Therapeutic Drug Monitoring (TDM) by rub18840

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									                Edward Dunn, PhD FCACB, Director, Research and Development, Gamma-Dynacare Medical Laboratories, Burlington, ON

                Feature



    Therapeutic Drug
    Monitoring (TDM)
     T
                herapeutic drug monitoring (TDM)        of the drug may occur in the liver or specific    permissible, above which there is a poten-
                is the measurement of drugs and         tissues and finally the drug and metabolites      tial for toxicity. If the therapeutic range
                their active metabolites in patients    are excreted, usually in the urine or feces.     (window) is large, then the drug is consid-
                receiving medications for the pur-          Pharmacodynamics describes the physi-        ered to be safer since a larger dose of drug
     pose of optimizing their therapeutic effect        ological effect of the drug and metabolites.     is required to produce toxicity. Many of the
     while minimizing adverse effects. The basic        This includes the desired therapeutic effect     newer antiepileptic drugs (e.g. Lamotrigine)
     assumption of TDM is that the circulating          of the drug as well as unwanted side-effects.    and serotonin selective reuptake inhibitors
     concentration of a drug correlates better with     Pharmacodynamic variability can arise from       (e.g. Paxil, Zoloft) have a wide therapeutic
     pharmacological effect than does the dosage        differences in drug-receptor interaction and     range and therefore do not require therapeu-
     of the drug given to the patient. Therefore,       receptor response.                               tic drug monitoring. Dosages can be titrated
     there are a number of things to be considered                                                       upward until the desired therapeutic effect is
     in order for therapeutic drug monitoring to be     Criteria for Therapeutic                         reached and tapered if clinical signs of tox-
     effective and this article will briefly address     Drug Monitoring                                  icity are noted.
     some of these.                                                                                          Drugs such as aminoglycosides, digoxin,
         Before discussing the indications for          1. Test Availability                             theophylline, and lithium have a narrow ther-
     therapeutic drug monitoring, it is essential to       Obviously, a test for the drug and active     apeutic range. This means that there is a very
     have an understanding of basic pharmacolo-         metabolites must exist in order to perform       limited range of drug concentration that will
     gy. When a drug is administered to a patient,      therapeutic drug monitoring. Most routine        produce a therapeutic effect. Below this range
     a number of things happen. First, the body         chemistry analyzers offer immunoassays for       the drug will be ineffective or partially effec-
     must be able to take up the drug and distrib-      the more common therapeutic drugs. Some          tive and above which it will be toxic. There-
     ute it to the target site of action. A change in
     the amount of drug or metabolite in various
     body compartments over time is determined
                                                             … a drug or other therapeutic agent with a narrow therapeutic
     by pharmacokinetics. Once at the target site            range (i.e. with little difference between toxic and therapeutic
     the drug must produce the desired effect, usu-
     ally through binding with specific receptors.            doses) may have its dosage adjusted according to measurements
     The effect a drug has on the body is deter-
     mined by pharmacodynamics.                              of the actual blood levels.
         Pharmacokinetics describes what hap-
     pens when a drug is administered and is            drugs require more specialized chromato-         fore, a drug or other therapeutic agent with a
     dependent on the extent and rate of Absorp-        graphic techniques such as gas chromatog-        narrow therapeutic range (i.e. with little dif-
     tion, Distribution, Metabolism and Elimina-        raphy (GC) or liquid chromatography (LC).        ference between toxic and therapeutic doses)
     tion (ADME). Typically, most drugs are ad-         This type of equipment is not commonly           may have its dosage adjusted according to
     ministered orally and the amount absorbed          found in most clinical laboratories. There-      measurements of the actual blood levels.
     (bioavailability) depends on a number of           fore, monitoring for these drugs may require
     factors such as the formulation (fast acting       sending the sample to a reference laboratory     3.   Compliance
     vs. extended release), solubility and pK of        for analysis. The turn-around time for these         Therapeutic drug monitoring can be con-
     the drug, co-administration of other drugs or      analyses must be quick enough to produce         sidered in patients that do not show an appar-
     food, and gastric emptying times. The drug         clinically meaningful results, especially if a   ent clinical response to a drug despite being on
     is usually absorbed in the small intestine by      change in dosage is required due to toxicity     a seemingly adequate dosage. If the measured
     passive diffusion. After the drug is absorbed      or adverse reaction.                             drug concentration appears consistent with the
     it enters the hepatic portal system and is                                                          dosage of the drug, then the patient may be
     transported directly to the liver. In the liver    2.   Narrow Safety Margin                        considered a non-responder to therapy. If the
     the drug may be extensively metabolized by             As mentioned above, the basic assump-        measured concentrations are very low or not
     hepatic enzymes before reaching the general        tion for TDM is that the concentration of drug   detected then the patient is either “non-com-
     circulatory system. Once in circulation, the       circulating in the bloodstream correlates well   pliant” or is an unusually “fast metaboliser”.
     drug is distributed to various fluids and tis-      with the pharmacological effect of the drug.
     sues. The volume of distribution (VD) of a         The drug concentration usually also corre-       4.   High pharmacokinetic variability
     drug describes the extent of distribution and      lates with the toxicity of the drug.                Inter-individual variation in drug absorp-
     is dependent on the solubility of the drug,            The therapeutic range often describes the    tion, metabolism, and excretion can produce
     rate of perfusion of the tissue, and the ex-       minimum concentration required for effec-
     tent of protein binding. Further metabolism        tive therapy and the maximum concentration                              Continued on page 6



