Therapeutic Drug Monitoring

Mohammed Ahmed Bakheit Alkheider

B.pharm , Msc clinical pharmacy

What is therapeutic drug monitoring?

refers to the individualization of dosage by maintaining plasma or blood drug concentrations within a target range (therapeutic range, therapeutic window).

TDM encompasses the measurement of serum drug levels and application of clinical pharmacokinetics to improve patient care.

TDM is defined as the use of drug levels, pharmacokinetic principles and pharmacodynamic factors to optimize drug therapy in individual patients.

sources of variability between individual patients in drug response:

• dose and plasma concentration (pharmacokinetic variability)

• drug concentration at the receptor and response (pharmacodynamic variability).

Major sources of pharmacokinetic variability

Compliance

Age - neonates, children, elderly

Physiology - gender, pregnancy

Disease - hepatic, renal, cardiovascular, respiratory

Drug interactions

Environmental influences on drug metabolism

Genetic polymorphisms of drug metabolism

For which drugs is monitoring helpful ?

marked pharmacokinetic variability

concentration related therapeutic and adverse effects

narrow therapeutic index

defined therapeutic (target) concentration range

desired therapeutic effect difficult to monitor

TDM is used in two major situations:

drugs used prophylactically to maintain the absence of a condition such as seizures, cardiac arrhythmias, depressive or manic episodes, asthma relapses or organ rejection.

to avoid serious toxicity as with the aminoglycoside antibiotics which, unlike most antibiotics, have a narrow therapeutic range.

Characteristics of drugs that monitored

Narrow therapeutic index

Poor correlation between dose and effect

Good correlation between serum level and effect

Wide interpatient variation in clearance

A toxicity profile that is difficult to recognize clinically

What information is required for interpretation?

Time of sample in relation to last dose

Duration of treatment with the current dose

Dosing schedule

Age, gender

Other drug therapy

Relevant disease states

Reason for request e.g. lack of effect, routine monitoring, suspected toxicity

Drugs that commonly monitored include:

Aminoglycosides – gentamycin, tobramycin, netilmicin, amikacin, vancomycin.

Antiepileptic – phenytoin, carbamazepine, phenobarbital.

Cardioactive a gent – digoxin, procainamide, lidocaine, disopyramide, flecainide.

Others – theophylline, lithium, methotrexate, cilcosporin.

Time to maximal response:

By knowing the half-life of a drug, the time to reach a steady state may be estimated ,and also when the maximal therapeutic response is likely to occur, irrespective of whether drug level monitoring is needed.

Need for a loading dose:

The same type of information can be used to determine whether the loading dose of a drug is necessary, since drugs with longer half-lives are more likely to require loading doses for acute treatment.

Dosage alterations:

Clinical pharmacokinetics can be useful in determining dosage alteration if the route of elimination is impaired through end organ failure (e.g. renal failure) or drug interaction. Using limited pharmacokinetic information such as the fraction that should be excreted unchanged (value), which can be found in most pharmacology textbooks, quantitative dosage changes can be estimated.

Zero-order reaction

Consider the rate of elimination of drug A from the body. If the amount of the drug, A is decreasing at a constant rate, then the rate of elimination of can be described as:

dA/ dt = -k*

Where k* = the zero-order rate constant.

The reaction proceeds at a constant a rate and is independent of the concentration of A present in the body. An example is the elimination of alcohol.

Drugs that show this type of elimination will show accumulation of plasma levels of the drug and hence nonlinear pharmacokinetics.

First-order reaction

if the amount of drug A is decreasing at a rate that is proportional to A, the amount of drug A remaining in the body, then the rate of elimination of drug A can be described as:

dA/dt = -kA

Where k = the first-order rate constant.

Most drugs used in clinical practice at therapeutic dosages will show first-order rate processes.

There are notable exception, e.g: phenytoin and high-dose salicylates.

For drugs that show first order reaction, as the amount of the drug administered increases, the body is able to eliminate the drug accordingly and accumulation will not occur.

