Dept of pharmacology & biochemistry lab

A Practical guide for optimization TDM (1)

Prepared by Dr. Ahmed Shaker Ali Ahmedshaker21@yahoo.com

Drug monitoring specialist at KAUH 1997-2007 Associate professor of pharmacology dept of pharmacology 2007-2009

1430 H/ 2009

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Table of content

INTRODUCTION..........................................................................................................................2

BASIC PHARMACOKINETIC PARAMETERS..........................................................................3

VARIABILITY IN PK PARAMETER VALUES........................................................................4

WHAT IS TDM ?...........................................................................................................................6

Indication of TDM:..................................................................................................................................................6

Criteria for Optimal TDM service............................................................................................................................6

GENERAL GUIDELINES.............................................................................................................7

1. OPTIMIZING TDM OF ANTIEPILEPTIC DRUGS................................................................7

1.1. Justify is the purpose of monitoring...................................................................................................................7

1.2.Consider the method of analysis, units...............................................................................................................7

1.4. Consider a schedule for starting & repeating TDM..........................................................................................7

1.5. Insure optimal sampling.....................................................................................................................................7

1.6. Consider the following Criteria for judging the results.....................................................................................8

1.8 Enhance patient compliance,..............................................................................................................................8

1.2.OPTIMIZING TDM OF ANTIBIOTICS................................................................................9

1.2.1.Introduction......................................................................................................................................................9

1.2.2 Justify the reason for TDM,.............................................................................................................................9

1.2.3 Provide clear instructions for sampling..........................................................................................................9

1.2.4 Provide essential information :......................................................................................................................9

1.2.5 Consider the following points before interpretation of results......................................................................9

1.2.6- Pharmacokinetic (PK) approach for optimal dosing....................................................................................10

1.3. OPTIMIZING TDM OF CYCLOSPORINE A...................................................................11

1.3.1. Introduction:..................................................................................................................................................11

1.3.2.Trough level monitoring (C-0) is simple but of little benefit........................................................................11

1.3.3.Area under curve monitoring (AUC) is accurate but not practical................................................................11

1.3.4. Two-hour post dose monitoring (C-2) is simple and accurate......................................................................11

1.3.4 Recommended Target .C-2 levels ±20 % in adult KTP11............................................................................11

1.4. INTERPRETATION OF SERUM DRUG LEVELS............................................................12

1.4.1.Judgment is essential......................................................................................................................................12

1.4.2. Management of abnormal values..................................................................................................................12

1.4.2.1. verify analytical or pre-analytical errors...................................................................................................12

1.4.2.2.Review patient’s specific data & investigations.........................................................................................12

1.4.2.3 Consider the PK/PD variables..................................................................................................................12

1.4.2.4. Consider other reasons..............................................................................................................................13

II- OPTIMAL SAMPLING FOR TDM........................................................................................14

2.1. Introduction:.....................................................................................................................................................14

2.2.Optimal sampling time:.....................................................................................................................................14

2.2.10 References....................................................................................................................................................15

2.2.11. Diagrams for optimal sampling time..........................................................................................................16

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REFERENCES.............................................................................................................................17

4.1 references for Sections 1.1, 1.2 & 1.4...............................................................................................................17

4.3. References for Section 1.3...............................................................................................................................17

4.3. Additional references for aminoglycosides.....................................................................................................18

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INTRODUCTIONPharmacokinetics: Study of the time course of a drug and its metabolites in the body after administration by any route.An appropriate response to a drug requires the appropriate concentration of drug at the site of action. The dosage regimen required to attain and maintain the appropriate concentration depends on Pharmacokinetics. The appropriate concentration and dosage regimen depend on the patient's clinical state, severity of the disorder, presence of concurrent disease, use of other drugs, and other factors.Because of individual differences, drug administration must be based on each patient's needs--traditionally, by empirically adjusting dosage until the therapeutic objective is met. This approach is frequently inadequate because optimal response may be delayed or serious toxic reactions may occur. Alternatively, a drug can be administered according to its expected absorption and disposition (distribution and elimination-- in a patient, and dosage can be adjusted by monitoring plasma drug concentration and drug effects. This approach requires knowledge of the drug's pharmacokinetics as a function of the patient's age and weight and the kinetic consequences of concurrent diseases (eg, renal, hepatic, or cardiovascular disease or a combination of diseases).

BASIC PHARMACOKINETIC PARAMETERS The pharmacokinetic behavior of most drugs can be summarized by the following parameters, whose formulas are listed in table 1 the parameters are constants, although their values may differ from patient to patient and in the same patient under different conditions.Bioavailability expresses the extent of drug absorption into the systemic circulation The absorption rate constant expresses the speed of absorption. These parameters influence the maximum (peak) concentration, the time at which the maximum concentration occurs (peak time), and the area under the concentration-time curve (AUC) after a single oral dose. During long-term drug therapy, the extent of absorption is the more important measurement because average concentration depends on it; the degree of fluctuation is related to the absorption rate constant.The apparent volume of distribution is the amount of fluid that would be required to contain the drug in the body at the same concentration as in the blood or plasma. It can be used to estimate the dose required producing a given concentration and the concentration expected for a given dose. The unbound concentration is closely associated with drug effects, so unbound fraction is a useful measure, particularly when plasma protein binding is altered--e.g., by hypoalbuminemia, renal or hepatic disease, or displacement interactions. The apparent volume of distribution and the unbound fraction in plasma are the most widely used parameters for drug distribution The rate of elimination of a drug from the body varies with the plasma concentration. The parameter relating elimination rate to plasma concentration is total clearance, which equals renal clearance plus extra renal (metabolic) clearance The fraction, excreted unchanged helps assess the potential effect of renal and hepatic diseases on drug elimination. A low fraction indicates that hepatic metabolism is the likely mechanism of elimination and that hepatic disease may therefore affect drug elimination. Renal diseases produce greater effects on the kinetics of drugs with a high fraction excreted unchanged.The extraction rate of a drug from the blood by an eliminating organ, such as the liver, cannot exceed the rate of drug delivery to the organ. Thus, clearance has an upper limit,

