TDM

Cha # 04 Theraputic Drug Monitoring

By Mr.Iftikhar Ahmad

Page | 1

Chapter # 04 THERAPUTIC DRUG MONITORING

TDM, in general sense, is about using serum drug concentration, pharmacokinetics and

pharmacodynamics to individualize and optimize patient response to therapy.

AIM

To promote optimize drug treatment by maintaining serum drug concentration within a

therapeutic range above which drug induced toxicity occurs too often and below which the drug

is too often ineffective.

Specific definition of TDM

The practice applied to the small group of drugs in which there is direct relation b/w serum drug

concentration (SDC) and pharmacological response as well as a narrow range of concentration

that are safe and effective and for which serum drug concentrations are used in conjunction with

other measures of clinical observation to assess patient status.

Rationale (logic base for a course of action or belief) for TDM:

It is based upon three assumptions:

Direct relationship b/w serum drug concentration (SDC) and pharmacological response.

SDC is better predictor of patient response than is the dose.

SDC provides an opportunity to adjust the variations in the patient pharmacokinetics by

individualizing dosage regimen.

Reasons for TDM

1. Drug levels are used in conjunction with other clinical data to assist practitioner to

determine how patient is responding.

2. It provides the base for individualizing patient dosage regimen.

3. If a change in patient specific pharmacokinetic has occurred during the course of

treatment, the drug levels assist in determining either this change has occurred as a result

of change in physiological states, change in diet or addition of other drugs.



Page | 2

4. SDC is used to assure patient compliance but it is unreliable because some patients show

tooth brush behavior or pre-appointment behavior.

Therapeutic range (Serum Drug Concentration)

It is the range of drug concentration with in the plasma within which the probability of desired

clinical response is relatively high and probability of inacceptable toxicities is relatively low.

It is also known as serum drug concentration (SDC).

Examples:

For Digoxin, therapeutic range is 0.5-2 ug/L.

For theophylline, it is 10-20 ug/L.

For phenytoin: 10-20 ug/L.

Therapeutic window

It is the ratio between minimum toxic concentrations to that of minimum effective concentration

of a drug in the plasma.

Therapeutic index

It is a ratio between LD-50 and ED-50.

Requirements for TDM

Drugs which are included for TDM procedure are termed as candidate drugs. The requirements

for TDM are as follows;

i. Narrow therapeutic index drugs.

ii. Drugs that exhibit non-linear pharmacokinetics.

iii. Inter-patient pharmacokinetic variability.

iv. Steep-dose response curve.

v. Major side effects related to the concentration of drugs.

vi. Certain pharmacokinetics parameters such as :



Page | 3

- Protein binding

- Active metabolites

- Tolerance about the drug receptors level.

- Reversible pharmacological response.

- Sound clinical judgment.

i. Narrow therapeutic index drugs

TDM is necessary for such drugs because a small increase in the dose may cause toxic

manifestation.

ii. Drugs that exhibit non-linear pharmacokinetics

The drugs which obey non-linear pharmacokinetics i.e. the increase or decrease in the dose has

no direct effect on the pharmacological response, are suitable candidates for TDM. Examples of

such drugs are phenytoin, alcohol, salicylic acid etc.

There is no need of TDM for drugs with linear pharmacokinetics.

iii. Inter-variables

Internal individual pharmacokinetic variables also produce varying degree of pharmacological

response in different individuals. For example, rapid acetylators and slow acetylators.

In case of rapid acetylators, the dose of the drug is to be increased otherwise no pharmacological

response may be observed.

In case of slow acetylators, the dose is to be reduced otherwise toxic effects may be observed.

Such drugs require TDM.

iv. Steep dose response curve

It is the narrow range between the effective dose and toxic dose. Such drugs have low safety

margins and require TDM and subsequent dose adjustment. For example, barbiturates and

benzodiazepines.



