Download factors affecting therapeutic drug monitoring

FACTORS AFFECTING
THERAPEUTIC DRUG
MONITORING
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INTRODUCTION
• Therapeutic drug monitoring (TDM) is generally defined as the
clinical laboratory measurement of a chemical parameter that, with
appropriate medical interpretation, will directly influence drug
prescribing procedures by combining knowledge of pharmaceutics,
pharmacokinetics, and pharmacodynamics.
CLINICAL USEFULNESS OF TDM
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Maximize efficacy of drug
Avoiding toxicity
Identifying therapeutic failure
Facilitating dose adjustment
Facilitating therapeutic effects
Factors Affecting TDM
1. Patient demographics
2. Patient Compliance
3. Individuals capacity to absorb/distribute/metabolize/excrete
the drug
4. Genetic factors
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Factors Affecting TDM…
5. Concomitant disease, Tropical disease and nutritional
deficiencies
6. Alternative system of medicine
7. Ethnic differences and extrapolation of the normal range
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Factors Affecting TDM…
8. Alcohol & Tobacco use
9. Quality of medication and generic formulation
10. Control of drug assay
11. Medication or sampling errors
12. Laboratory errors
13. Cost effectiveness
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1. Patient demographics
• Age, sex and lean body weight are particularly important for renally
cleared drugs as knowledge of these allows calculation of creatinine
clearance.
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2. Patient Compliance
• If the concentration of the drug is lower than expected, the
possibility of non compliance should be considered before a dose
increase is recommended.
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3. Individuals capacity to
absorb/distribute/metabolize/excrete the
drug
Absorption:
The rate of absorption and extent of absorption are dependent on
various factors such as:
• Drug formulation
• Manufacturer
• Route of administration
• Intra-individual variations
• Another aspect of absorption is bioavailability. This is the fraction
of the administered dose that reaches the systemic circulation.
• Bioavailability is 100% for IV injection.
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Distribution:
(Vd) = dose/plasma concentration
The absolute bioavailability of a drug.
• For example if a drug has a half life of four hours, four hours after
the initial dose, 50% of the drug will be removed.
• Eight hours after the initial dose, half of the remaining drug (25%
of total) will be removed, for a total of 75% having been removed
at that time, and so on.
• Half-life information is used to determine the correct drug dose
required to attain the desired therapeutic range
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Metabolism:
• In addition, drug metabolites can be either protein bound (inactive) or
free (active).
• The drug dosage will depend on how the drug metabolizes.
• Factors that impact drug metabolism includes genetics, environment,
nutrition, and age.
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Excretion:
• Drug excretion from the body occurs through the kidneys,
or fluids excreted through the lungs, GI or skin.
• Renal dysfunction reduces drug clearance and may
contribute to drug accumulation and increased risk of
adverse drug effects.
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Some other causes
• Age: In general, drugs metabolized more slowly in foetal, neonatal,
and geriatric populations
• Physical properties of the drug (hydrophobicity, pKa, solubility)
• If the drug is administered in a fed or fasted state
• Gastric emptying rate
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• Interactions with other drugs (e.g. antacids, alcohol, nicotine)
• Interactions with other foods.
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Enzyme induction/inhibition by other drugs/foods:• Enzyme induction (increase rate of metabolism). e.g. Phenytoin,
barbiturates, carbamazepine, glutethimide, primidone, rifampicin
induces CYP1A2, CYP2C9, CYP2C19 and CYP3A4, , which is involved
in a drug's metabolism may reduce the drug's activity
• Enzyme inhibition (decrease rate of metabolism), resulting in
↑ drug activity, e.g. Protease inhibitors, Nitrogen mustard, Mtx,
Cidenafil Citrate
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Drug Interactions
• TDM results should be interpreted in light of the patients other
drug therapy
• For example: patient on digoxin may have unexpected high
digoxin serum concentration and develop digoxin toxicity if drug
such as verapamil are started without a reduction in digoxin
dose. The serum concentration of some hepatically cleared drugs
may be affected by cessation of drugs with either induce or
inhibit hepatic cytochrome P450 isoenzymes.
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5. Concomitant disease, Tropical disease
and nutritional deficiencies
This includes diseases highly prevalent in developing
countries such as
• Infections,
• Diarrhoea,
• Worm infestations,
• Tuberculosis,
• Nutritional deficiencies, plus a
• Higher proportion of patients with diabetes and AIDS
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6. Alternative system of medicine
• India is unique in having at least three
systems of medicine coexisting with
‘western’ medicine (allopathy);
ayurveda, homeopathy and unani.
• A patient with a history of generalized
tonic-clonic (GTC) seizures, well
controlled and with plasma phenytoin
levels within the therapeutic range,
presented with sudden loss of seizure
control.
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8. Alcohol & Tobacco use
• Chronic use of alcohol has been shown to cause non-specific hepatic
microsomal enzyme induction, resulting in increased clearance and
decreased serum concentrations of hepatically cleared drugs.
• Cigarette smoking increases the hepatic clearance of theophylline and
patients who have recently stopped smoking may have unexpectedly
high theophylline concentrations
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9. Medication or sampling errors
• In cases where the TDM result is incompatible with drug
administration records, the possibility of a medication or
sampling error should be considered.
• For Example, the drug may have been given to the wrong
patient, or blood may have been mistakenly drawn from a
patient in a neighbouring bed.
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10. Laboratory errors
• If a laboratory error is suspected, the laboratory should be
contacted and asked to repeat the assay.
• Alternatively, a new blood sample can be drawn and sent to a
different laboratory for assay.
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11. Cost effectiveness
• Rapid and cost-effective measurement of most drugs for which TDM
is indicated can be achieved using commercial kits run on automated
analysers using a number of different methodologies including
fluorescence polarisation immunoassay.
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Testing Methodologies
• In HPLC liquid containing sample is injected at one end of the column.
high pressure is used to overcome resistance to flow As liquid flows
some molecule move faster than others due to diff in solubility. The
exact time for each molecule to flow through the column is measured
by detector. The retention time is calculated. An internal standard
compound similar in structure to the specimen to be analyzed is also
run through the column. By comparing retention time of sample and
standard molecule can be identified. Concentration of drug can also be
determine that peak produce during run.
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THANK YOU
-PHARMA STREET
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