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based on drug delivery and hence on blood flow to the organ. Furthermore, when the eliminating organ is the liver or gut wall and a drug is given orally, part of the dose may be metabolized as it passes through the tissues to the systemic circulation; this process is called first-pass metabolism. Thus, if extraction (clearance) of a drug is high in the liver or gut wall, oral bioavailability is low, sometimes precluding oral administration or requiring an oral dose much larger than an equivalent parenteral dose. Drugs with extensive first-pass metabolism include hydralazine, isoproterenol, lidocaine, meperidine, morphine, nifedipine, nitroglycerin, propranolol, testosterone, and verapamil.The elimination rate constant is a function of how a drug is cleared from the blood by the eliminating organs and how the drug distributes throughout the body.Half-life (elimination) is the time required for the plasma drug concentration or the amount of drug in the body to decrease by 50%. For most drugs, half-life remains the same regardless of how much drug is in the body. Exceptions include phenytoin, theophylline, and heparin.Mean residence time (MRT), another measure of drug elimination, is the average time a drug molecule remains in the body after rapid IV injection. Like clearance, its value is independent of dose. After an IV bolus,

AUMC is the area under the first moment of the plasma concentration-time curve. For a drug with one-compartment distribution characteristics, MRT equals the reciprocal of the elimination rate constant.

VARIABILITY IN PK PARAMETER VALUES Many factors affecting pharmacokinetic parameters should be considered when tailoring drug administration for a particular patient. Even with dosage adjustment, however, sufficient variability usually remains; thus, drug response and, in some cases, plasma drug concentration must be closely monitored.Age and weight: For some drugs, the effects of age and weight on pharmacokinetics are well established. For persons aged 6 mo to 20 yr, renal function appears to correlate well with BSA. Thus, for drugs primarily eliminated unchanged by renal excretion, clearance in children varies with age according to change in BSA. For persons > 20 yr, renal function decreases about 1%/yr. Thus, dosage of these drugs can be adjusted by age. BSA also correlates with metabolic clearance in children, although exceptions are common. For newborns and infants, renal and hepatic functions are not fully developed, and generalizations, except for the occurrence of rapid change, are less accurate.Renal function impairment: Renal clearance of most drugs appears to vary directly with creatinine clearance, regardless of which renal disease is present. The change in total clearance depends on the contribution of the kidneys to total elimination. Thus, total clearance should be proportional to renal function (creatinine clearance) for drugs excreted unchanged and to be unaffected for drugs eliminated by metabolism.Renal failure may change the apparent volume of distribution, which decreases for digoxin because of decreased tissue binding and increases for phenytoin, salicylic acid, and many other drugs because of decreased binding to plasma proteins.Physiologic stress: Concentration of the acute-phase protein 1-acid glycoprotein increases during physiologic stress (eg, MI, surgery, ulcerative colitis, Crohn's disease). Consequently, the of several drugs (eg, propranolol, quinidine, disopyramide) to this

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protein increases, and the apparent volume of distribution of these drugs decreases accordingly.Hepatic disease: Hepatic dysfunction can change metabolic clearance, but good correlates or predictors of the changes are unavailable. Hepatic cirrhosis can dramatically reduce drug metabolism and often results in reduced plasma protein binding because of lowered plasma albumin. Acute hepatitis, with elevated serum enzymes, usually does not alter drug metabolism.Other diseases: Heart failure, pneumonia, hyperthyroidism, and many other diseases can alter the pharmacokinetics of drugs.Drug interactions: Pharmacokinetic parameter values and, therefore, drug response may be affected by drug interactions. Most interactions are graded, and the extent of the interaction depends on the concentrations of both drugs. Thus, determining and adjusting drug dosage is difficult Dosage: In some instances, changes in dose, dosing rate, or duration of therapy alter a drug's kinetics. For example, as dose is increased, the bioavailability of griseofulvin decreases because of the drug's low solubility in the fluids of the upper GI tract. For phenytoin, steady-state plasma concentration increases disproportionately when dosing rate is increased, because the metabolizing enzyme has a limited capacity to eliminate the drug, and the usual dosing rate approaches the maximum rate of metabolism. Plasma carbamazepine concentration decreases during long-term use because carbamazepine induces its own metabolism. Other causes of dosage-dependent kinetic changes are saturable plasma protein and tissue binding (eg, phenylbutazone), saturable secretion in the kidneys (eg, high-dose penicillin), and saturable metabolism during the first pass through the liver (eg, propranolol).