If you double the dose you will double the plasma concentration.

If you continue to increase the amount of drug administered then all drugs will change from showing a first-order process to zero-order process, e.g: in an over dose situation.

First-order reaction

Pharmacokinetic models

Are hypothetical structures used to describe the fate of drug in biological system following its administration.

One-compartment model:

Following drug adminstration, the body is depicted as a kinetically homogenous unit. T

Two-compartment Model:

It resolves the body into a central and peripheral compartment.

Multicompartment models:

The drug distributes into more than one compartment .

Pharmacokinetic parameters

Elimination rate constant:

Consider a single IV bolus of drug X. As time proceeds, the amount of drug in the body is eliminated. Thus the rate of elimination can be described( assuming first-order elimination) as:

dX/dt = -kX

Hence:

X = X0 exp(-kt)

Where X=amount of drug X, X0 = dose and k = elimination rate constant.

Volume of distribution:

is the volume of plasma in which the total amount of drug in the body would be required to be dissolved in order to reflect the drug concentration attained in plasma.

Vd = D/Cp

Half life

Is the time required to reduce the plasma concentration to one half its initial value.

T1/2 = 0.693/k

Clearance :

Clearance (Cl) is computed by taking the ratio of the dose (D) and area under the serum concentration/time curve (AUC) for a drug that is administer intravenously: Cl = D/AUC.

If the dose is administered extravascularly, the bioavailability fraction (F) must be included to compensate for drug that does not reach the systemic vascular system:

Cl = (FD)/AUC

The definition of clearance is the volume of serum or blood completely cleared of the drug per unit time.

Clearance (Cl) is the most important pharmacokinetic parameter because it determines the maintenance dose (MD) that is required to obtain a given steady-state serum concentration (Css): MD = Css ⋅ Cl. If one knows the clearance of a drug, and wants to achieve a certain steady-state serum concentration, it is easy to compute the required maintenance dose. Target steady-state concentrations are usually chosen from previous studies in patients that have determined minimum effective concentrations and maximum concentrations that produce the desired pharmacological effect but avoid toxic side effects.

• For example, the therapeutic range for theophylline is generally accepted as 10–20 μg/mL for the treatment of asthma with concentrations of 8–12 μg/mL considered as a reasonable starting point. If it were known that the theophylline clearance for a patient equaled 3 L/h and the desired steady-state theophylline serum concentration was 10 μg/mL, the theophylline maintenance dose to achieve this concentration would be 30 mg/h (10 μg/mL = 10 mg/L; MD = Css ⋅ Cl;

• MD = 10 mg/L ⋅ 3 L/h = 30 mg/h).

LINEAR VERSUS NONLINEAR PHARMACOKINETICS

• When drugs are given on a constant basis, such as a continuous intravenous infusion or an oral medication given every 12 hours, serum drug concentrations increase until the rate of drug administration equals the rate of drug metabolism and excretion. At that point, serum drug concentrations become constant during a continuous intravenous infusion or exhibit a repeating pattern over each dosage interval for medications given at a scheduled time.

• For example, if theophylline is given as a continuous infusion at a rate of 50 mg/h, theophylline serum concentrations will increase until the removal of theophylline via hepatic metabolism and renal excretion equals 50 mg/h. If cyclosporine is given orally at a dose of 300 mg every 12 hours, cyclosporine blood concentrations will follow a repeating pattern over the dosage interval which will increase after a dose is given (due to drug absorption from the gastrointestinal tract) and decrease after absorption is complete.

When medications are given on a continuous basis, serum concentrations increase until the rate of drug administration equals the elimination rate. In this case, the solid line shows serum concentrations in a patient receiving intravenous theophylline at a rate of 50 mg/h (solid line) and oral theophylline 300 mg every 6 hours (dashed line). Since the oral dosing rate (dose/dosage interval = 300 mg/6 h = 50 mg/h) equals the intravenous infusion rate, the drug accumulation patterns are similar. For the intravenous infusion, serum concentrations increase in a smooth pattern until steady state is achieved. During oral dosing, the serum concentrations oscillate around the intravenous profile, increasing during drug absorption and decreasing after absorption is complete and elimination takes place.