Page | 4

v. Major side effects

The drugs which show major and important side effects related to the concentration of the

drug should be monitored.

vi. Pharmacokinetic variables

a. Protein binding:

Drug in the body may be either bound to plasma proteins or may be in free form.

The unbound/free drug can be absorbed, distributed and show its pharmacological

effects.

The drug with high protein binding do requires TDM because slight replacement

of the drug may result in life threatening consequences.

Example of such drug is warfarin. About 99 % of warfarin is protein bound while

only 1 % is free.

Similarly, 10-20 ug/L of phenytoin is bound while 1-2 ug/L is free.

For such drugs, TDM is necessary.

b. Active metabolites

There are certain drugs which after metabolism are converted into their active

metabolites. So during TDM of such drugs, the concentration of active

metabolites is to be determined instead of parent drug.

Examples of some drugs and their active metabolites are :

Carbamazepine ---------------------------> carbamazepine -10,11-epoxide.

Procainamide ---------------------------> N-acetylprocainamide

Theophylline ----------------------------> caffien

Tryptaline ----------------------------> Nor-tryptaline

Primodone ----------------------------> Phenobarbital

c. Tolerance at the receptor level

TDM is required for the drugs which do not cause tolerance at the receptor level.

For the drugs which cause tolerance, such as morphine, there is no need to

perform TDM because in this case increasing the dose is not associated with

toxicity but is related to pharmacological action.



Page | 5

d. Reversible pharmacological effects

Drugs producing reversible pharmacological effects need TDM. However, there

are certain drugs which show long lasting effects and their pharmacological

actions are irreversible, such drugs do not require TDM e.g alkylating agents.

e. Sound clinical judgment

Clinical judgment is of extreme importance.

Do not treat the condition, instead treat the patient.

SAMPLE COLLECTION IN TDM

Three methods are used for sample collection in TDM.

1. Drug analysis technique

2. Blood sample collection

3. Drug sample collection time

Sample used may be blood, plasma or serum depending upon the equipment.

1. Drug analysis technique:

It includes;

i. Immunoassay technique

a) Radioimmunoassay technique

b) Enzyme linked immune-sorbent assay

ii. Gas chromatography

iii. HPLC

These methods have specific sensitivity, accuracy and precision.

2. Blood sample collection

The collection of blood sample is the responsibility of clinical pharmacist. Blood sample

is taken from the patient in testing tube and it is then centrifuged to separate the plasma

and cells. The plasma portion is then collected as it contains most of the sample drug.



Page | 6

However, cyclosporine is an exception in which whole blood is taken instead of plasma

portion. This is because upon storage or temperature change, there is shift of drug from

the plasma portion to the cells.

Certain drugs have affinity for gel, so these drugs will be adsorbed on the gel and to

recover the adsorbed DRUG, non-adsorbent technique is used.

3. Drug sample collection time

It is the most critical step in TDM. After the administration of a drug, the drug undergoes

absorption, distribution and elimination. In absorption phase the plasma concentration is

high whereas in distribution phase the plasma concentration is low. So, the most ideal for

sample collection among these phases is the elimination phase which gives clue about

any impaired functioning organ.

It is also of importance to consider that the collection should be at loading dose or steady

state.

If we are interested in loading dose, then the sample is taken in post (before) distribution

phase and if we are interested in steady state concentration, then the sample is taken in

elimination phase.

Usual sampling time:

To determine the usual sampling time, we have to select elimination half-life. The

elimination half-life varies for different drugs because of different in pharmacokinetics.

Difference in collecting sample time depends upon:

- Nature of medication i.e. solid, semisolid, liquid etc., all these affect

pharmacokinetics of a drug.

- Frequency of administration i.e OD, BID, TID, QID, etc.

- Steady state concentration: it is also different for different drugs.

- Dosing and dosing interval

- Duration of treatment

- Route of administration

Ideal sampling time:

When the sample is taken at steady state concentration, then it is called ideal sampling

time.



Page | 7

At Css (steady state concentration)

Rate of input = Rate of output

In order to achieve steady state concentration, 4 or 5 t½ are required.