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WHAT IS TDM ? Therapeutic drug monitoring (TDM) is the process of quantifying drug concentrations in patients and using these measurements to design individualized dosing regimens (dose, formulation, route, and frequency of administration). The potential for TDM to improve care is being increasingly recognized When performed correctly, TDM has been shown to efficiently maximize efficacy and minimize toxicity in many patient populations TDM has become a routine method to maintain "therapeutic" concentrations of numerous drugs . However, it requires drug concentrations to be interpreted for each specific patient's complete clinical, pharmacokinetic, and pharmacodynamic information. Unfortunately, too many laboratories report (and laboratory certifying bodies accept) "numbers only"—i.e., concentration without complete and accurate medical and drug dosing information. When done poorly, as in a "numbers only" laboratory, TDM has not been effective and can be dangerous (1 -3 ).

Indication of TDM:o Drugs with a narrow therapeutic index where therapeutic drug levels do not differ

greatly from levels associated with serious toxicity .e.g digoxin o Patients who have impaired clearance of a drug with a narrow therapeutic index are

candidates for drug monitoring.. Example: Patients with renal impairment have decreased clearance of vancomycin and therefore are at a higher risk for vancomycin toxicity.

o Drugs whose toxicity is difficult to distinguish from a patient’s underlying disease may require monitoring. Example: Theophylline in patients with chronic obstructive pulmonary disease.

o Drugs whose efficacy is difficult to establish clinically May require monitoring of plasma levels. Example: Phenytoin.

Criteria for Optimal TDM service A good clinical indication for the test such as : no response to treatment; suspected

non-compliance; signs of toxicity; The collection of an appropriately timed and dated specimen with proper patient

information; Adequate clinical information to allow the interpretation of results.

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GENERAL GUIDELINES

1. OPTIMIZING TDM OF ANTIEPILEPTIC DRUGS Commonly monitored anticonvulsant drugs ACDs are carbamazepine, phenytoin, Valproic acid, & Phenobarbital. The following guidelines aims to optimize TDM of these ACD in case of long-term therapy of epilepsy in children and adults

1.1. Justify is the purpose of monitoring Clinician must specify the reason for TDM in the request form to support

interpretation. TDM of ACDs may have several purposes: monitoring compliance following the results of AED dosage changes establishing a patient's maximum tolerated serum level looking for early signs of adverse effects (e.g., hepatic ) Support management of toxicity Inadequate response, or altered clinical response ; etc Management of drug interactions especially with other ACDs.1.2.Consider the method of analysis, units

Monitoring of Total AED serum levels is the most common procedure. Total serum levels can be misleading in some patients. Free unbound serum levels of phenytoin and valproate should be checked in patients with low albumin levels or patients who are taking multiple drugs that are tightly protein-bound. Results may presented in ug/ml or umol/L, appropriate conversion is required to compare results from different labs if different units are used.

1.3. considereMonitoring of other parameters In many cases Serum level alone don’t insure safe use of ACDs Other tests may include measurements of electrolyte levels, liver and kidney function tests, and blood-cell counts, depending on the patient's history and the type of adverse effects reported with the AED being used.

1.4. Consider a schedule for starting & repeating TDM TDM often performed after initiation of treatment and should be repeated at the at steady state .The frequency of testing usually requires clinical judgment on the necessity for testing. For example when high level ( up side of ref range ) of phenytoin or Phenobarbital is observed, further follow up must be considered to insure no further accumulation .

1.5. Insure optimal sampling At steady state optimal sampling time is not critical for Phenobarbital, phenytoin & carbamazepine due to long half-life. i.e random sample are practically acceptable. However the optimal sampling time given below provide more consistent results

To evaluate efficacy , Obtain a trough level (just before next dose), once the steady state conditions have been reached, ( practically after 4-5 half-lives of the drug ) Written instructions to the patient : “do not take your morning pill until you have had your blood taken

Transiant toxicity:

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Collect blood samples when the signs of toxicity are present (usually associated with peak level; 1-2 hr after IV dose or 4-6 hr after oral administration of conventional formulations of phenytoin or carbamazepine , and 2-3 hr in case of Valproic acid ) . Written instructions to the patient “go to the lab and have your blood taken when your symptoms are present

Management of toxicity Collect a Random sample, repeat measurement in view of the observed level and clinical need

1.6. Consider the following Criteria for judging the results

Clinical Judgment Drug concentrations can’t replace clinical assessment of patients for efficacy and adverse effects. The drug concentration can only be regarded as a guide for dose adjustment Dosages should be changed based on clinical grounds such as seizure breakthrough or side effects, not because of the serum level. Using blood levels to check for compliance is not always reliable. pharmacokinetic and pharmacodynamic variables: Many PK/PD variables including formulations, route of administration, attaining steady state , interaction with other ACDs should be considered for both optimal dosing and interpretation of results.) Several PK /PD variables showed be considered for appropriate interpretation of results for example the free level of phenytoin is higher in case of co-administration of Valproic acid Neonates subjected to neonatal asphyxia have a significant reduced clearance of Phenobarbital. Phenytoin is is erratically absorbed orally in neonates. range”. {more examples will be given under Interoperation of results)Therapeutic ranges are only provided as a guide.Great inter-individual variations in pharmacokinetic (absorption, biotransformation,) and pharmacodynamic (clinical response and adverse effects) of antiepileptic drugs are observed. Patients may develop toxic symptoms at levels “within the therapeutic range”. Some patients may require and tolerate concentrations above the “therapeutic.

1.7. Consider Other factors may influence serum levels: laboratory error generic substitution for brand-name AEDs variable potency of pills (following improper storage, for example) menstrual cycle (midcycle serum AED levels may be higher than during the premenstrual period or menses)

1.8 Enhance patient compliance, We observed that patient non-compliance is the main reason for very low level of Antiepileptic drugs. Irregular drug intake prior to drug concentration measurement (non-compliance confounds the interpretation of the result.)1.9. Provide the required information in TDM request FORM: Providing these information will take few mints but may allow proper interpration , safe of time & reagents. These include patient age, sex, weight, other illness, how long the patient was taking the current dose, when the last 2-3 doses were taken, and the sample collection time. Other medications, presence of disease that alters protein binding or liver impairment.

