Clinically, be formed between drug molecules and other macromolecular

Clinically, the body is perceived as a single
compartment; it is assumed that a drug distributes quickly and evenly
throughout the blood and tissues with high blood flow. However, the body may
consist of several compartments for a particular drug, with specific
compartments requiring longer periods of time to achieve equilibrium (Stangier 2008).  In
the pharmacokinetic sense, these drugs are described best by multi-compartment
models. Factors that influence drug distribution from
serum to specific body compartment include the mechanism of transport (active
or passive), the permeability of membranes, lipid solubility and the extent to
which drug molecules are ionized or charged and extent of drug binding in serum
(Burton 2006). For example
penetration of the intact blood-brain barrier is favored for highly
lipid-soluble drugs such as the antiepileptic’s, but does not occur for relatively
polar antibiotics that exist largely in an ionized state in serum, such as
penicillin G. Another aspect of drug distribution involves the binding of drug
to serum proteins (Greenblatt et al. 1982).

One of the assumptions made in developing the general
picture of the distribution of drugs is that the drug remains as a solute in
the fluid of various compartments of the body. Obviously, the rate of movement
of a drug across biologic barriers is determined by its own physicochemical
properties only when it exists as an independent entity. This ideal behavior is
characteristic of very few drugs. The same kind of bonds that are formed when a
drug interacts with its receptor can be formed between drug molecules and other
macromolecular components like plasma proteins (Ambrose and Winter 2004).
The major difference is that the drug-receptor combination leads directly to a
sequence of events measurable as a biologic effect, whereas binding with a non-receptor
substance does not. The binding sites that do not function as true receptors
are frequently referred to as secondary receptors, silent receptors or sites of
loss. The molecules of a drug that are bound to the non -receptor macromolecule
are neither free to move to a site of action nor free to produce a biologic
effect. Albumin, the principal protein of plasma, is also the protein with
which the greatest variety of drugs combined.  The fraction of drug that is free to leave the
plasma is determined only by the concentration of drug and strength of the
binding. At low drug concentrations, the stronger the bond between the drug and
protein, the smaller the fraction that is free. As drug concentration
increases, the concentration of free drug also gradually rises until all the
binding capacity of the protein has been saturated. At this point, any
additional drug will remain unbound and pass to the site of action (figure 5).  

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Figure 5: Relationship of serum to tissue drug

Figure 5 source:


Analytical issues in TDM


The practice of therapeutic drug monitoring requires the
integration of several disciplines, including pharmacokinetics,
pharmacodynamics, and laboratory analysis. When it comes to blood sample
collection, timing is very critical (Bowers 1998). Usually, there are two types of a specimen is drawn
from the patient; one is to determine the trough concentration which is the
concentration just right before next dose, it is usually low. The second is to
determine the peak concentration which is usually 1-2 hours after oral dose (it
might vary for IV and IM). So the main goal in designing a dosage regimen is to
achieve a trough concentration that is in the therapeutic range and peak
concentration that is not in the toxic range. Similarly, in relation to TDM,
the timing of blood sample collection is critical for correct interpretation of
patient response. The absorption and distribution phases should be complete and
a steady-state concentration achieved before the sample is drawn (Linder and Keck 1998). Levels obtained
before a steady-state concentration exists may be falsely low; and increasing
the dosage based on such a result could produce toxic concentration   The
selection of time that the sample is drawn in relation to drug administration
should be based on the pharmacokinetics properties of the drug, its dosage form
and the clinical reason for assaying the sample, for example, assessment of
efficacy or clarification of possible drug-induced toxicity. For routine serum
level monitoring of drugs with short half-lives, both a steady-state peak and
trough sample may be collected to characterize the plasma concentration
profile; for drugs with a long half-life, steady-state trough samples alone are
generally sufficient.

spectrophotometry and colorimetry were the main techniques broadly utilized as
a part of research centers for estimation of drug levels, however, these
strategies are constrained by poor sensitivity, variable specificity, and high
cost. Immunoassays for drugs have become popular in the last 20 years. In the
radioimmunoassay (RIA), drug presents in serum compete with a
radioisotope-labeled ligand for antibody binding sites. The RIA techniques are
found to be highly sensitive, yet require the utilization of radioactive
material and are costly. Chromatography is a technique for isolating blends of
substances in view of their physicochemical qualities, so at least one of those
substances might be particularly detected. Regularly it is possible to
distinguish and quantitate the parent medication and some or all of its major
metabolites at the same time (Friedman and Greenblatt 1986).