For example: t½ of phenytoin is 24 hrs. In order to reach Css, 5 days are required.

Similarly,

Digoxin requires 5-7 days to reach Css.

Gentamicin requires 7.5-20 hours to reach Css.

TDM OF PHENYTOIN

1. Introduction

Clinical use: as antiepileptic

Nature: hepatic enzyme inducer, so exhibits significance drug interactions.

ADRs: CNS stimulation, scissors, osteomalacia and hypoglycemia.

Displaces drugs from albumin and increase their serum concentration, leading to toxicity.

2. Rational for TDM

i. Detection of non-adherence to regimen.

ii. Suspected toxicity.

iii. Adjustment of the dose.

iv. Management of the drug interactions

3. Sereum drug concentration (SDC) relationship:

There is good serum drug concentration relationship.

Unit is mg/L.



Page | 8

SDC :

If SDC < 5, then no effect is observed.

If SDC ranges from 5-10, some anticonvulsant effect may be observed.

If SDC ranges from 10-20, it is the optimum range i.e target dose.

If SDC ranges from 20-30, then toxicities like blurred vision and nystagmus may occur.

If SDC > 30, ataxia, dysarthria ( speech disorder) and comma are likely to occur.

If SDC > 100 mg, it is lethal.

4. Pharmacokinetics

Onset of action: I.V 0.5-1 hr.

Absorption: Slow oral absorption

Distribution: Two compartment model best describes its distribution.

Css : it takes five days to achieve steady state concentration.

Elimination:

- > 95 % : Hepatic elimination.

- < 5 % : Renal as unchanged.

Elimination is always first order. Hepatic elimination is capacity dependent.

For this Michelis menten equation is used because it exhibits non-linear pharmacokinetics.

Protein binding: 90-95 %

5. Population data:

Vd :

Child: 0.7 lit/kg



Page | 9

Adults: 0.6-0.7 lit/kg

Elimination half life:

For normal liver function : 24 hrs

In hepatic impairment: 30-100 hrs

Rate of change of plasma concentration is determined by Michaelis menten equation:

V = Vm x Cp …………………… 1

Km + Cpss

V = S X F X Dose ………………… 2

tau

S = salt factor

Tau= dose interval

Compairing equation 1 & 2 and performing mathematical operations, we get ;

Cpss = ( S x F x Dose ) / tau

Vm - ( S x F x dose/ )

Vm is more predictable at 7 mg/ lit.

6. Factors affecting drug clearance

i. Factors increasing drug clearance:

- Isoniazid

- Barbiturates



Page | 10

- Cimetidine

- Acute nephritis

ii. Factors decreasing drug clearance:

- Alcohol

- Chronic liver disease

CASE STUDY: A 60 kg woman taking phenytoin at 100 mg tid for last six months. She visits

out patient clinic and complaints of having fits despite of taking drugs regularly. Her serum drug

level is 10 mg/L. What dose of 100mg is required to raise the level upto 15mg/L if phenytoin

suspension suggests the dose adjustment ?

TDM OF DIGOXIN

1. Clinical use:

It is used in the treatment of ;

- Heart failure

- Atrial fibrilliation

2. Rational for use:

Non compliance is frequent particularly for elder patient

Show drug interactions with p-glycoprotien inhibitors which increases its serum concentration.

Toxicity : nausea, vomiting, adsorption, arrhythmia depending upon the serum concentration.

It is excreted renally, so renal functions and therapeutic functions must be monitored.

Poor response even at recommended dose require monitoring.

3. Serum drug concentration relationship

Unit : ug/ml



Page | 11

SDC values Effects

0.5 No therapeutic effect

0.7 +ve ionotropic effect and conduction blocking effect

0.8-2 Optimum concentration i.e target dose

2-2.5 Toxicity occurs

>2.5 GI, CVS, and CNS disturbances.