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1.2.OPTIMIZING TDM OF ANTIBIOTICS.1.2.1.Introduction.

The following guidelines aim to insure proper utilization of TDM service to enhance efficacy and minimize toxicity of commonly monitored antibiotics; aminoglycosides ( Gentamaicin , amikacin ), and vancomycin .

1.2.2 Justify the reason for TDM, Debate exists concerning determination of vancomycin peak level and aminoglycosides peak-level in case of once daily dosing, However, peak levels though to be of little value in some cases may be valuable in other situations e.g. neonates or renal impairment ( small doses are given at extended interval )etc

1.2.3 Provide clear instructions for samplingDifferent instructions for sampling are currently applied depending on the drug being tested and regimen. Clear instruction should be written to guide personnel responsible for sampling e.g. take sample for trough (pre ) within 30 min before next dose, sample for peak gentamicin level 30 min after end of infusion. N.B :Samples for peak levels taken later than specified time may provide false lower values. Samples for trough level taken earlier may provide false higher results . Such results may be misleading and confusing

1.2.4 Provide essential information : Some information are essential for interpretation and avoiding artifacts or misleading results. These include demographic characteristics, diagnosis , site severity of infection , treatment regimen including other medication, sampling time , renal function, clinical response and any other observations seemed of value for interpretation..

1.2.5 Consider the following points before interpretation of results. A-Therapeutic range only serves as a guideIndividual patients results should be interpreted in light clinical status and variables including , severity and site of infection, duration of treatment, administration of other nephrotoxic drugs etc . e.g values higher than ref range may be acceptable in life threatening infections. Slightly high trough level is acceptable in case of short courses but review of regimen should be considered in case of long courses. Results are usually presented either in mg/L or umol/L appropriate conversion are required to compare these values .B-Efficacy of aminoglycoside is concentration-dependent Usually High peak ( 8-10 MIC ) is recommended to enhance the efficacy. Very Low trough level for short period 3-5 hr minimizes the toxicity and usually doesn’t reduce the efficacy ( due to Post antibiotic effect ) . This explains why regimens of relatively high doses and longer interval are more recommended. C- Efficacy of vancomycin is time dependent : High peak usually don’t enhance efficacy in most infections ( except meningitis- due to low penetration of the drug) trough level within ref range 3-7 umol/L should be maintained. Thus regimens of small dose and short interval are usually preferred.D- High once daily dosing (OD) of aminoglycosides has different. protocolSeveral approaches are proposed for sampling and interpretation 1- determination of trough level only to monitor potential toxicity ( level should be very low ). 2-Taking a timed random sample ( 6-14 hr ) post dose and applying Hartford Hospital OD-

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Aminoglycosides Nomogram to guide the dosing interval.( Nicolau et al 1996 ) It is applied only to gentamicin 7 mg/kg once daily. 3-Computerized PK-approach has been proposed by TDM unit to predicate the level in view of dose, renal function and sampling time This concept was evaluated in limited number of patients and showed

good results Further evaluation is. currently in progress .( Ali AS 2005 )

Confirm and verify the reason for abnormal values Review sampling time, review previous results and clinical status of the patients to trace any supporting evidence . Low peak low trough may indicate sub-optimal dosing, high peak high trough may indicate potential toxicity.– Peak level very close to trough level suggest wrong sampling. If the results still confusing , repeat the measurement at the specified time.

1.2.6- Pharmacokinetic (PK) approach for optimal dosing Many programs are available that make this approach simple and practical..[ e.g Antibiotic Kinetics http://www.rxkinetics.com/ The basic procedures are: Take two accurately timed samples ,( t1 & t2 ,) determine serum level (C1, C2 ) , estimation of the half-life is performed using conventional PK equation ( Ke=Ln (C1/C2)/ (t2-t1), half life =0.693/ ke ). Scientific calculators or Excel [ used by staff of the unit ] are valuable when these programs are not available.

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1.3. OPTIMIZING TDM OF CYCLOSPORINE A 1.3.1. Introduction:

Cyclosporine A (CsA) has been the mainstay of most immunosuppressive standard protocols and used for management of some autoimmune diseases. CsA blocks the signal to lymphocytes to produce IL-1, IL-2, IL-3, IL-4, and interferon gamma. CsA is a lipophillic molecule, with complex and highly variable pharmacokinetics (PK) profile. It’s bioavailability is dependent on food, bile, diurnal variation and other interacting factors. Bioavailability was improved by using microemulsion formulation (Neoral). CsA is extensively metabolized in the liver by the cytochrome P450 3A system, which is subject to considerable inter-individual variation and drug interaction .It is eliminated mainly through the bile, renal elimination < 1 %. Distribution of CsA depends on biological carriers such as lipoproteins and erythrocytes in blood. Cyclophilin, a binding protein for CsA influences distribution of CsA in the body. The drug has narrow therapeutic index. Elevated CsA level can increase the risk of Nephrotoxicity, while its decrease can increase the risk of graft rejection. Therefore CsA is considered a critical-dose drug and therapeutic drug monitoring (TDM) is an integral part of CsA therapy. CsA is strongly bond to erythrocyte (50-60%) in temperature dependant pattern, therefore whole-blood concentrations is the matrix of choice for its analysis. CsA has several metabolites some of them are biologically active and HPLC is the only assay that is completely specific for the parent drug. 1