While most drugs follow linear pharmacokinetics, in some cases drug concentrations do not change proportionally with dose.

When steady-state concentrations change in a disproportionate fashion after the dose is altered, a plot of steady-state concentration versus dose is not a straight line and the drug is said to follow nonlinear pharmacokinetics.

When steady-state concentrations increase more than expected after a dosage increase, the most likely explanation is that the processes removing the drug from the body have become saturated.

This phenomenon is known as saturable or Michaelis-Menten pharmacokinetics. Both phenytoin2 and salicylic acid3 follow Michaelis-Menten pharmacokinetics.

When steady-state concentrations increase less than expected after a dosage increase, there are two typical explanations.

Some drugs, such as valproic acid4 and disopyramide,5 saturate plasma protein binding sites so that as the dosage is increased steady-state serum concentrations increase less than expected.

Other drugs, such as carbamazepine,6 increase their own rate of metabolism from the body as dose is increased so steady-state serum concentrations increase less than anticipated. This process is known as autoinduction of drug metabolism.

• A patient with liver failure and a patient with heart failure need to be treated with a new antiarrhythmic drug. You find a research study that contains the following information for Stopabeat in patients similar to the ones you need to treat: normal subjects: clearance = 45 L/h, volume of distribution = 175 L; liver failure: clearance = 15 L/h, volume of distribution = 300 L; heart failure: clearance = 30 L/h, volume of distribution = 100 L. Recommend an intravenous loading dose (LD) and continuous intravenous infusion maintenance dose (MD) to achieve a steady-state concentration of 10 mg/L for your two patients based on this data and estimate the time it will take to achieve steady-state conditions.

Sol:

The liver failure patient would likely have pharmacokinetic parameters similar to the liver failure patients in the research study (Cl = 15 L/h, V = 300 L): LD = V ⋅ Css, LD = (300 L)(10 mg/L) = 3000 mg intravenous bolus; MD = Cl ⋅ Css, MD = (15 L/h) (10 mg/L) = 150 mg/h intravenous infusion. The half-life would be estimated using the clearance and volume of distribution: t1/2 = (0.693 V)/Cl, t1/2 = [(0.693)(300 L)] / (15 L/h) = 13.9 h. Steady state would be achieved in 3–5 t1/2 equal to 42–70 hours. The heart failure patient would likely have pharmacokinetic parameters similar to the heart failure patients in the research study (Cl = 30 L/h, V = 100 L): LD = V ⋅ Css, LD = (100 L)(10 mg/L) = 1000 mg intravenous bolus; MD = Cl ⋅ Css, MD = (30 L/h) (10 mg/L) = 300 mg/h intravenous infusion. The half-life would be estimated using the clearance and volume of distribution: t1/2 = (0.693 V)/Cl, t1/2 = [(0.693)(100 L)]/ (30 L/h) = 2.3 h. Steady state would be achieved in 3–5 t1/2 equal to 7–12 hours.

Average values of Michaelis-Menten pharmacokinetic parameters for phenytoin in adults are Vmax = 500 mg/d and Km = 4 mg/L. What are the expected average doses of phenytoin that would produce steady-state concentrations at the lower and upper limits of the therapeutic range (10–20 mg/L)?

Sol:

Since phenytoin follows saturable pharmacokinetics, the Michaelis-Menten equation can be used for concentrations of 10 mg/L and 20 mg/L: MD = (Vmax ⋅Css)/(Km + Css); MD = [(500 mg/d)(10 mg/L)]/(4 mg/L + 10 mg/L) = 357 mg/d for Css = 10 mg/L; MD = [(500 mg/d)(20 mg/L)]/(4 mg/L + 20 mg/L) = 417 mg/d for Css = 20 mg/L.