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 ® Âfree 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). ÂEffect 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
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