3.

Clinical Pharmacokinetics
• Individualization and optimization of drug therapy

• Therapeutic drug monitoring (TDM)

Page 1 of 68 1
 …
• Clinical pharmacokinetics: is the process of applying
pharmacokinetic principles to determine the dosage
regimens of specific drug products for specific patients

• To the safe and effective therapeutic management of drugs in

an individual patient

• Important concepts of pharmacokinetics can serve to

characterize the individuality of the patient

• A drug's effect is often related to its concentration at the

site of action, so it would be useful to monitor this
concentration

Page 2 of 68 2
  Kinetic homogeneity -
describes the predictable
relationship between plasma
drug concentration and
concentration at the receptor
site

 Changes in the plasma drug

concentration reflect changes
in drug concentrations in other
tissues/sites

Figure: Relationship of plasma to tissue concentrations

Page 3 of 68 3
 …
• For most drugs plasma concentration range (therapeutic
range) that is safe and effective in treating specific diseases
is set.

• But, no absolute boundaries divide sub-therapeutic,

therapeutic, and toxic drug concentrations

• Due to variability in individual patient response, and

• Variability in fundamental relationship between drug

pharmacokinetics and pharmacologic response

Page 4 of 68 4
 …
• Why for Clinical Pharmacokinetics?

• Those patients who suffer from chronic ailments such as

diabetes and epilepsy may have to take drugs every day for
the rest of their lives,

• At the other extreme are those patients who take a single

dose of the drug to relieve an occasional headache,

• The duration of drug therapy is usually between the extremes.

Page 5 of 68 5
Individualization and Optimization of
drug therapy
1. Dosage regimen adjustment in renal impairment

2. Dosage regimen adjustment in hepatic impairment

3. Dosage regimen adjustment in Pediatrics

4. Dosage regimen adjustment in Geriatrics

5. Dosage regimen adjustment in Obesity

6. Pharmacokinetic drug interactions in combination

therapy

Page 6 of 68 6
 Therapeutic Drug Monitoring (TDM)

• TDM, the measurement and interpretation of drug concentration,

has been used to individualize drug therapy since the early 1970s

• The aim of TDM is to optimize pharmacotherapy by maximizing

therapeutic efficacy, while minimizing adverse events

• In those instances where the blood concentration of the

drug is a better predictor of the desired effect(s) than the
dose

Page 7 of 68 7
Figure: Process for reaching Dosage decision with TDM

Page 8 of 68 8
 …
• Clinical pharmacokinetics enables drug regimens to be
tailored for individual patients, while minimizing treatment
failures and adverse effects.

• Particularly valuable for:

• Drugs showing a close correlation between effects and

plasma concentration

• Drugs with a narrow margin between toxic and therapeutic

effects

Page 9 of 68 9
 …
• Generally, features of drugs that need clinical monitoring
include:

• Narrow therapeutic range

• Poor relationship between dose and plasma concentrations

• Good relationship between plasma concentration and effects

• Lack of therapeutic effects is dangerous

• Difficulty in interpreting therapeutic failure

Page 10 of 68 10
 …
• Drugs that do not need clinical monitoring:

• Drugs that are used for treating diseases of which their clinical end
points can easily be monitored (e.g., BP, cardiac rhythm, blood
sugar)

• Drugs whose serum concentrations show no correlation with

therapeutic or toxic effects

• Drugs with less complicated pharmacokinetics

• Drugs that are used to treat less complicated or not life threatening
diseases

Page 11 of 68 11
 …
• Generally accepted indications for measuring drug
concentrations are as follows:

1. To evaluate concentration-related toxicity:

• Unexpectedly slow drug elimination

• Accidental or purposeful overdose

• Surreptitious drug taking

• Dispensing errors

Page 12 of 68 12
 …
2. To evaluate lack of therapeutic efficacy:

