Therapeutic Drug Monitoring (TDM) PDF

Therapeutic Drug Monitoring (TDM) Dr Patricia Vella Bonanno 1  Monitoring of drug therapy Why monitor drug treatment in clinical practice? - to see whether there is a therapeutic response (efficacy of treatment) - to assess...

Therapeutic Drug Monitoring (TDM) Dr Patricia Vella Bonanno 1  Monitoring of drug therapy Why monitor drug treatment in clinical practice? - to see whether there is a therapeutic response (efficacy of treatment) - to assess drug toxicity (safety) - to assess adherence to treatment (patient taking treatment as prescribed) Questions when monitoring drug treatment - Is there a directly measurable therapeutic response? - Is there a directly measurable response that, although itself is not the end-point, may be related to the end-point? - Is the amount of drug in the body appropriate? Monitoring the effects of drugs is an essential part of therapy. Where possible look for the therapeutic or toxic effects of drugs2  Measuring drug plasma concentrations Drug plasma concentrations are measured for few drugs: - Aminoglycoside antibiotics – gentamicin, tobramycin, netilmicin, amikacin (only administered parentally) - Anticonvulsants: phenytoin, carbamazepine, phenytoin - Digoxin and digitoxin (cardiac glycosides) - Lithium (prophylaxis and treatment of mania) - Theophylline (xanthine used as a bronchodilator) - Cyclosporin (calcineurin inhibitor, immunosuppressant) - Tacrolimus and sirolimus (immunosuppressants) The same dose of a medicine will result in different plasma concentrations if given to different patients People vary considerably in the extent to which they absorb, distribute, metabolise and excrete medicines 3  Factors that modify drug plasma concentrations for a given dose Formulation e.g. Digoxin is better absorbed from the liquid formulation than from the tablets; phenytoin toxicity reported after chemical change in excipient in phenytoin capsules Genetic variation e.g. Fast and slow acetylators Environmental variation Smoking increases the rate of clearance of theophylline Effects of disease Renal impairment decreases elimination of gentamicin & lithium Hepatic disease decreases metabolism of phenytoin Drug interactions 4  Plasma concentration vs. time Plasma concentration of drug MSC – Risk of toxicity increases maximum safe conc. Therapeutic window Effect likely to be sub-therapeutic MEC – minimum effective conc. Time5  Clinical usefulness of TDM When measuring drug plasma concentrations: - Tailor the dosage to the individual patient - Obtain the maximum therapeutic effect with minimal risk of toxicity Pharmaceutical response of many drugs correlates better with the blood concentration of the drug than with the dose due to inter-patient differences in pharmacokinetic parameters There are often features which are specific to an individual patient and that may alter the patient’s therapeutic range Treat the patient and not the plasma concentrations. It is important to do a clinical assessment of the patient’s response. 6  Factors that modify the effect of the drug for a given drug plasma concentration Drug interactions Aminoglycoside antibiotics + other nephrotoxic drugs Electrolyte balance Hypokalaemia increases muscle sensitivity to effects of digoxin Acid-base balance Acidosis enhances the effect of digoxin Age Increased sensitivity to digoxin in the elderly Bacterial resistance Although plasma concentrations of gentamicin are within therapeutic window, resistant organisms are not affected Plasma protein binding 7 Only unbound drug has therapeutic effect e.g.hypoalbuminaemia  Criteria which must be satisfied for the plasma concentration of a drug to be useful: 1. Difficulty in interpreting clinical evidence of therapeutic or toxic effects Difficult to measure therapeutic effects of phenytoin, tailor the dose to have the concentration within the therapeutic window. Digoxin toxicity and CHF can present as nausea, anorexia, arrhythmias 2. A good relationship between the plasma concentration of a drug and either its therapeutic or toxic effect High peak concentration of gentamicin is associated with toxic effects 3. A low toxic to therapeutic ratio (narrow therapeutic window) Some drugs (gentamicin, lithium, phenytoin & digoxin) have narrow therapeutic window:high risk of toxicity with increased concentration 4. The drug should not be metabolised into active metabolites 8 If metabolite is also active, both drug and metabolite must be measured  Circumstances in which plasma drug concentration measurement may be useful: Measuring adherence Low concentrations reflect poor adherence (provided dose is adequate) Individualising therapy Tailor the dosage to the individual Diagnosing under treatment If observing poor clinical response or for drugs used as prophylaxis Avoiding toxicity Measurement during early stages of treatment avoids high concentrations Diagnosing toxicity Important where drug toxicity may mimic effects of the underlying disease Drug interactions If a potentially interacting drug is added, may need change in dose Stopping treatment 9 e.g. If concentrations of digoxin are below MEC, can stop treatment  How to use plasma concentration measurements properly There is no justification for routine measurements of plasma concentrations without a definite purpose It may be of value when an interacting drug is introduced and when dose adjustment is required 1. Timing of the blood samples Correct timing after dosing, note whether steady state has