In the last 10 years, the technology for determining drug
concentration in body fluids has progressed from relatively nonspecific,
time-consuming, complex procedures requiring large sample volumes, to those
using micro-samples and displaying improved sensitivity, specificity, and
simplified protocols. Serum drug analysis as a clinical tool requires that the
methods selected be sufficiently sensitive and highly specific; interference
from other drugs must be minimal. The assays that have been developed include
Enzyme-Linked Immunosorbent Assay (ELISA, the most common used assay) (Uglietti et al. 2007). Despite
the advances in developing assays to measure serum drug concentration, there
are still limitations. For example, the main limitation of double antigen ELISA
the most common type of ELISA is the inability of accurately measure antidrug
antibody in the presence of the drug. In addition, to minimize the inaccurate
interpretation of drug response it is best to always use the same assays so
that the results can be compared among patients and interpreted longitudinally




Practical issues in TDM

 In clinical use,
therapeutic drug monitoring is somewhat analogous to the ECG or radiograph,
where the interpretation of the test is as important as the test itself. If an
assay is to be fully utilized, results must be interpreted in light of the
complete clinical profile of the patient (Misan et al. 1990), (Reynolds and Aronson 1993).
Patient factors that may affect serum concentration monitoring and
interpretation are:

and weightSex-linked
hepatic and cardiac diseasesDiseases
affecting renal and/or hepatic perfusionMalabsorptionHypoalbuminemiaConcomitant
drug therapy    2.5
Economic considerations of TDMNaturally,
the expenses involved must also be considered when the value of therapeutic
drug monitoring is weighed. Regardless of the methodology used in measuring
serum drug concentration, the cost to the patient should be considered. When
choosing a reliable, cost-efficient assay methodology, several factors must be
considered. The  Methodology
must have an acceptable level of precision, accuracy, Specificity
and sensitivity for the drug being monitored (Touw et al. 2005). These results
should be attainable by technologist or technician level personnel. The assay
equipment should be reasonably priced and easily maintained. The assay reagents
must be inexpensive and stable for a reasonable period of time. The standard
curve should be stable and not require daily adjustments. Fast result
turnaround capabilities should be available at reasonable cost. Finally, the
supplies and reagents for serum drug concentration analysis should be available
at a reasonable price.It
is difficult to put a dollar value on quality patient care, especially when it
involves preventive medicine. A pharmacoeconomic analysis of the impact of TDM
in adult patients with generalized tonic-clonic epilepsy showed that patients
undergoing TDM had much more effective seizure control, fewer adverse events,
better-earning capacity, lower costs to the patient, savings from lower
hospitalizations per seizure, and greater chances of remission (Rane et al. 2001) As an intervention method, TDM goals to
improve patient responses to important life-sustaining drugs and to decrease
adverse drug reactions. Furthermore, theResources
consumed by TDM methods will likely be regained by positive outcomes, including
decreased hospitalizations (Schumacher and Barr 1998)


utility of TDM for monitoring response:

Physicians and patients benefit from using TDM:

Physicians often face the
challenge of managing patients when they respond to treatment initially and
then lose response, which can be frustrating for both patient and physician.  Intuitive decisions about treatment can result
in delays before the most appropriate approach to treatment optimization is
implemented, thus delaying the patient return to clinical response or
remission. TDM allows the clinician to better understand the cause of loss of
response thus guiding the clinical decision making to optimize treatment with
the right medication and right dose (Figure 6).
This approach helps to improve the outcomes for patients in achieving clinical
response more rapidly. With TDM patients know they are receiving the most
appropriate therapy at the most appropriate dose as soon as possible. TDM
allows patients to receive personalized drug dosing with more confidence in the
long-term efficacy and safety of their therapy. It is important to know that by
implementing TDM approach instead of intuitively dose escalating, the cost can
be reduced (Rane et al. 2001). Therefore using TDM in clinical
practice means more informed health care decisions and an overall more
efficient use of drugs.


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