Volume 16/Issue 2    Summer 2009                                                                                                                       5
               Feature


    Continued from page 5                             there may be no more need for continued           diffuse into the oral fluid, some drugs are ac-
                                                      TDM as long as the patient’s clinical condi-      tively secreted. Some drugs may reduce pro-
    a poor correlation between drug concentra-        tion remains the same.                            duction and flow of saliva and stimulation of
    tion and dosage. Pharmacokinetic variability                                                        saliva flow may alter pH and hence diffusion
    between patients can arise from multiple fac-     5. Therapeutic effect difficult to monitor         of the drug.
    tors:                                                 If there is an obvious clinical effect of a
    • Age – large pharmacokinetic differences         medication then TDM is usually not neces-         2. Timing of Sample
       between neonates, children, adults and ge-     sary. For example, drugs that lower blood             An important part of therapeutic drug
       riatric individuals                            pressure can be monitored directly by measur-     monitoring is the timing of the blood col-
    • Gender – differences due to body fat com-       ing blood pressure. Anticoagulants are more       lection. When a drug is administered, the
        position                                      effectively monitored by measuring INR. If        blood concentration increases until it reach-
    • Pregnancy – for example, plasma drug            there is no clear physiological response to       es a peak and then the concentration begins
        levels of phenytoin and phenobarbitone        monitor and a drug is being used prophylac-       to fall. The lowest concentration (trough) is
        tend to be reduced during pregnancy           tically, e.g. anticonvulsants, antiarrhythmics,   usually just before the next dose. The time
                                                                                                        required for the serum concentration of a
                                                                                                        drug to decrease by 50% is called the half-
    An important part of therapeutic drug monitoring is the timing                                      life of the drug. When a drug is adminis-
    of the blood collection. When a drug is administered, the blood                                     tered in intervals approximately equal to its
                                                                                                        half-life, a steady state concentration will
    concentration increases until it reaches a peak and then the                                        be achieved after 4-5 half-lives. For drugs
                                                                                                        with a long half-life, there is little differ-
    concentration begins to fall.                                                                       ence between the steady state peak and
                                                                                                        trough concentrations. For drugs with a
    • Drug-drug interactions – co-administra-         depression, asthma, or organ rejection, then      short half-life, the differences between the
        tion of drugs which inhibit metabolism        TDM may be warranted. Seizure activity in         peak and trough concentrations can be sig-
        may lead to higher than expected con-         a patient taking anticonvulsants may indicate     nificant and both are usually measured (i.e.
        centrations and toxicity while co-admin-      low drug concentrations or toxicity. The deci-    aminoglycosides).
        istration of drugs that induce metabolic      sion to increase or decrease the dose is most         Drugs that are given intravenously require
        enzymes may reduce concentrations and         efficiently made on the basis of the serum         time to redistribute into the different body
        lead to ineffectiveness                       concentration.                                    compartments. In general, intravenous medi-
    • Genetic polymorphisms in drug metabo-                                                             cations can be sampled 30-60 minutes post
        lizing enzymes (pharmacogenetics) – cer-      Considerations                                    administration. Digoxin however requires 6
        tain individuals may have polymorphic         for TDM                                           hours for redistribution to occur.
        enzymes which are inactive or partially
        active resulting in delayed clearance while   1.   Sample type                                  3.   Interpretation
        others may have multiple gene copies en-          Serum or plasma samples are usually               Drug concentration determinations must
        coding for the enzyme resulting in “fast”     collected for TDM. Serum separator tubes          always be interpreted in the context of the
        or “rapid” metabolism of the drug             should be avoided since lipophilic drugs can      clinical situation. For example, a concentra-
    • Malabsorption – increased microfloral            dissolve in the gel barrier.                      tion of digoxin that would normally be thera-
        colonization, accelerated GI transit, de-         The use of oral fluid (saliva) for drug mon-   peutic could be toxic if the patient also has
        layed gastric emptying, bowel surgery         itoring has received a great deal of attention.   hypokalemia.
        may influence the amount of drug ab-           Measuring drugs in oral fluid is appealing be-
        sorbed                                        cause samples can be obtained non-invasively.     Conclusion
    • Liver disease – decreased metabolism            There are however a number of limitations to          Therapeutic drug monitoring may be use-
    • Kidney disease – decreased renal clear-         using oral fluid. The concentration of a drug      ful for establishing initial dosing and moni-
        ance                                          in saliva is proportional to the concentration    toring certain medications. TDM cannot com-
    • Cardiovascular disease – decreased perfu-       of the unbound drug rather than to the total of   pensate for errors in diagnosis, poor choice of
        sion                                          bound and unbound drug, usually measured          drug, errors in dispensing and dosages, errors
       Therapeutic drug monitoring may be use-        in a plasma sample. Intuitively, this should be   in sample timing, non-compliance, etc. How-
    ful in establishing the initial individualized    preferred since the free unbound fraction of      ever, when used in combination with good
    dosage for a given patient in the above situa-    the drug should represent the active amount of    clinical observation, it can lead to optimal
    tions. Once the dosage is established however,    drug in the body. While most drugs passively      drug therapy. ❖




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