventional drugs havebeen documented forliquorice, ginseng, tannicacids, plantain, uzara root, hawthorn andkyushin all of which may be prescribed bypractitioners of the alternative systems.September 28, 201223
  • 7. Ethnic differences The fact that interpopulation variations in drugpharmacokinetics can result in higher or lowerplasma drug concentrations is well known. Mani has reported that the effectiveanticonvulsant dosage may be lower in Indiansthan in EuropeansSeptember 28, 201224
  • 8. Alcohol & Tobacco use Chronic use of alcohol has been shown tocause non-specific hepatic microsomalenzyme induction, resulting in increasedclearance and decreased serumconcentrations of hepatically cleareddrugs such as Phenytoin.September 28, 201225
  •  Cigarette smoking increases the hepaticclearance of theophylline and patientswho have recently stopped smoking mayhave unexpectedly high theophyllineconcentrations.September 28, 201226
  • 9. Quality of medication andgeneric formulation Quality of products (drugcontent, bioavailability) is importantespecially for drugs with a narrow marginof safety which is just those drugs forwhich TDM is relevant. Authors have already reported fromPakistan and Vietnam that quality ofdrugs used may be substandard andneed additional quality control.September 28, 201227
  • 10. Quality control in drugassays For TDM programs, quality control is vitallyimportant and in developing countriesthere are hardly any procedures forlaboratory accreditation or externalquality control.September 28, 201228
  •  In view of the mushrooming of private‘pathobiochem’ laboratories which offera range of pathology and biochemicalinvestigations, the state Food and DrugAdministration’s are proposing laboratoryinspections for standardizing and ensuringquality of results. There are no such proposals for drugassay laboratories.September 28, 201229
  • 11. Medication or samplingerrors In cases where the TDM result isincompatible with drug administrationrecords, the possibility of a medication orsampling error should be considered. For Example, the drug may have beengiven to the wrong patient, or blood mayhave been mistakenly drawn from apatient in a neighbouring bed.September 28, 201230
  • 12. Laboratory errorsSeptember 28, 201231 If a laboratory error issuspected, thelaboratory should becontacted andasked to repeat theassay. Alternatively, a newblood sample can bedrawn and sent to adifferent laboratoryfor assay.
  • 13. Cost effectiveness Rapid and cost-effective measurement ofmost drugs for which TDM is indicated canbe achieved using commercial kits run onautomated analysers using a number ofdifferent methodologies includingfluorescence polarisation immunoassay.September 28, 201232
  • References A Textbook of Clinical Pharmacy Practice (Second Edition)G Parthasarathi, Karin Nyfort-Hansen & Milap C Nahata (Eds.)2012; 331 pp; 978-81-7371-756-7 Therapeutic drug monitoring in a developing country: anoverviewN J Gogtay, N A Kshirsagar, S S Dalvi Br J Clin Pharmacol. 1999November; 48(5): 649–654. doi: 10.1046/j.1365-2125.1999.00088.xPMCID: PMC2014358Web link:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014358/ Therapeutic drug monitoring D.J. Birkett, Professor of ClinicalPharmacology, Flinders University of South Australia, AdelaideWeb link:http://www.australianprescriber.com/magazine/20/1/9/11/ Therapeutic Drug Monitoring (TDM) - An Educational GuideWeb link:http://www.medical.siemens.com/siemens/en_GLOBAL/gg_diag_FBAs/files/products_disease_states/TDM/TDM_Guide_FINAL.pdfSeptember 28, 201233
  • September 28, 201234Thank You