• Patient noncompliance with prescribed therapy

• Poor drug absorption

• Unexpectedly rapid drug elimination

3. To ensure that the dose regimen is likely to provide

effective prophylaxis

4. To use pharmacokinetic principles to guide dose

adjustment

Page 13 of 68 13
 …
• TDM or clinical pharmacokinetic services (CPKS) have been
established in many hospitals to evaluate the response of
the patient to the recommended dosage regimen

• The improvement in the clinical effectiveness of the drug by

TDM may decrease the cost of medical care by preventing
untoward adverse drug effects

Page 14 of 68 14
 …
• The functions of a TDM service are:

• Select drug

• Design dosage regimen

• Evaluate patient response

• Determine need for measuring serum drug concentrations

• Assay for drug concentration in biological fluids

Page 15 of 68 15
 …
• Perform pharmacokinetic evaluation of drug concentrations

• Readjust dosage regimen, if necessary

• Monitor serum drug concentrations

• Recommend special requirements

Page 16 of 68 16
Page 17 of 68 17
 …
Sample matrices

Venous blood, Serum or Plasma

• Usually drugs are monitored in this matrice

• Whole blood may be used for some drugs like

• Cyclosporine

• Tacrolimus

• Sirolimus and everolimus which distribute between erythrocytes and

plasma

Page 18 of 68 18
 …
Saliva

• It can be used instead of blood in case of infants and children

• It can also be used in the elderly and pregnant women and

sometimes in adult patients when venipuncture is difficult

• Easy to collect and preferred by the medical staff as it minimizes their

contact to blood samples

• Drugs that can be monitored using saliva are: Phenytoin,

Carbamazepine, Theophylline, Digoxin, and lithium

• Drugs of abuse such as morphine and cocaine can also be monitored

by saliva

Page 19 of 68 19
 …
Urine

• Urine as a biological matrix for drug monitoring has many

advantages

• Samples can be easily collected and are well accepted by patients

• Its window for identifying drug use is broader compared to blood

• Used in TDM service to anticonvulsant and psychoactive

drugs

Page 20 of 68 20
 …
Tears

• Used to a lesser extent

• Due to its pH, only unionized and acidic drugs with high pKa values
distribute in tears in a predictable manner

• Limits its use to small variety of drugs like valproic acid

Hair and nails

• They are used in drug abuse and forensic examination

• Moreover, they can be used in antifungal drugs monitoring

Page 21 of 68 21
 …
Feces

• Limited to studies in new drug development and may

provide information on excretion of drugs and metabolites

Fetus blood and amniotic fluid

• Used for detecting of drugs that can affect the fetus such as
some antibiotics, anticonvulsants and tranquillizers

Page 22 of 68
 …
Breast milk

• Used to determine the amount of drug that can be ingested

by the breastfeeding infant

• Phenobarbital, theophylline, and some psychoactive drugs

as well as drugs of abuse might be detected in breast milk

Page 23 of 68
 …
CSF

• Necessary to establish if the concentration of a drug in the

CNS is desirable for the drug effect or not

• Collection of CSF is not an easy technique since it is done by

lumbar puncture

• Examples: antibiotics that are used in CNS infections,

anticonvulsants, psychoactive drugs, and protease inhibitors

Page 24 of 68
 …
Bronchial secretions and peritoneal fluid

• Are rarely used

• Used for patients with serious diseases

• Require invasive techniques for sample collection

Seminal fluid

• Drugs like antimicrobials, sulfasalazine, salicylate, propranolol, and

protease inhibitors are monitored in the seminal fluid

Page 25 of 68
 …
• Analytical techniques used
in TDM:

• UV Spectrophotometry • Enzyme- Linked

Immunosorbent Assay
technique (ELISA)
• Gas-Liquid Chromatography
(GLC)
• High Pressure Liquid
Chromatography (HPLC)
• Radioimmunoassay (RIA)
technique
• Turbulent Flow
Chromatography (TFC)
• An automated, homogeneous
Enzyme Immunoassay
Techniques (EMIT) • Fluorescence Polarization
Immunoassay (FPIA)

Page 26 of 68
 …
• We will see selected drugs to illustrate the clinical use of PK
in improving the prospects for successful drug therapy:

• Aminoglycosides: Gentamicin

• Anticonvulsants: Phenytoin

• Cardiac Glycosides: Digoxin

• Immunosuppressants: Cyclosporine (Read)

• Other drugs: Theophylline and Lithum

Page 27 of 68
 …
Aminoglycosides: Gentamicin

• Aminoglycosides have concentration-dependent bactericidal

activity against Gram-negative aerobic bacteria.