1.3.2.Trough level monitoring (C-0) is simple but of little benefit Trough concentrations correlate poorly with clinical response. Trough level alone is not a reliable factor to predict either acute rejection or nephrotoxicity2

1.3.3.Area under curve monitoring (AUC) is accurate but not practical Variability in absorption was considered as a risk factor for chronic rejection. AUC precisely reflects the variability in absorption and total drug exposure3 AUC has been considered the most sensitive pk predictor for acute and chronic rejection in kidney transplant patients (KTP). Limited AUC (AUC0-4) approach has been recommended as an accurate alternative way to extended AUC0-12 method4 however, due to multiple blood sampling AUC approach: is impractical, especially in the outpatient setting.

1.3.4. Two-hour post dose monitoring (C-2) is simple and accurate C-2 is practical, simple, and effective way to improve outcomes in organ transplant patients. Target C-2 level showed good relationship with “Neoral” doses and considered as a good measure for CsA absorption (total drug exposure), hence simplify dosage regimen adjustment5-7. Good correlation between C-2 level and AUC0-4. (r2=0.85) was observed8,9 . Use of C-2 is organ transplant patients proved to be superior to C-0 in terms of efficacy and safety profile of CsA. C-2 with neoral reduces the incidence and severity of acute rejection, improves renal function, and lowers the incidence of hypertension. In KTP C-2 shown to predict sub clinical rejections10,11. Success of this approach requires compliance to TDM guidelines: Samples should be taken exactly 2h post morning dose. (to avoid diurnal variation). The time to reach the target level ranges between 3-5 days in KTP

1.3.4 Recommended Target .C-2 levels ±20 % in adult KTP11

Time (month) 1 2 3 4-6 7-12 >12

level ug/ml; (umol/L) 1.7 (1400) 1.5 (1250) 1.3(1080) 1.1(910) 0.9(750) 0.8(660)

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1.4. INTERPRETATION OF SERUM DRUG LEVELS 1.4.1.Judgment is essential

Measurement of the serum drug concentration (SDC) is of little value without appropriate interpretation, which requires consideration of pharmacodynamic (PD) and pharmacokinetic (PK) profiles of the drug as well as patient specific profiles (i.e. various variables affecting PK/PD of the drug).

1.4.2. Management of abnormal values Many variables influence SDC and patient clinical response. Therefore judgment is always essential before approval of results or clinical decision. TDM request form should contain accurate information that allows TDM staff to provide the appropriate comment . The following are the most important practical issues :

1.4.2.1. verify analytical or pre-analytical errors. TDM-staff should confirm accuracy of the results , double check any abnormal results after appropriate review of all procedures, QC etc. Pre-analytical errors, also should be considered before approval of unexpected results. Clinicians should consider all possibilities before final decision . ( wrong request, dosing error, sampling timer error , etc ) . Frequently repeating the test is the most simple and straightforward procedure

1.4.2.2.Review patient’s specific data & investigationsMany variables should be considered, including, age, other medications, severity of illness, clinical response, signs of toxicity. Certain biochemical parameters, e.g. reduced creatinine clearance (Clcr < 80 ml / min ) can help to support abnormally high random digoxin or trough gentamicin/ amikacin levels . Specific ECG abnormalities support elevated digoxin level. Note that many adverse effects are not concentration dependent and some other parameters should be evaluated e.g CBC to monitor hematological disorders due to carbamazepine

1.4.2.3 Consider the PK/PD variables Most hospitalized patients are supposed to receive standard dosage regimens. However, some have toxic symptoms, others have inadequate efficacy. Several PK and PD variables can explain these abnormal responses—. Properly interpreted TDM results can identify clinically important problems. Important special populations where TDM is useful either predict or prevent toxicity or improve therapeutic outcomes include : neonates & elderly, patients with impaired renal or liver function , dosing problems,& patients who have unusual PK as a result drug interaction, physiological, environmental, disease, or genetic factors (1). Neonates & elderly PK and PD behavior (16) differ greatly in neonates & elderly , compared with "normal" adult populations. All PK processes are involved. Dosing uncertainty is a problem in both the very old and the very young as a result of erroneously measured, refused, vomited, repeated, or forgotten doses. Dosing errors are more documented in neonates .Weight can change dramatically in neonates during a single course of therapy. Distribution of drugs is also altered in these populations because of differences in body composition Clearance of drugs (both metabolic and renal) is altered by age and disease-related changes, as well as by drug and diet interactions.,. The ability to tolerate or communicate drug effects is also diminished at both extremes of age. A number of unique, practical additional considerations are present in neonates (19).

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Therapeutic ranges for some drugs are quite different; e.g., therapeutic theophylline concentrations are lower for neonates (5–15 mg/L) than for adults (10–20 mg/L).

Time of drug administration is not simple to determine in neonates; it may take hours for a dose, even if administered into an intravenous line, to actually reach a neonate (20).

Assay interference from endogenous substances is also more common than in adults; e.g., digoxin-like immunoreactive substances (DLIS) (21)..

Metabolic pathways may differ qualitatively as well as quantitatively. Caffeine is present in significant quantities in neonates who are given theophylline—a result of the metabolism of theophylline.