4. Pharmacokinetic profile

Absorption : rapid, peak concentration is achieved with in 1 hr

Bioavailability: 0.55-0.78

Distribution: Regarding the distribution, it follows two compartment model.

It takes 6 hrs to distribute, however actual concentration is achieved after 8 hrs.

Elimination : Renal

Css: Achieved with in 5-7 days

Clearance: depends upon renal function

Half life:

40 hrs in normal renal function.

120 hrs in impaired renal function.

Population data:

For tab , F=0.63 and for elixirs, F= 0.75

Vd= 7.3 lit/kg ( normal renal function)



Page | 12

For impaired renal function ;

Vd = 3.12 x CrCl + 3.84 x IBW

IBW:

For male ;

IBW = 50 kg + 2.3 kg for every inch above 5 feet.

For female;

IBW = 45.5 kg + 2.3 kg for every inch above 5 ft.

Clearance:

Cl = 0.06 x CrCl + 0.05 x IBW

CrCl:

For female;

CrCl = { ( 140 – age ) IBW } x 1.04

Serum conc

For male;

CrCl = { ( 140 – age ) IBW } x 1.23

Serum conc

Loading dose:

L.D = Vd ( Cp desired – Cp observed )

S x F



Page | 13

For digoxin , S = 1 and F = 1

Maintenance dose:

M.D = ( Cl x Cpss x dose instructed )/ S x F

5. Factors affecting digoxin serum concentration

i. Factors that increase serum concentration;

- Diuretics ( by virtue of hypokaelemia )

- Calcium channel blocker ( e.g verapamil , however nifidipine and diltiazem have

lethal effects)

- Atorvastatin

- Macrolides ( 10 % increase in digoxin concentration )

- Benzodiazepines

ii. Factors that decrease digoxin serum concentration;

- Rifampicin

- Oral antacids

CASE STUDY: A woman of weight 65 kg with 160 cm height and age of 50 years is in acute

atrial fibrillation. Her serum creatinine is 180 µmol/lit. calculate the I.V loading and oral

maintenance dose of digoxin.

TDM OF CARBAMAZEPINE

1. Introduction

It is antiepileptic.



Page | 14

Clinically it is used in the treatment of :

- Simple and complex partial seizures

- Tonic clonic seizures

- Trigeminal neuralgia

It has the capability to induce its own metabolism.

Toxicities include: CNS effects, rashes and rarely hepatotoxicity.

2. Rational for TDM

i. Non-adherence to regimen.

ii. Suspected toxicity

iii. Adjustment of the dose

iv. Management of pharmacokinetic interactions.

3. Serum Drug concentration relationship

Unit: mg/L

SDC Effects

< 4 Little therapeutic effect

4-9 Optimum conc/target dose in case used in combination with other anticonvulsants.

4-12 Optimum concentration in case of monotherapy.

> 9 Ataxia, drowsiness, dyplopia, nystagmus.

> 12 Ataxia, drowsiness, disarthria, coma.

4. Pharmacokinetic profile

Aabsorption: Slow and variable, with 75-85 % bioavailability.

No parentral formulations are available.



Page | 15

Distribution: Rapid because of lipid solubility and it concentrates in the liver and kidneys.

Protein binding: 70-90 %

Vd: 0.8-2 lit/kg

Elimination:

> 98 % …………………. Liver metabolism

< 2 % ………………….Unchanged drug in the urine.

Clearance: Initially less, ranging from 0.01-0.3 lit/hr, then increases to 0.05-0.1, on chronic use

because of self metabolism.

Elimination half life: Initially 35 hrs, then it decreases to 5-7 hrs.

Usual sampling time: Usual sampling time is trough level i.e immediate before next dose.

Pharmacokinetic equations: No pharmacokinetic equations are used in TDM of carbamazepine

because dose adjustment depends upon patient response.

5. Factors affecting carbamazepine srum concentration:

Drugs decreasing carbamazepine serum concentration:

- Cimetidine

- Ketoconazole

- Verapamil

- Diltiazem

Drugs increasing carbamazepine serum concentration:

- Phenytoin and all other hepatic enzyme inducers.