• The higher the concentration, the more extensive and the

faster is the degree of bactericidal effect

• It has been shown that aminoglycosides eradicate bacteria best

when they achieve a Cmax:MIC ratio of at least 8-10

Page 28 of 68
 …
• AG related toxicity is increased if peak levels are
consistently maintained above 12 to 14 µg/ml or trough
levels consistently exceed 2 µg/ml.

• In addition to variation in bacterial sensitivity which alter the

minimum effective concentrations, there is also the difficulty
of relating plasma concentration to potential for toxicity.

• Variability exist both in bacterial resistance and patient

sensitivity.

Page 29 of 68
 …
Pharmacokinetics (aminoglycosides)

• When given by IV infusion over 30 minutes, aminoglycosides

follow a 3-compartment pharmacokinetic model; α (distribution), ß
(elimination), and γ (tissue release)

• When infused over one hour, the distribution phase is usually

not observed

• The γ-phase begins approximately 16 hrs post infusion

• Because of complexity of this model, the simpler one

compartment model is widely used

Page 30 of 68
 …
 Absorption

 AGs have a limited oral bioavailability; must be administered

parenterally to treat systemic infections.

 Distribution

 AGs are water soluble compounds that rapidly distribute into the
ECF and highly perfused tissues, and concentrate in the kidneys.

 Plasma protein binding is negligible (<20%)

 The average Vd in healthy adults is 0.26 L/kg (range: 0.2-0.3

L/kg)

Page 31 of 68
 …
 Elimination

 Eliminated almost entirely by the kidney via glomerular

filtration

 Because of the narrow therapeutic margins of these drugs,

dosage should be reduced in patients with renal impairment

 AG elimination is closely correlated with creatinine clearance

 Cystic fibrosis patients, major body burn, ICU patients show

increased AG elimination

Page 32 of 68
 …
The need for monitoring

• The narrow therapeutic index,

• Wide patient variability,

• Serum concentration are highly unpredictable,

• The t1/2 values show wide inter-subject variation,

• Variations in bacterial sensitivity

Page 33 of 68
 …
Dosage considerations

• The mean values for AG half-lives are generally reported as

2-3 hrs and the volume of distribution as 0.2-0.3 L/kg

• Influenced by age, disease, and subject to variability

• AGs do not distribute into adipose tissue, but they do enter

the ECF. Therefore, correction required for:

• Obese patients, patients with cystic fibrosis, patients with

ascites, and dehydration

Page 34 of 68
 …
• Since AGs are primarily distributed throughout ECF, dosing
on a body weight basis may result in overdoses.

• It has been tried to improve this by adjusting the dosage

based on lean body weight.

• Still this fails to consider the dosing interval which is

dependent on both renal clearance and distribution.

• It suggested to use a “corrected creatinine clearance” to

account for the fact that a single clearance value may be
operating on different Vd values.

Page 35 of 68
 …
• Dosing weight (DW) is normally estimated from the ideal
body weight (IBW) and actual body weight (ABW) of the
patient:

• Males: IBW = 50 kg + 2.3 kg for every inch over 5 ft

• Females: IBW = 45.5 kg + 2.3 kg for every inch over 5 ft

DW = IBW + 0.4(ABW – IBW)

Page 36 of 68
 …
• The reduced dose during renal insufficiency may be
approximated from:
𝑪𝑳𝑪𝑹
𝑨𝒅𝒋𝒖𝒔𝒕𝒆𝒅 𝒅𝒐𝒔𝒆 ≡ 𝑫𝒐𝒔𝒆
𝟏𝟎𝟎

where the creatinine clearance, 𝐶𝐿𝐶𝑅 value in ml/min

Page 37 of 68
 …
• 𝐶𝐿𝐶𝑅 values may be roughly approximated from creatinine
serum concentration 𝐶𝐶𝑅