Protein binding can be quite different in neonates, producing very different therapeutic ranges for highly protein-bound drugs such as phenytoin. ( 25-60 umol ) Impaired renal or liver function Tests of organ function (renal or hepatic) are commonly used to predict which patients are at greater risk of unusual PK behavior. Significant increase of Serum creatine level ( 25% of base line value ) can support toxicity due to aminoglycosidesNonlinear kineticForm mostt therapeutic drugs measured, clearance is independent of plasma drug concentration, so that a change in dose is reflected in a similar change in plasma level. If, however, clearance is dose dependent , dosage adjustments produce disproportionately large changes in plasma levels and must be made cautiously. Example: PhenytoinMultiple medications and drug interactionsPatients on multiple drugs are also more likely to have altered and changing PK or PD characteristics For example patients are more susbtable to aminoglycoside toxcicity in case of co-administeration of other nephrotoxic drugs e.g fursimide or vanvomycinAltered Protein binding of drugs.All routine drug level analysis involves assessment of both protein-bound and free drug. However, pharmacologic activity depends on only the free drug level. Changes in protein binding (eg, in uremia or hypoalbuminemia) may significantly affect interpretation of reported levels for drugs that are highly protein-bound. Example: Phenytoin. In such cases, where the ratio of free to total measured drug level is increased, the usual therapeutic range based on total drug level will not apply.

1.4.2.4. Consider other reasons Non compliance :Poor compliance is seen in patients with life-threatening asthma (25) and is also one of the most common causes of organ transplant-rejection episodes in adolescents, for example (26). Overdose by the patient or his family is a form of overcompliance and can occur as a result of poor understanding, or a desire to hasten or increase the magnitude of effects. TDM unit at KAUH documented a case of seriously toxic Valproic acid ( 17000 umol/L) level in a child 2 yr due to administration of the drug by nursing bottle by his mother.Dosing errors

TDM can be useful to detect over- and under dosing e.g., errors in dosage calculations (especially 10-fold errors),

.For many serious conditions, use of less than maximally effective doses is much more toxic (i.e., dangerous) than is overdosing. For example, mortality is greatly increased by under dosing of aminoglycosides in patients with serious infections

Patients receiving enteral feedings are at risk of under dosing of anticonvulsant medications because the tube-feeding solutions may interfere with drug absorption. Poor bioavailability of phenytoin was observed in neonates .

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Renal patients are also often underdosed because of confusion between their need for lower maintenance doses (low renal clearance) and their need for greater than usual loading doses to achieve therapeutic concentrations (larger volumes of distribution). A septic, anaphoric patient may need 4 or 5 mg/kg as an initial gentamicin dose rather than the 2.5 mg/kg given to a "normal" patient, .

II- OPTIMAL SAMPLING FOR TDM2.1. Introduction:

TDM is an important function of modern clinical laboratories. When used properly it improves drug therapy. To be effective TDM requires the acquisition of a valid specimen, rapid and accurate determination of drug concentration and appropriate interpretation. These elements should be considered as a network and efforts should be directed to optimizing all of them. In fact, determination of drug level is of little value and may be misleading without interpretation that requires clinical judgment in light of pharmacokinetic (PK), pharmacodynamic (PD) and patient profile .i.e. in the context of dose, time of last dose , severity of illness, clinical response, biochemical profile , investigations etc. We demonstrated that errors in sampling time and noncompliance are the main reason for abnormal serum levels of antibiotics & antiepileptic drug respectively. Therefore we calls for multidisciplinary efforts and cooperation of Total quality management , & Continuous education depts., physicians, nurses, phlebotomists, Pharmacists, Pharmacologists, lab technologists to insure optimal TDM service.

2.2.Optimal sampling time: Optimal sampling time depends on the drug's PK characteristics ( half-life, distribution ), purpose of TDM, and dosing regimen. 2.2.1 Why sampling time is critical for some drugs ?

2.2.1.1.Antibiotics :

commonly monitored antibiotics have relatively short half-life ( gentamicin & amikacin 2-3 hr , vancomycin : 5 hr ) in patients with normal renal function. After IV administered their serum level will decline rapidly. For example sampling for a peak level ( post dose ) 1 hr later than the specified time will lead to a false low level ; sampling for a trough level (pre dose ) 1- 2 hr earlier will lead to false high level. 2.2.1.2.Cyclosporine A .

Peak level [ C2; 2 hr post dose ] is recommended in transplant patient to evaluate adequate absorption. We frequently document random sampling which can lead to a false impression of inadequate absorption or inadequate dose2.2.2.2. Digoxin :

Digoxin has long distribution phase, peak tissue concentration occurs 6-10 hr after administration. Tthe appropriate time of should be > 6 hr after administration to insure correlation between tissue concentration and plasma level.2.2.2.3.Acetaminophen & MethotrexateNo interoperation of the serum level could be provided unless sampling time relative to the time of administration is carefully reported.

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2.2.3.Why trough level is recommended for many drugs taken orally ?

Time of Peak level of dugs administered orally ( e,g antiepileptic drug ) is affected by several variables including , formulation, food etc. For these reasons it is practically difficult to obtain consistent peak levels, hence trough level (pre dose) is usually satisfactory as representative of overall effect specially for those with long half-life ( e.g. phenytoin, Phenobarbital & carbamazepine ). 2.2.4.What is the importance of sampling at steady state (SS) ?

