Bez nadpisu

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Therapeutic drug monitoring - TDM
Martínková J., 2005
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TDM
is measurement of drug concentrations in the
blood or plasma that facilitates adjustment of
dosage to produce a desired response
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• 2 ways of measuring responses
• to individualize the dosage that is needed
• for the patient
• pharmacodynamic measures
• pharmacokinetic measures

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• pharmacodynamic measures of response
• include clinical or laboratory measurements such
  arterial blood pressure in patients with
  hypertension,
• or INR in patients treated with oral
  anticoagulants

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• pharmacokinetic measures include
• measurement of drug concentrations
• in the blood or plasma (serum) -TDM
• that facilitates adjustement of dosage to
  
• produce a desired response when

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• there is a direct relationship between the drug
• (or active metabolite) concentrations in plasma
  
• or other
  accessible fluids
• and pharmacological or toxic effects, i.e.
• a therapeutic window has been established
• a therapeutic window is narrow
• aminoglycoside antibiotics,
• antiepileptics, MTX,
• lithium, digoxin, theophylline,
• cyclosporin A,
  antiarrhythmics

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• clinical end point is quantal (a grand mal
  seizures),
• and there is no satisfactory intermediate
  endpoint
• which is a continuous variable
• (such as blood pressure in antihypertensive
  therapy)
• antiepileptics

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• interindividual variability in plasma
  concentrations
• from the same dose is large and unpredictable
• (due to zero-order kinetics or polymorphism in
  metabolism)
• phenytoin with zero-order kinetics

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Relationship between daily dose of phenytoin and
resulting steady-state serum level in five
patients on several different doses of drug.
Serum phenytoin (?mol/l)
Phenytoin dose (mg/day)
(from A. Richens and A. Dunlop, Lancet ii247,
1975)
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• noncompliance with therapy
• in antiepileptics, cytostatics,

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• insufficiency
• or impairment
• of function of eliminating organs

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POSTNATAL DEVELOPMENT OF SPECIFIC HEPATIC AND
RENAL FUNCTION (from Gladtke 1979).
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Plazma concentrations of gentamicin in 6 immature
neonates with the low body weight on day 4 of
the postnatal life.
Plasma concentrations in log
h after i.v. inf.
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impairment of renal function
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• the dosage of the antagonist adjusted according
  to plasma concentrations of the agonist
• HDMTX and leucovorin

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I.v. infusion of HDMTX
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TDM and evaluation of pharmacotherapy quality
of life benefit of pharmacotherapy
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quality of life
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Demonstration of effective palliative treatment
with respect to quality of life.
curative treatment
)
effective

(

palliation
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f
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l

f
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natural course
y
t
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l
of disease
a
u
q
overtreatment
start of
time
(from Martz 1979)
treatment
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benefit of pharmacotherapy
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Conceptural model of biomarkers and surrogate
endpoints
Clinical endopoints (for efficacy)
Surrogate endpoint (for efficacy)
Evaluate patient benefit
Biomarkers (for efficacy)
Establish linkage of biomarker with Clinical
Endpoint
Conduct provisional integrated evaluation
Global intervention assessment
Surrogate endpoint (for toxicity)
Evaluate patient risk
Biomarkers (for toxicity)
Clinical endopoints (for toxicity)