• Males:
𝟏𝟒𝟎 − 𝒂𝒈𝒆(𝒚𝒓) 𝒘𝒕(𝒌𝒈)
𝑪𝑳𝑪𝑹 ≡
𝟕𝟐𝑪𝑪𝑹

• Females
𝑪𝑳𝑪𝑹 ≡ 𝟎. 𝟖𝟓𝑪𝑳𝑪𝑹 (𝑴𝒂𝒍𝒆𝒔)

Page 38 of 68
 …
Individualized Dosage

• Since creatinine renal clearance values don’t result in reliable

dosage adjustments, it has been suggested that the drug itself be
used to calibrate the patient

• An initial dose must be administered in order to determine the

Gentamicin time course and calculate subsequent doses

• The test dose and subsequent doses are given by constant-rate

infusion over a 1hr period and a minimum of three blood samples
are analyzed during the post-infusion phase

• Usually 30min after termination and 1 and 3hr later

Page 39 of 68
 …
Anticonvulsants: Phenytoin

Pharmacokinetics

• Phenytoin exhibits zero-order pharmacokinetics;

• Phenytoin pharmacokinetics are significantly affected by a

number of other drugs and metabolites

Page 40 of 68
 …
 Absorption

 Phenytoin is a relatively insoluble weak acid, usually administered as the

sodium salt

 Particle size is the most important determinant of phenytoin absorption

 Distribution

 Phenytoin has a moderately large volume of distribution and is

approximately 90% bound to plasma proteins

 Phenytoin diffuses rapidly into the tissues

 It has a volume of distribution of 0.65 L/kg

 Following IV administration, the distribution phase lasts about 2h

Page 41 of 68
 …
 Metabolism
 Phenytoin is largely cleared by hepatic metabolism
 The metabolism of phenytoin is capacity limited
 The enzyme system involved is saturable within the therapeutic
range of serum concentrations
 This gives rise to a non linear dose-concentration relationship

 Elimination
 To achieve therapeutic concentrations, the rate of administration must
approach the maximum rate at which Phenytoin can be eliminated
 Saturation elimination kinetics occur within the therapeutic range of
serum concentrations

Page 42 of 68
 …
 The free Phenytoin level is the best indicator of adequate therapy

 10% of Phenytoin circulates in the free, unbound form

 Phenytoin, Total
 Therapeutic concentration: 10.0-20.0 µg/mL
 Toxic concentration: ≥ 30.0 µg/mL

 Clinically important displacement can be caused by bilirubin and

several drugs, particularly sodium valproate

Page 43 of 68
 …
Pharmacokinetics of Phenytoin in Special Situations

Neonates

• Phenytoin readily crosses the placenta and, maternal and neonatal

serum concentrations are roughly equal at birth

• Neonates born to epileptic mothers are able to metabolize phenytoin

effectively

• Indeed the short half-lives they show suggests that the fetal liver
may have been induced

• However, plasma protein binding of phenytoin is lower in the neonate

Page 44 of 68
 …
Elderly

• Serum phenytoin concentrations for a given daily dose are

higher in the elderly than in young adults (??)

• As the serum albumin tends to fall with age, allowance

should be made for reduced binding

Page 45 of 68
 …
Pregnancy

• Serum Phenytoin concentrations tend to fall during

pregnancy:

• Increase in Vd during pregnancy,

• The reduction in serum albumin concentration,

• The most likely explanation is enhanced hepatic metabolism

Page 46 of 68
 …
Liver Disease

• The binding of Phenytoin to serum proteins is reduced in liver

disease.