been reached 2. Types of samples Sample taken in a heparinised tube, or allowed to clot 3. Measurement technique Important that assay is as specific, sensitive and precise as possible 4. Interpretation of results - treatment should be tailored to the patient’s needs - consider concentration and also clinical features etc 10  If the patient’s values vary widely The reason for this deviation should be sought: 1. Patient concurrent drug therapy is checked 2. Patient adherence 3. Drug interactions 4. Medication errors 5. Change in the patient’s clinical status 6. Malabsorption 7. Incorrect assay result 8. Timing of samples 9. Site of sampling 10. Storage of sample (degradation or haemolysis) If no explanation can be discovered for the deviation and all the factors above have been examined, then it is likely that the patient’s data do differ significantly from the population mean data. Any advice on alteration in dosage must be made in view of the patient’s clinical condition and the assumptions and limitations of 11 therapeutic ranges.  Dosing of treatment using population data Population PK describes patient variability through: Fixed effects – population average values of PK parameters. Are a function of patient demographic characteristics, underlying disease and pharmacological considerations. Random effects – quantify residual discrepancies due to variability between patients Data for population parameters are estimated from: - single dose patient pharmacokinetic studies OR - during steady-state conditions following multiple doses samples are taken at known specific times and analysed using linear correlation or non-linear models such as NONMEM Since population parameters are mean values, the patient’s actual parameters will lie within two standard deviations from the mean population value. Dosing can be done through one of these methods: 1. Intuitive dosing based on previous experience (most common) 2. Using data generated from patients taking a single dose, measuring conc. at a fixed time point afterwards and correlating with concentration taken at steady state 12 3. Using nomograms and simple formulae based on population data  Dosing of treatment using Therapeutic Drug Monitoring In TDM patient variability is addressed through: Dose individualisation Interpretation of results of drug concentration - The most widely used method for interpretation of results is through comparing predicted concentrations and measured concentrations using simple kinetic formulae. - Aids and programmes (e.g.calculators and computer software packages) are available to facilitate interpretation. - Whichever software package is used, the user must be sure that the principles of the programme, the pharmacokinetic model used and the associated assumptions and limitations are fully understood. 13  Interpretation of results of TDM The following information about the patient and the drug is obtained: - Patient’s physical details, clinical and biochemical status; - Patient’s drug history (the most recent drug history), concurrent medication, sampling details 1 - Pharmacokinetic information of the drug in question and the population pharmacokinetic data for the drug Based on this information about the patient and population pharmacokinetic data the patient’s individual PK parameters for the drug are estimated: 2 ie. clearance (Cl), volume of distribution (Vd), and the elimination rate constant (k). Based on the information about the patient and the estimated PK parameters for the drug in the specific patient there is an estimation of : - the recommended initial dose for the patient 3 - the plasma concentrations for the drug in the patient at the time that the blood samples are to be taken Treatment of the patient is started using the initial recommended dose Blood samples are taken at the right time 4 Blood samples are sent to the lab to measure the actual plasma concentrations of the drug in the patient The actual patient plasma concentrations measured at the lab are compared to the estimated plasma concentrations The actual PK parameters for the drug in the patient e.g. elimination rate constant and clearance are calculated and 5 compared to the population PK The patient’s treatment is reviewed and treatment is continued at the same dose as per recommended initial dose or changed depending on the patient’s actual drug plasma concentrations and how these compare to the population PK. 6 14  Routes of administration of medicines Gastro-intestinal Skin tract Oral buccal Vascular Topical preparations mouth system s.c. injection i.m. injection Circulatory system stomach i.v. injection (drug or metabolites) Small Vascular Direct Lungs intestine system or Large Hepato- Vascular Aerosols intestine enteric system Gases Rectal rectum rectal preparations Drug or metabolite in tissues and extra cellular fluid Drug in Drug in faeces Kidneys saliva, exhaled air Drug in etc. urine Excretion and elimination Schematic diagram illustrating pathways a medicine may take following 15 administration of a dosage form by different routes  Concentration-time curves single oral dose Absorption Elimination phase phase Medicine Conc. 0 Time Concentration against time curve for a single dose by the oral route 16  Concentration-time curves: 3 different formulations of the same medicine Max safe conc Medicine concentration Therapeutic window Min effective conc Formulation 1 Formulation 2 Formulation 3 Time following administration of a single dose Concentration against time