Therapeutic Drug Monitoring (TDM) - Adverse Drug Reactions (ADR)

Therapeutic Drug Monitoring (TDM)

·        Used to titrate the „usual dose‟ to an individual

·        Monitoring Cp (plasma concentration) assumes no receptor tolerance, accurate determination of the biological effect and accurate determination of the plasma level

·        Indications for TDM:

o  Availability of an accurate, precise, specific and inexpensive test 

o  Long term drug therapy where clinical definition of efficacy is difficult (ie won‟t know if it‟s working by observing the patient)

o  Dose related adverse effects for which there are few clinical warning signs/symptoms

o  Substantial inter- and intra-individual variability in pharmacokinetics

o  Multiple drug interactions

o  Drugs with a narrow therapeutic index: phenytoin, digoxin, theophylline, lithium, gentamicin

o  Suspected non-compliance

o  Unexpected lack of response or signs of toxicity

o  But TDM should not replace clinical judgement

·        Therapeutic index: top and bottom are blurred margins/probabilities

·        Blood sampling for TDM:

o  Often done badly

o  When absorption and distribution phases are complete

o  Steady state plasma conc. (5 half lives after started) 

o  Sample just prior to next dose when dosing 2 * T½. Sample 3 – 5 hours post dose for slow release formulations

·        Examples:

o  Phenytoin: Has dose dependent kinetics. Dose changes should not exceed 20% of total daily dose. Metabolised by CYP450 with many interactions. CNS toxicity correlates well with blood concentrations (nystagmus, ataxia, atypical convulsions). Therapeutic concentrations controversial (based on studies in severe epileptics). Reduce in hypoalbuminaemia (Same dose ® ¯binding available ® ­free conc.) Frequent error: sample in trough of plasma concentration – then appears to be below TI

o  Lithium: narrow TI for maintenance – 0.4 – 0.8 mmol/L. Minor symptoms (eg tremour, nausea) don‟t predict serious toxicity. Renal clearance ¯ by diuretics, theophylline, caffeine, dehydration, low sodium diet. TDM mandatory when side effect, relapse, serious illness, dose adjustment. 3 monthly monitoring for Li levels, electrolytes, thyroid fn

o  Theophylline (bronchodilator): Dose related toxicity: seizures, arrhythmias. Elimination reduced with erythromycin, ciprofloxacin, cimetidine, smoking cessation, hypothyroidism (all ¯P450)

o  Digoxin: variable bioavailability (eg with cholesterol binding agents, antacids) and large variability of clearance (¯with NSAIDs, spironolactone, verapamil, amiodarone). ­Effect in hypokalaemia, hypothyroidism, elderly. ¯Effect in hyperthyroidism and `pregnancy. Sample 8 – 12 hours post dose (long distribution phase).

o  Aminoglycosides: Dose predictions performed by pharmacy