6. Pharmacokinetic implications:

- Pharmacokinetic data is not required for dose adjustment.

- If carbamazepine is used in combination with other anticonvulsant drugs such as

phenytoin, then interactions occur and every 100 mg increases the Css by 1 mg/L.



Page | 16

CASE STUDY: a woman of 40 years old has epilepsy for 10 years. She has on carbamazepine,

taking 40 mg t.i.d. A month ago, Lamotrigene was prescribed to her to control her seizures and

she has experienced dissiness, diploplia and unsteadiness ( sever weakness ). TDM shows no

change in blood level of carbamazepine.

a. What is the likely reason for these ADRs ?

b. How would you deal with these ADRs ?

TDM Of Theophylline

1. Introduction:

Clinical uses: it is used in bronchial asthma and Chronic Obstructive Pulmonary Disease (

COPD ).

Presently it has not become the ist drug of choice in asthma, still it is used in combination with

β-stimulants.

Adverse effects:

- Nausea, vomiting and other GIT problems.

- If given as rapid I.V bolus, it causes palpitations, tachycardia, CNS stimulation,

insomnia and convulsions.

2. Rational for TDM

i. It has narrow therapeutic index.

ii. Has some seriously reported toxicities such as arrhythmias, seizures without any warning

sign.

iii. Shows significant interpatient variability in clearance.

iv. Known factors for decreasing the clearance.

3. Serum concentration response relationship:

Unit: mg/L

SDC Effects



Page | 17

< 5 No therapeutic effect.

5-10 Little thrombolytic effect.

10-20 Optimum effect/ target dose.

20-30 Nausea, vomiting, arrhythmias.

> 20 cardiac arrhythmias, uncontrolled seizures.

4. Pharmacokinetic profile:

i. Absorption: Absorption is rapid, with 100 % bioavalibilty.

ii. Distribution: Rapidly distributed to all parts of the body except fat.

Two compartments model best fits the situation.

Distribution time is 40 min.

iii. Elimination:

- > 90 % hepatic.

- < 10 % renally as unchanged.

iv. Elimination ½: 6-12 hrs.

v. Css: 1.5-2.5 days.

vi. Product formulation:

Aminophylline: It is ethylene dione salt of theophylline in which theophylline is 80 %.

S.R formulations are available, however they behave different in different individual.

For formulation of S.R dosage form, the important factor is Pka i.e decrease the Pka

value, more effective will be the S.R formulation.

vii. Usual sampling time: Usual sampling time is trough concentration.

viii. Peak serum concentration: Peak serum concentration is 4-7 hrs after administration.

5. Population data:

i. Volume of distribution:

Vd= 0.5 lit/kg.

ii. Clearance:



Page | 18

Cl= 0.041 lit/ hr/ kg.

iii. Dose:

iv. Dose = Cp x Vd

Cl

v. Rate constant:

K = ln ( C2/ 1) x Vd

t½

vi. Half life:

t½ = ln2 x Vd

Cl

vii. Cpss:

Cpss = F x S x D

Tau x Cl

viii. Cpt:

Cpt= Cp°e¯ ᵏᵗ

6. Factors affecting clearance

i. Factors decreasing clearance:

- Cimetidine

- Alluporinol

- Ciprofloxacin

- Interferon

- Corpulmonale

- Pulmonary edema

- Hepatic dysfunction

ii. Factors increasing the clearance:

- Barbiturates

- Rifampicin

- Cystic fibrosis



Page | 19

- Hyperthyroidism

- Smoking

- High protein intake

7. Practical implications:

Aminophylline injection should be given slowly to avoid high transient concentration and

toxicity.

Modified dosage forms are frequently used.

Smoking factors and children factors should be considered in dose adjustment.

