THERAPEUTICS DRUG MONITORING

Valentina Meta Srikartika

+ Jelaskan yang anda ketahui
mengenai TDM
+
INTRODUCTION
!  Respon obat pada masing-masing individu dapat berbeda "
!  Variasi pada fase farmakokinetik
!  Variasi pada fase farmakodinamika

Monitoring terapi obat melalui

respon biologi " variabel yang
dapat diukur dan berhubungan
erat dengan outcome klinik

Contoh:
-  Obat anti HT " monitor efek pada
TD
-  Statin " monitor efek pada serum
kolesterol
-  Antikoagulan oral " monitor efek
pada INR
+
INTRODUCTION
Pada kondisi tertentu tidak terdapat
variabel berkelanjutan yg dapat diukur "
khususnya untuk penyakit dengan kondisi
yg sulit diprediksi dan fluktuatif

Mengukur konsentrasi serum/plasma "

farmakokinetik" untuk adjustment dosis
e.g penderita epilepsi dgn obat
antikonvulsan

THERAPEUTIC DRUG
MONITORING
+
DEFINITION

Therapeutic Drug Monitoring (TDM) in a general

sense is about using serum drug concentration
(SDCs), pharmacokinetics, and pharmacodynamics
to individualized and optimize patient response to drug
therapy
 TDM aims to promote optimum drug treatment by
maintaining serum drug concentration within a
therapeutic range, below which drug-induced toxicity
occurs too often and above the drug is too often ineffective
Reasons for TDM

!  Certain drug have a narrow

theraupetic range

!  In concentration above the

!  Not all patients have the same
upper limit of the range, the
response at similar doses
drug can be toxic

!  In contretation below the lower

limit of the range, the drug can
be innefective
 ASSUMPTIONS

!  TDM based on the principle that for

some drugs there is a close
relationship between serum drug
const / plasma level of drug and
its clinical effect

!  Drug metabolism varies

from patient to patient
ASSUMPTIONS
!  Whena precise therapeutics end point is
difficult to define, monitoring serum drug const
may be considerable therapeutics assitance

!  Routine monitoring is however not advocated

for most drugs

!  Only
clinically meaningful tests should
be performed
+
Criteria for TDM

appropriate analytical test for

!  An
drug and active metabolites must
exist

!  Drug should have a narrow

therapeutic range

!  Patientsnot showing adequate

clinical response to drug despite
being on adequate dose
Criteria for TDM

therapeutic effect can

!  The
not be readily assesed by
the clinical observation
(e.g anticonvulsants, anti
arrythmics, antidepressant,
etc)

!  Largeindividual variability
in steady state plasma
concentration exist at any
given dose, eg phenytion,
doxepine, imipramine, etc
+

Drug Often Monitored Using Serum

Drug Concentration
+
Drug Often Monitored Using Serum
Drug Concentration
+
Indications for TDM

!  Low therapeutic index

!  Poorly defined clinical end point

!  Non compliance
!  Anticonvulsant const in patients having frequent seizures

!  Therapeutics failure
!  Particularly important for prophylactic drugs such lithium
in preventing manic-depressive attacks, phenytoin in
preventing fits after neurosurgery trauma, cyclosporine in
preventing transplant rejection
Indications for TDM

!  Drugs with saturable metabolism

!  E.g Phenytoin, salicyclic acid,
theophylline, valproic acid

!  Wide variation in the metabolism

of drugs

!  For
diagnosis of suspected toxicity and
determining drug abuse
!  E.g
Fenitoin (gejala toksisitas dapat dideteksi) VS
Digoksin (gejala toksisitas menyerupai gejala
penyakit CV)
+
Indications for TDM
!  Drugs with steep dose response curve (small increase in dose can
result a marked increase in desired/undesired response, e.g theophylline)

!  When another drug alter the relationship between dose and

plasma concentration (e.g plasma concentration of lithium is increased
by thiazide)

!  Renal disease (alters the relationship between dose and plasma const.
Important in case of digoxin, lithium, and aminoglycoside antibiotics
+
TDM is UNNECESSARY when

!  Clinical
outcome is unrelated either to dose or to
plasma concentration
!  Drug used at const which give a maximal response
!  Acute tolerance (tachyphylaxis) develop, eg
Amphetamine or cocaine

!  Dosage need not be individualized

!  Thepharmacological effects can be clinically

quantified (e.g BP, HR, blood sugar, urine volume,
etc)
+
TDM is UNNECESSARY when

!  Whenconcentration effect relationship remains

unestablished

!  Drug
with wide therapeutic range (e.g beta
blockers and calcium channel blockers)
TDM PROCESS

Decision to request a drug level

The biological sample
The request
+ Laboratory measurement
Communication of result by the laboratory
Clinical interpretation
Therapeutic management
+
TDM PROCESS
Decision to request Drug Level
!  Must be based on the
proper reason:
!  Suspected toxicity
!  Lack of response/
compliance
!  To asses therapy
following change in
dose
!  Change in clinical state
of patient
!  Potential drug
interactions due to
concomitant medications
The Biological Sample
!  Usually serum or plasma
samples
!  Blood sample should be
collected once the drug
concentration have attained
steady state (SS) (at-least
5 half lives at the current
dosage regimen)
!  Drug with long half-lives
should be monitored
before SS is achieved
!  If toxicity is suspected "
TDM asap
+
TDM PROCESS
The Request Laboratory measurement

!  Following details must !  Theassay procedure

be effectively should be a validated
communicated: one
!  Time of sample
!  Ideally, the
result of the
!  Dosage Regimen assay should be
!  Patient demographics available before the next
(age, sex, ethnicity) dose is given
!  Co-medications, if any
!  Various
analytical tech:
!  Indication for
TLC, HPLC, GLC, RIA,
monitoring FPIA,
!  PK and therapeutic Spectrophotometry,
range of drug Enzyme Immuno Assay
Sample timing for some important
drugs:
+
TDM PROCESS
Result communication by Lab
!  The
results should be
communicated ASAP
once it os verified
(preferably within 24 hr)
!  Theresult should clearly
state the therapeutic
const range for the drug
assayed
Clinical Interpretation
!  Therapeutic ranges are
available but should only
be used as a guide
!  Just relating drug const to
a published therapeutic
range is not an adequate
interpretation
!  Const must always be
interpreted in the light of
clinical response,
individual patient
demographic and dosage
regimen used
+
*Clinical Interpretation

Serum concentration lower than Serum concentration higher than

anticipated anticipated

!  Patient compliance, error in !  Patient compliance, error in

dosage regimen, wrong drug dosage regimen, poor
metabolizer, high plasma
product, poor bioavailability
protein bounding

Serum concentration correct but

patient does not respond to
therapy

!  Altered receptor sensitivity eg

tolerance, drug interaction at
receptor
+
TDM PROCESS
Therapeutic Management

!  The clinician will modify a drug dosage regimen in light of

all available information

!  New dose = Old dose x Desired Css / Old Css