Clinically, assumptions made in developing the general

Clinically, the body is perceived as a singlecompartment; it is assumed that a drug distributes quickly and evenlythroughout the blood and tissues with high blood flow. However, the body mayconsist of several compartments for a particular drug, with specificcompartments requiring longer periods of time to achieve equilibrium (Stangier 2008).  Inthe pharmacokinetic sense, these drugs are described best by multi-compartmentmodels. Factors that influence drug distribution fromserum to specific body compartment include the mechanism of transport (activeor passive), the permeability of membranes, lipid solubility and the extent towhich drug molecules are ionized or charged and extent of drug binding in serum(Burton 2006). For examplepenetration of the intact blood-brain barrier is favored for highlylipid-soluble drugs such as the antiepileptic’s, but does not occur for relativelypolar antibiotics that exist largely in an ionized state in serum, such aspenicillin G. Another aspect of drug distribution involves the binding of drugto serum proteins (Greenblatt et al. 1982).

One of the assumptions made in developing the generalpicture of the distribution of drugs is that the drug remains as a solute inthe fluid of various compartments of the body. Obviously, the rate of movementof a drug across biologic barriers is determined by its own physicochemicalproperties only when it exists as an independent entity. This ideal behavior ischaracteristic of very few drugs. The same kind of bonds that are formed when adrug interacts with its receptor can be formed between drug molecules and othermacromolecular components like plasma proteins (Ambrose and Winter 2004).

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The major difference is that the drug-receptor combination leads directly to asequence of events measurable as a biologic effect, whereas binding with a non-receptorsubstance does not. The binding sites that do not function as true receptorsare frequently referred to as secondary receptors, silent receptors or sites ofloss. The molecules of a drug that are bound to the non -receptor macromoleculeare neither free to move to a site of action nor free to produce a biologiceffect. Albumin, the principal protein of plasma, is also the protein withwhich the greatest variety of drugs combined.  The fraction of drug that is free to leave theplasma is determined only by the concentration of drug and strength of thebinding. At low drug concentrations, the stronger the bond between the drug andprotein, the smaller the fraction that is free.

As drug concentrationincreases, the concentration of free drug also gradually rises until all thebinding capacity of the protein has been saturated. At this point, anyadditional drug will remain unbound and pass to the site of action (figure 5).   Figure 5: Relationship of serum to tissue drugconcentrationsFigure 5 source: 2.

3Analytical issues in TDM The practice of therapeutic drug monitoring requires theintegration of several disciplines, including pharmacokinetics,pharmacodynamics, and laboratory analysis. When it comes to blood samplecollection, timing is very critical (Bowers 1998). Usually, there are two types of a specimen is drawnfrom the patient; one is to determine the trough concentration which is theconcentration just right before next dose, it is usually low. The second is todetermine the peak concentration which is usually 1-2 hours after oral dose (itmight vary for IV and IM). So the main goal in designing a dosage regimen is toachieve a trough concentration that is in the therapeutic range and peakconcentration that is not in the toxic range. Similarly, in relation to TDM,the timing of blood sample collection is critical for correct interpretation ofpatient response.

The absorption and distribution phases should be complete anda steady-state concentration achieved before the sample is drawn (Linder and Keck 1998). Levels obtainedbefore a steady-state concentration exists may be falsely low; and increasingthe dosage based on such a result could produce toxic concentration   Theselection of time that the sample is drawn in relation to drug administrationshould be based on the pharmacokinetics properties of the drug, its dosage formand the clinical reason for assaying the sample, for example, assessment ofefficacy or clarification of possible drug-induced toxicity. For routine serumlevel monitoring of drugs with short half-lives, both a steady-state peak andtrough sample may be collected to characterize the plasma concentrationprofile; for drugs with a long half-life, steady-state trough samples alone aregenerally sufficient. Historically,spectrophotometry and colorimetry were the main techniques broadly utilized asa part of research centers for estimation of drug levels, however, thesestrategies are constrained by poor sensitivity, variable specificity, and highcost. Immunoassays for drugs have become popular in the last 20 years. In theradioimmunoassay (RIA), drug presents in serum compete with aradioisotope-labeled ligand for antibody binding sites.