CASE STUDY:

A man, 63 kg having height 176 cmwith the risk of COPD is currently taking triotropium 18 µg

daily, salmetrol 50 µg b.d and salbutamol 100 µg as needed. He is smoker. Because of decrease

in exercise, tolerance and SOB, theophylline is added in the prescription.

i. What is suggested therapeutic range in COPD ?

ii. What dosage regimen do you recommend to achieve Css of 10 mg/L.

( Smoking factor = 15 and F= 0.85 )

iii. When should ist blood sample taken and Css is attained, if measured level is 8 mg/L,

what do you recommend and what serum level do you except after 20 hrs ?

TDM Of Gentamicin

Introduction

All aminoglycosides are bacteriocidal and active against some gram positive and many gram

negative bacteria.

Amikacin, gentamicin and tobramicin are also effective against pseudomonas aeroginosa.



Page | 20

Selection of the dose and dosage regimen depends upon patient weight, concurrent disease state

renal function.

Rational for TDM

It is based upon two factors:

i. Too much high concentration of aminoglycosides cause patient harm in terms of

nephrotoxicity and ototoxicity.

ii. Too much decrease concentration of aminoglycosides may harm by the progression of

overwhelming infection because it follows concentration dependent killing.

Therapeutic range

For severe gm –ve infections, high peak concentration ranging from 10-12 mg/L is required.

For gm +ve such as gm +ve endocarditis, it is used in combination with β-lactam antibiotics in

low concentration of 3-6 mg/L .This concentration may be achieved by I.V bolus, I.M injection

for 1 hr or I.V infusion over 30 mins.

Pharmacokinetics:

1. Oral bioavalability: Poor, < 1 %.

2. Distribution: As these are polar drugs, so are distributed extracellularly. When the colon

is inflamed, its rate of absorption is more.

Its distribution pattern best fits two compartment model.

Distribution time is 1 hr.

3. Elimination:Elimination is through glomerular filteration and some active secretion is

also there.

4. Elimination ½ : 1.5 to 4 hrs.

5. Css: Css is axhieved with in 7.5 to 20 hrs.

Population data



Page | 21

1. Vd: Vd is 0.06 to 0.08 L/kg. ( Avg Vd= 0.321)

2. Use IBW to calculate high peak concentration.

3. Clearance is approximate to CrCl.

4. Ke = Cl/Vd

5. Dosing interval: Cp2 = Cp1 x e ˗ᵏᵗ

6. Maximum dose: Cpmax = F x S x Dose

Vd ( 1 – e ˗ᵏᵗ )

Minimum dose: Cpmin = F x S x Dose x e˗ᵏᵗ

Vd ( 1 – e ˗ᵏᵗ )

Factors affecting Gentamicin

Diseases

Dehydration ……………. Vd is increased.

Obesity ………………. . . Vd is increased.

Edema ………………….. Vd is increased.

Ascitis …………………. Vd is increased.

Burns ………………….. Vd is decreased.

Renal impairment …….. clearance is decreased.

CCF ………………… Clearance is decreased.

Fever ………………. Clearance is increased.

Drugs

Carbinicillin and ticarcillin interacts with gentamicin.

Initial dose: It depends upon the physiological parameters of the patient.



Page | 22

Maintenance dose: It also depends upon pharmacokinetic because if we increase the dose, both

peak concentration and trough concentration are changed. So we will have to use p.k equations.

ODD: ODD stands for once daily dosing. It is a new concept but it should not be used for

pediatrics, pregnant and lactating mother, severe burns etc.

Case study: a 74 yrs old, 60 kg man is commenced on gentamicin I.V in a dose of 80 mg every

7 hrs. However, if serum critinine is raised in 220 umol/L and the doctor is worried about

toxicity.So pharmacist is asked for advise. Normal range of gentamicin is 75-115 µmol/L.

( Clue : for advise, the pharmacist has to calculate CrCl , Ke , and dosing interval ).

ByIftikhar Ahmad (E)Session: 2009-14F/Pharmacy,Gomal University, D.I.Khan.

TDM

Documents