Sampling at SS ( usually trough level) is important to adjust dosage regimens or to evaluate drug efficacy in case of drugs used chronically (e.g. antiepileptic, digoxin, Theophylline ). For practical purpose, SS is considered to be attained after regular administration for a period ≈ 5 half-lives. Examples : Theophylline in adults it has a half life of ≈ 6 hr, SS is attained after 24 -30 hr , in neonates it has longer half-life ( 30 hrs ) , SS requires at least 6-7 days. However, when a loading dose is provided a shorter interval is required to attain SS. Digoxin ss requires at least 5 days after initiation of therapy and 2-3 days after changing the dose. Actual carbamazepine SS is attained after 3-4 weeks because it stimulate its own metabolism, leading to shorter half life 2.2.5.Can we take the sample before SS ?

Serum drug level can be determined before attaining SS in certain situations e.g suspected or documented toxicity, over dose, evaluation of the loading dose , patients with impaired renal or liver function. 2.2.6 What is the optimal sampling time for drugs given by low IV infusion?

Theophylline may be indicated in severe asthma . A loading dose of is usually administered by slow IV, You may evaluate peak level 1 hr after end of administration. The maintenance dose is usually administered by constant rate Iv infusion. In this case Theophylline. serum level depends on infusion rate and SS is usually attained after 6 hr of stating infusion. Due to its short half-life , ideal sampling time should be within 6 -12 hr during infusion or within 1 hr after stopping infusion. Sampling several hours after stopping of infusion may show false low level . 2.2.7.When we take a random sample?

Random sample is acceptable for phenytoin, phenobarbital & carbamazepine due to their long half-life. i.e the drug concentration does not change rapidly during dosing interval. Random sample is valuable in case of suspected digoxin toxicity, suspected non compliance for all drugs taken orally. Sometimes unreasonable high level is observed , in such cases TDM lab usually request a random sample to verify if the previous level is due to sample contamination during sample withdrawal ( i.e by the traces of the pure drug)2.2.8.When we take a timed sample ?

Timed samples are samples taken at specified times post dose. It is a recommended approach for evolution of high dose once daily (OD) regimen of aminoglycosides. It is essential for evaluation of potential Methotrexate or acetaminophen toxicity. It is also valuable for evaluation of pharmacokinetic parameters e.g patients with renal impairment.

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2.2.9.Additional Notes:

Antibiotics : In adult patients with normal renal function determination of Peak level is no longer a routine practice in case of OD dosing of aminoglycosides & vancomycin. For practical purpose sampling for Aminoglycosides starts after 4th dose (multiple daily dosing) or after the 1st dose in case of high single daily dosing (OD) regimen. Cyclosporine A Trough level ( before next dose ) may be requested when , toxicity or using CsA for management of some diseases

2.2.10. optimal sampling time & reference range , notes about individual drugs are provided in part 2.. In case of PK studies, dialysis patients , unconventional dosing regimen consult TDM staff or the clinical pharmacist for appropriate guidance.

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REFERENCES 4.1 references for Sections 1.1, 1.2 & 1.4

Robinson JD , Tylor WJ, Interpretation of serum drug concentration In Therapeutic drug monitoring and pharmacokinetics “ ABBOTT diagnostic division, Iriving Texas , 1986. pp31-45.Buritis CA, Aswood ER “ Therapeutic drug monitoring “ In Titez, Fundamentals of Clin. Chemstry, 5th ed. 2003 , PP 608-635Nicholson PW, Dobbs SM, Rodgers EM Ideal sampling time for drug. Br J Clin Pharmacol. 1980 May;9(5):467-702 Schumacher GE.Choosing optimal sampling times for therapeutic drug monitoring. Clin Pharm. 1985 Jan-Feb;4(1):84-92.TDM clinical guide : ABBOTT diagnostic division 1992Nicolau DP, Wu AH, Finocchiaro S, Once daily Aminoglycoside dosing , Therapeutic drug monitoring ; 18: 263-266, 1996 .Ahmed S. Ali , Randa Moumena ; Computerized Pharmacokinetics for optimal dosing of gentamicin OD dosing. Submitted to “ Pharmacy profession in transition “ Riyadh 19 April 2005: Schachter SC. Treatment of seizures. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 61-74

4.3. References for Section 1.31-Fahr A. Cyclosporin clinical pharmacokinetics. Clin Pharmacokinet 1993 Jun;24(6):472-952-Soliman MI;. Islam SI , Shaheen M, . ALi AS , Long impact of cyclosporine A use in kidney transplant patients ; Final report, project 101/416 King Abdulaziz university 1999 -3-David-Neto E, Araujo LP, Feres Alves C, Sumita N, et al . strategy to calculate cyclosporin A area under the time-concentration curve in pediatric renal transplantation. Pediatr Transplant. 2002 Sep;6(4):313-8.4-Meier-Kriesche HU, Kaplan B, Brannan P, Kahan BD, Portman RJ.A limited sampling strategy for the estimation of eight-hour neoral areas under the curve in renal transplantation. Ther Drug Monit. 1998 Aug;20(4):401-7.5-Grant D, Kneteman N, Tchervenkov J, Roy A, Murphy G, et al., Peak cyclosporine levels (Cmax) correlate with freedom from liver graft rejection: results of a prospective, randomized comparison of neoral and sandimmune for liver transplantation (NOF-8) Transplantation. 1999 Apr 27;67(8):1133-7.6-Oellerich M, Armstrong VW. Two-hour cyclosporine concentration determination: an appropriate tool to monitor neoral therapy Ther Drug Monit 2002 Feb;24(1):40-67-Cantarovich M, Besner JG, Barkun JS, Elstein E, Loertscher R. Two-hour cyclosporine level determination is the appropriate tool to monitor Neoral therapy. Clin Transplant. 1998 Jun;12(3):243-9.