The RIA techniques arefound to be highly sensitive, yet require the utilization of radioactivematerial and are costly. Chromatography is a technique for isolating blends ofsubstances in view of their physicochemical qualities, so at least one of thosesubstances might be particularly detected. Regularly it is possible todistinguish and quantitate the parent medication and some or all of its majormetabolites at the same time (Friedman and Greenblatt 1986).In the last 10 years, the technology for determining drugconcentration in body fluids has progressed from relatively nonspecific,time-consuming, complex procedures requiring large sample volumes, to thoseusing micro-samples and displaying improved sensitivity, specificity, andsimplified protocols. Serum drug analysis as a clinical tool requires that themethods selected be sufficiently sensitive and highly specific; interferencefrom other drugs must be minimal.

The assays that have been developed includeEnzyme-Linked Immunosorbent Assay (ELISA, the most common used assay) (Uglietti et al. 2007). Despitethe advances in developing assays to measure serum drug concentration, thereare still limitations. For example, the main limitation of double antigen ELISAthe most common type of ELISA is the inability of accurately measure antidrugantibody in the presence of the drug.

In addition, to minimize the inaccurateinterpretation of drug response it is best to always use the same assays sothat the results can be compared among patients and interpreted longitudinally                                                                                                                                     2.4Practical 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 anassay is to be fully utilized, results must be interpreted in light of thecomplete clinical profile of the patient (Misan et al. 1990), (Reynolds and Aronson 1993).

Patient factors that may affect serum concentration monitoring andinterpretation are:PregnancyAgeand weightSex-linkedcharacteristicsGeneticsRenal,hepatic and cardiac diseasesDiseasesaffecting renal and/or hepatic perfusionMalabsorptionHypoalbuminemiaConcomitantdrug therapy    2.5Economic considerations of TDMNaturally,the expenses involved must also be considered when the value of therapeuticdrug monitoring is weighed. Regardless of the methodology used in measuringserum drug concentration, the cost to the patient should be considered. Whenchoosing a reliable, cost-efficient assay methodology, several factors must beconsidered. The  Methodologymust have an acceptable level of precision, accuracy, Specificityand sensitivity for the drug being monitored (Touw et al. 2005).

These resultsshould be attainable by technologist or technician level personnel. The assayequipment should be reasonably priced and easily maintained. The assay reagentsmust be inexpensive and stable for a reasonable period of time. The standardcurve should be stable and not require daily adjustments. Fast resultturnaround capabilities should be available at reasonable cost. Finally, thesupplies and reagents for serum drug concentration analysis should be availableat a reasonable price.Itis difficult to put a dollar value on quality patient care, especially when itinvolves preventive medicine. A pharmacoeconomic analysis of the impact of TDMin adult patients with generalized tonic-clonic epilepsy showed that patientsundergoing TDM had much more effective seizure control, fewer adverse events,better-earning capacity, lower costs to the patient, savings from lowerhospitalizations per seizure, and greater chances of remission (Rane et al.

2001) As an intervention method, TDM goals toimprove patient responses to important life-sustaining drugs and to decreaseadverse drug reactions. Furthermore, theResourcesconsumed by TDM methods will likely be regained by positive outcomes, includingdecreased hospitalizations (Schumacher and Barr 1998)3Clinicalutility of TDM for monitoring response:3.1Physicians and patients benefit from using TDM:Physicians often face thechallenge of managing patients when they respond to treatment initially andthen lose response, which can be frustrating for both patient and physician.  Intuitive decisions about treatment can resultin delays before the most appropriate approach to treatment optimization isimplemented, thus delaying the patient return to clinical response orremission.

TDM allows the clinician to better understand the cause of loss ofresponse thus guiding the clinical decision making to optimize treatment withthe right medication and right dose (Figure 6).This approach helps to improve the outcomes for patients in achieving clinicalresponse more rapidly. With TDM patients know they are receiving the mostappropriate therapy at the most appropriate dose as soon as possible. TDMallows patients to receive personalized drug dosing with more confidence in thelong-term efficacy and safety of their therapy. It is important to know that byimplementing TDM approach instead of intuitively dose escalating, the cost canbe reduced (Rane et al. 2001).

Therefore using TDM in clinicalpractice means more informed health care decisions and an overall moreefficient use of drugs.


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