THERAPEUTIC DRUG MONITORING:-
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.
TDM enables the assessment of the efficacy and safety of a particular
medication in a variety of clinical settings the goal of this process is to
individualize therapeutic regimens for optimal patient benefit.
CLINICAL USEFULNESS OF TDM:-
Clinical usefulness of TDM 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 distribute/metabolize/excrete
the drug
4. Genetic factors
5. Concomitant
disease, Tropical disease and nutritional deficiencies
6. Alternative
system of medicine
7. Ethnic
differences and extrapolation of the normal range
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
1. Patient demographics:-
The patient’s age sex body weight and ethnicity should be considered
when interpreting TDM results. Age sex and lean body weight are particularly
important for renally cleared drugs as knowledge of these allows calculation of
creatinine clearance. Ethnicity may be an important consideration for TDM of
some hepatically cleared drugs.
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.
The simplest way to check for non-compliance is to ask the patient in a non
judgemental way about their compliance. However in some situations for example,
a patient who is confused after a seizure, this may not be a reliable method.
3. Individuals capacity to distribute/metabolize/excrete the drug:-
Pharmacokinetics is the study of what the body does to a drug after
administration. It is divided into
four categories:
§ Absorption,
§ Distribution,
§ Metabolism and
§ Excretion.
Major Pharmacokinetics Processes Affecting Drug Concentration
§ Distribution
§ Absorption
§ Elimination (metabolism &
excretion)
§ Time (hours) 4 8 12 16 20 24 28
§ Serum concentration
Ø Absorption:
Absorption refers to the ability and process of a dosage reaching the
bloodstream. There are different routes of drug administration. The most
common are:
§ Oral
§ Intramuscular
§ Subcutaneous
§ Rectal
§ Transdermal
§ Intravenous
Drugs administered intravenously do not require absorption since they
immediately reach the vascular system. Oral agents must first be
absorbed into the GI tract and may be metabolized there or by hepatic enzymes prior
to reaching the circulation.
Transdermally administered drugs do not pass through either the GI tract
or the liver.
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.
Ø Distribution:
Once the drug is absorbed, a certain drug concentration is reached
in the body. The volume in which the drug is distributed is a product
of the drug’s dose divided by the plasma concentration.
(Vd) = dose/plasma concentration
The absolute bioavailability of a drug, when administered by an extra
vascular route, is usually less than one (i.e. F<1 o:p="o:p">
The distribution phase represents the early period in the dose/time
curve
when the drug is being circulated in the blood throughout the body and
into the body fluids, organs and tissues. Vd is directly related to the
half-life of the drug.
A drug with a large Vd compared to a drug with a small Vd, given similar
clearance rates, will have a longer half-life and remain in the body longer.
Half-life refers to the time required for the concentration of the drug
in the body to be reduced by one half. 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.
Ø Metabolism:
Drug metabolism occurs primarily in the liver, and also in the GI tract.
Drug metabolism is the process in which the body breaks down
and converts the drug into active chemical substances. Knowing how
the drug is metabolized is important for several reasons. When two
or more drugs are administered at similar times how they metabolize
will impact any drug interactions. 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.
Ø 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.
Some other factors also affect these parameters are-
·
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
·
Circadian differences
·
Interactions with other drugs (e.g. antacids, alcohol, nicotine)
·
Interactions with other foods (e.g. grapefruit juice, pomello, cranberry
juice)
·
Transporters: Substrate of an efflux transporter (e.g. P-glycoprotein)
·
Health of the GI tract
·
Enzyme induction/inhibition by other drugs/foods:
o 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
o Enzyme inhibition (decrease rate of
metabolism). E.g. which is involved in drug metabolism, resulting in
↑ drug activity, prolonging the action of various drugs, including
chloramphenicol, cimetidine, disulfiram (Antabuse), isoniazid, methyldopa,
metronidazole, phenylbutazone and sulphonamides, grapefruit juice inhibits
CYP3A --> higher nifedipine concentrations,
·
Individual Variation in Metabolic Differences
·
Phenotypic differences, enter hepatic circulation, diet, gender.
4.
Genetic factors: - It plays an as yet poorly
defined role in therapeutic drug monitoring, as is the case of the poor ability
of some racial groups to acetylated drugs.
5. Concomitant disease, Tropical disease and nutritional deficiencies:-
Ill health is a serious problem impeding progress in most developing
countries. This includes diseases highly prevalent in these countries such as
infections, diarrhoea, worm infestations, tuberculosis, neurocysticercosis and
nutritional deficiencies, plus a higher proportion of patients with diabetes
and AIDS. Patients often seek treatment late in their illness. Nutritional
deficiencies are often subclinical and escape detection and they have been
shown to affect drug pharmacokinetics.
Felder & Steware have shown that the rural black population in South
Africa often has albumin concentrations below the accepted reference range of
35–50 g l−1. In a study which estimated free and total phenytoin and albumin
levels in these patients, they were able to show that, because albumin levels
are lower, corrected phenytoin concentrations using the Sheiner Tozer equation
should be used and not the total phenytoin concentrations which can be
misleading. However, in our urban situation, over 100 consecutive patients
screened were found to have normal albumin levels. Iron deficiency anaemia is
common and may affect drug metabolism and absorption although we have not found
it to affect phenytoin pharmacokinetics. AIDS is a major problem in the
developing world, with India estimated to have the largest number of cases of
any country in the world. AIDS has been shown to reduce the absorption of
antituberculous drugs and there are specific recommendations for monitoring
antituberculin drug levels in these patients.