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8-Barama A et al, absorption profiling of cyclosporine therapy..., Transplantation, 2000, 69:s162,9-Morris RG, Russ GR, Cervelli MJ, Juneja R, McDonald SP et al; Comparison of trough, 2-hour, and limited AUC blood sampling for monitoring cyclosporin (Neoral) Ther Drug Monit. 2002 Aug;24(4):479-86.10-Mahalti K et al, transplantation 1999, 68:55-62, 7-Levey et al; Transplantation, 2000,69:S225. 8-11-Levy G, Burra P, Cavallari A, Duvoux C, Lake J et al; Improved clinical outcomes for liver transplant recipients using cyclosporine monitoring based on 2-hr post-dose levels (C2).Transplantation. 2002 Mar 27;73(6):953-9

4.3. Additional references for aminoglycosides Goodman & Gillman’s. The Pharmacological Basis of Therapeutics. 10th Ed. McGraw-Hill. New York. 2001. pp1219-1235.Gonzalez III, LS& Spencer JP. Aminoglycosides: A Practical Review.” American Family Physician. Mar 10, 2003. Zaske DE. "Aminoglycosides", in Evans W, Schentag J, Jusko J (eds): Applied Pharmacokinetics. San Francisco. Applied Therapeutics, 1986; pp 331-381. Kadry AA, Tawfik AF, Abu El-Asrar AA, Shibl AM ; Elucidation of antibiotic effectiveness against Staphylococcus epidermidis during intraocular lens implantation. Int J Antimicrob Agents. 2001 Jul;18(1):55-9.Konrad F, Wagner R, Neumeister B, Rommel H, Georgieff M. Studies on drug monitoring in thrice and once daily treatment with aminoglycosides. Intensive Care Med 1993;19:215–20.Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani R. Experience with a once-daily aminoglycoside program administered to 2184 adult patients. Antimicrob Agents Chemother 1995;39:650–5.Schumock GT, Raber SR, Crawford SY, Naderer OJ, Rodvold KA. National survey of once-daily dosing of aminoglycoside antibiotics. Pharmacotherapy 1995;15:201–9.Bailey TC, Little JR, Littenberg B, Reichley RM, Dunagan WC. Ameta-analysis of extended-interval dosing versus multiple daily dosing of aminoglycosides. Clin Inf Dis 1997;24:786–95.Marra F, Partovi N, Jewesson P. Aminoglycoside administration as a single daily dose. An improvement to current practice or a repeat of previous errors? Drugs 1996;52:344–70.Ali MZ, Goetz MB. A meta-analysis of the relative efficacy and toxicity of single daily dosing versus multiple daily dosing of aminoglycosides. Clin Inf Dis 1997;24:796–809.

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Thompson AH, Campbell KC, Kelman AW. Evaluation of six nomograms using a bayesian parameter estimation program. Ther Drug Monit 1984;6:432–7 Clinical Chemistry 44, No. 5, 1998 1137Sarubbi FA, Hull JW. Gentamicin serum concentrations: pharmacokinetic predicitions. Ann Intern Med 1976;85:183-189. Sawchuk RJ, Zaske DE, et al. Kinetic model for gentamicin dosing. Clin Pharmacol Ther 1977;21;3:362-369. Sarubbi FA, Hull JW. Amikacin serum concentrations: predicition of levels and dosage guidelines. Ann Intern Med 1978;89:612-618. Lesar TS, et al. Gentamicin dosing errors with four commonly used nomograms. JAMA 1982;248(10);1190-1193. Sheiner LB, Beal S. Bayesian individualization of pharmacokinetics: simple implementation and comparison with non-Bayesian methods. J Pharm Sci 1982 71:1344-1348. Yamaoka K, Nakagawa T, et al. A nonlinear multiple regression program based on Bayesian algorithm for microcomputers. J. Pharmacobio-Dyn., 8, 246-256 1985. Burton ME, Brater DC, et al. A Bayesian feedback method of aminoglycoside dosing. Clin Pharmacol Ther 37:349-357, 1985. Burton ME, Chow MSS, et al. Accuracy of Bayesian and Sawchuk-Zaske dosing methods for gentamicin. Clin Pharm 1986;5:143-149. Donahue T, Yates DJ. Predictability of aminoglycoside serum levels dosed by a pharmacy protocol. Hospital Pharmacy 1988:23;11-25 Rodvelt KA, Zokufa H, Rotschafer JC. Aminoglycoside pharmacokinetic monitoring: An integral part of patient care? Clin Pharm 1988:7:608-613. Okamoto MP, Chi A, et al. Comparison of two microcoputer Bayesian pharmacokinetic programs for predicting serum gentamicin concentrations. Clin Pharm 1990 9:708-11. Tsubaki T, Chandler MHH. Evaluating new and traditional methods for aminoglycoside dosing with various degrees of renal function. Pharmacotherapy 1994; 14:330-336. *Nicolau DP, Wu AH, Finocchiaro S, Udeh E et al . Once-daily aminoglycoside dosing : impact on requests and costs for TDM; Therap. Drug. Monit, 18263-266, 1966Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41.Schwartz GJ, Brion LC, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am 1987;343:571–90.Shargel L and Yu A; Applied Biopharm. Pharmacokin.; 4th ed. 1999. McGraw-Hill; Medical Publishing Div.; New York p S430-

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