curves for single dose administration for 3 different formulations of the same medicine administered in equal single doses by the same extravascular route 17  Concentration-time curves: oral route, different dosage frequency/intervals Medicine Conc. Therapeutic window oral route daily oral route bd 8 16 24 Time oral route tds Concentration against time curves at steady state for oral route bd, tds, daily 18  Concentration-time curves: intravenous administration different methods of administration Medicine Conc. Therapeutic window i.v. continuous i.v. bolus tds 8 16 24 Time i.v. intermittent infusion tds Concentration against time curves at steady state for i.v. continuous, i.v. 19 bolus tds and i.v. intermittent infusion tds  Concentration-time curves: oral route with and without loading dose Steady state Medicine Conc. Therapeutic window 8 16 24 32 Time -- no loading dose ------ with loading dose Concentration against time curve starting from zero and achieving steady state20 21  Administration of medicines Medicine – active ingredient plus excipients Dosage forms Routes of administration 22 Range of dosage forms for different routes of administration Route of Dosage forms administration Oral Solutions, syrups, elixirs, suspensions, emulsions, gel, powders, granules, capsules, tablets rectal Suppositories, ointments, creams, powders, solutions topical Ointments, creams, pastes, lotions, gels, solutions, topical aerosols parenteral Injections (solutions, suspensions, emulsion forms), implants, irrigation and dialysis solutions lungs Aerosols (solution, suspension, powder, emulsion forms), inhalations, sprays, gases nasal Solutions, inhalations eye Solutions, ointments ear Solutions, suspensions, ointments 23  Therapeutic regimens Activity – toxicity Pharmacokinetics Therapeutic window Liberation Side-effects Absorption Toxicity Distribution Concentration-response Metabolism relationship Excretion DOSAGE REGIMEN Clinical Factors Other factors State of patient: age, weight, Route of condition being treated, administration other disease states Dosage form Tolerance- Management of therapy: dependence multiple drug therapy, Pharmacogenetics – convenience of regimen, idiosyncrasy adherence to medicine Drug interactions Cost 24 25  Liberation and absorption of a medicine from a tablet Increase in effective surface area of medicine exposed to gastrointestinal fluids Intact tablet disintegration Granules deaggregation Primary drug particles Low rate of Moderate rate Relatively rapid rate of drug dissolution of drug drug dissolution dissolution Drug in solution in gastrointestinal fluid Absorption Drug in blood Factors influencing drug absorption from the GIT and bioavailability: physiological, pH, intestinal 26 motility, other medicines, food interaction, solubility of the drug, type of dosage form  Pharmacokinetic and pharmacodynamic considerations for the design of a dosage regimen Pharmacokinetics Pharmacodynamics Dosage Plasma Site of Effects regimen concentration action Plasma drug concentration-time data is used as Effects produced are used as feedback to feedback to modify the dosage regimen for some achieve optimal therapy medicines as indicated 27  Medication regimen factors Indication Ascertain indication for treatment, medicine prescribed appropriate for the indication, compatibility with guidelines Changes in regular treatment Confirm that changes to regular therapy are intentional Dose, frequency and strength Check that the dose, frequency and strength of prescribed medicines are appropriate considering the patient’s age, renal and hepatic function, weight and surface area (where appropriate), co-morbidities, concomitant drug therapy and lifestyle patterns The dosing of the formulation Check that the formulation, the dose and the frequency are appropriate Drug compatibility Evaluate regular and new therapies for any clinically significant interactions, duplications and antagonistic activity Monitoring requirements Check results and ascertain whether any dose adjustments are required 28  Adherence to medicines Adherence is the process by which patients take their medicines as prescribed/dispensed. There are three phases: - initiation, which occurs when the patient takes the first dose of the medicine - Implementation, which is the extent to which a patient’s actual dosing corresponds to the set dosage regimen, from initiation to the last dose - Discontinuation, occurs when the patient stops taking the medicine for whatever reason/s. The management of adherence includes the process of monitoring and supporting patient’s adherence The concept of adherence (which involves the will of the patient) has replaced the previous concept of compliance (which has a connotation of enforcement/patronisation) Summary of Product Characteristics (SPC) 1. Name of medicinal product 2. Qualitative and quantitative composition 3. Pharmaceutical form 4. Clinical Particulars 4.1 Therapeutic Indications 4.2 Posology and Method of Administration 4.3 Contraindications 4.4 Special Warnings and Precautions for Use 4.5 Interactions 4.6 Pregnancy and Lactation 4.7 Effect on Ability to Drive and Use Machines 4.8 Undesirable Effects 4.9 Overdose 5. Pharmacological Properties Electronic Medicines 5.1 Pharmacodynamic properties Compendium 5.2 Pharmacokinetic properties http://medicines.org.uk/emc 5.3 Preclinical safety data 6. Pharmaceutical Particulars Malta Medicines Authority Regulatory Data http://www.medicinesauthority.gov.mt/medicinesdatabase