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. Some
allopathic practitioners often coprescribe medicines from the alternative
systems particularly for chronic disorders. Our own experience in the TDM
clinic identified an interaction with ‘shankhapushpi’ an ayurvedic preparation
purported to be an anti epileptic and memory enhancer. 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. History revealed that he was taking ‘shakhapushpi’ and plasma analysis
showed that his phenytoin level had dropped. Experimental studies showed that
this drug had both pharmacokinetic and pharmacodynamic interactions with
phenytoin.
Two other interesting patients who presented to the TDM clinic had GTC
epilepsy and had switched over to ‘ayurvedic’ tablets and discontinued their
anticonvulsant medication. The patients had both phenytoin and phenobarbitone
detectable in their plasma and analysis of the tablets showed that they
contained a combination of phenytoin and phenobarbitone. Herbal medicines are
being used by an increasing number of patients worldwide, who may not
necessarily advise their clinicians of the concomitant use. Interaction with
conventional drugs have been documented for liquorice, ginseng, tannic acids,
plantain, uzara root, hawthorn and kyushin all of which may be prescribed by
practitioners of the alternative systems.
7. Ethnic differences and extrapolation of the normal range:-
The fact that interpopulation variations in drug pharmacokinetics can
result in higher or lower plasma drug concentrations is well known. For
example, the metabolism of phenytoin via para-hydroxylation is subject to wide
interindividual variation. Mani has reported that the effective anticonvulsant
dosage may be lower in Indians than in Europeans while other authors have
indicated that ethnic differences may have a significant influence on the
plasma clearance of phenytoin.
Shelley studied possible ethnic differences in the pharmacokinetics of
lithium carbonate in Caucasian and Afro-Caribbean volunteers under standardized
conditions. There was a non statistically significant trend towards more rapid
distribution and elimination, smaller area under the serum time-concentration
curve and greater urinary excretion in the Caucasian group. Lee studied the
variability in plasma phenobarbitone concentration in Asian children in Singapore.
This included Chinese, Malays and Indians and the mean phenobarbitone dosage
required to produce a plasma level of 15 μg ml−1 was 5.2 mg kg−1day−1 and varied between the three groups although the
differences were not statistically significant.
The standard therapeutic ranges for interpretation of TDM data are
derived from population studies in the west. Nomograms used for dosage
calculations for phenytoin have been made using pharmacokinetic data from
developed countries but the same nomograms are used in developing countries.
When we compared the expected phenytoin values (using the nomogram) with actual
phenytoin values in our patients after dose adjustment; we found 10–15% lower
levels than calculated values. This could be accounted for by pharmacokinetic
differences or different formulations with lower bioavailability.
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 such as Phenytoin.
Cigarette smoking
increases the hepatic clearance of theophylline and patients who have recently
stopped smoking may have unexpectedly high theophylline concentrations.
9. Quality of medication and generic formulation:-
World wide, there is
increasing prescription of generic products which are actively promoted by
health authorities for economic reasons. The prescription of generics by
primary care physicians has risen in England from 35% in 1985 to 55% in 1995.
Quality of products (drug content, bioavailability) is important especially for
drugs with a narrow margin of safety which is just those drugs for which TDM is
relevant.
In developing
countries, there is a constant attempt to provide drugs to the majority of the
population at low cost and bioavailability studies are done only at the time of
obtaining marketing approval. Authors have already reported from Pakistan and
Vietnam that quality of drugs used may be substandard and need additional
quality control. Given that generic drugs are freely available in developing
countries, quality assurance of manufacturing practice is essential. The TDM
service can be used to provide an important early indication of substandard
drugs. For example, we have identified substandard products by observing low
levels of phenytoin in patients otherwise known to be compliant and previously
having levels in the therapeutic range.
10.
Quality
control in drug assays:-
For TDM programs, quality control is vitally important [3] and in developing countries there are
hardly any procedures for laboratory accreditation or external quality control.
In India, one centre in Southern India offers an external quality control
program (for biochemical tests).
For drug levels, however, there is none and most departments and
laboratories such as ours use overseas quality control programs although this
increases the cost of running the laboratory. In view of the mushrooming of
private ‘pathobiochem’ laboratories which offer a range of pathology and
biochemical investigations, the state Food and Drug Administration’s are
proposing laboratory inspections for standardizing and ensuring quality of
results. There are no such proposals for drug assay laboratories.
11.
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.
12.
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.
13.
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.
Chromatographic and ultrafiltration techniques are time consuming and
require highly trained staff. It is most cost-effective for these assays to be
performed in only a limited number of centres of excellence with appropriately
qualified scientists and stringent quality assurance.
For many drugs the analytical techniques used, and their associated
costs, dictate that assays are performed in batches at predetermined times and
the drug concentrations may consequently not be available for a number of
dosage intervals.
Bibliography:-
|
1. A Textbook of Clinical Pharmacy
Practice (Second Edition)
|
|
|
G Parthasarathi, Karin
Nyfort-Hansen & Milap C Nahata (Eds.)
|
|
|
2012; 331 pp;
978-81-7371-756-7
|
|
N J Gogtay, N A Kshirsagar, S S Dalvi Br
J Clin Pharmacol. 1999 November; 48(5): 649–654. doi: 10.1046/j.1365-2125.1999.00088.x
PMCID: PMC2014358
3. Therapeutic drug monitoring
D.J. Birkett, Professor of Clinical
Pharmacology, Flinders University of South Australia, Adelaide
4. Therapeutic Drug Monitoring (TDM) - An
Educational Guide
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