• Due to hypo-albuminaemia, displacement by bilirubin or other

substances, &/or a change in the configuration of albumin

• This is expected to cause a fall in serum Phenytoin concentration

due to an increased fraction of unbound drug available for
metabolism

• But, this may lead to impairment of drug metabolism, which may

in turn cause Phenytoin intoxication

Page 47 of 68
 …
Renal Disease

• Uraemic patients have lower serum Phenytoin

concentrations than non-uraemic patients:

• Presence of binding inhibitors

• An alteration of the albumin molecule

• Induction of metabolism

• The concentration of albumin may be reduced in renal disease

Page 48 of 68
 …
 Why Phenytoin be Monitored?

 Large pharmacokinetic variability

 Low therapeutic indices

 Clinical effect not easily quantifiable

 Generally good correlations between plasma levels and therapeutic

effect

 Saturable metabolism with Phenytoin (Nonlinear)

 Absorption is variable

 Drug interactions common

Page 49 of 68
Description for Concentration-dose Relationship

 Michaelis-Menten equation is employed:

Vmax = maximum amount of drug that can be metabolized per unit time

Km = Michaelis-Menten constant, representing the concentration of

phenytoin at which the rate of this enzyme-saturable hepatic
metabolism is one-half of maximum

Css = average steady-state phenytoin concentration

Page 50 of 68
 The above equation can be expressed as*:

X0/τ = amount of phenytoin free acid divided by dosing interval (which

can also be expressed as Xd, meaning daily dose of phenytoin free
acid)

S = the salt factor or the fraction of phenytoin free acid in the salt form
used

* The oral bioavailability of phenytoin is considered to be 100%, so an F

factor is not needed in these calculations

Page 51 of 68
 The second equation can then be rearranged to solve for
Css:

Page 52 of 68
 …
Individualized Dosage

• Ideally, Km and D (the maximum dose that can be

metabolized) values should be derived for each patient before
treatment is begun

• But, in practice this is demanding because multiple serum

concentration estimations following administration of a single
dose are necessary

• Alternatively, a small dose, say 200mg a day in adults can be

started and the steady-state serum concentration measured
after 2 to 3 weeks

Page 53 of 68
 …
• From the value obtained, a prediction of the dose
adjustement necessary to produce a therapeutic
concentration can be made from Phenytoin nomogram

• Development of the nomogram required the assumption that

Km does not vary from one patient to another and this is
clearly incorrect

• Once a further steady-state concentration is available on a

second dose, more sophisticated methods can be used in
which individual Michaelis-Menten parameters are calculated

Page 54 of 68
 Rane (1979) pointed out that body surface area is, in fact,
a better guide to dose than body weight (particularly for
children)

 A median dose of phenytoin, the dose/kg of body weight

basis, in adults is 300 to 350mg/day (about 5mg/kg)

 A dose scheme which is approximately proportionate to

body surface area is given by:

Page 55 of 68
Dose Intervals and Time to Steady-state

 Because Phenytoin metabolism is saturable, the effective

plasma t1/2 gradually lengthens as the Css rises (i.e. the
clearance gradually decreases)

 On average, the effective t1/2 at very low serum concentrations

is about 13hr, but this lengthens to 46hr when the steady-state
concentration reaches the Cmax

 The time to steady-state therefore depends upon the dose and

the final concentration reached

 The rate of elimination on discontinuing therapy may be much

slower than expected

Page 56 of 68
 …
Cardiac Glycosides: Digoxin

Pharmacokinetics

• Following IV injection the serum digoxin concentration time course

may be described by a bi-exponential equation

• The first exponential is associated with delivery from the blood to

the site of action

– This rapid phase lasts 6-8hr with a half-life of approximately 40min

– Following this initial distribution, the response has been shown to be

correlated with digoxin plasma concentrations

Page 57 of 68
 Absorption
 Absorbed passively in small intestine

 Rate of absorption decreased with meals, but not the

extent

 Oral bioavailability (F) ranges from 0.5 - 0.9 (average ~

0.70)

 Distribution
 Best described by a two-compartment model

 Digoxin does not distribute into adipose tissue

Page 58 of 68
 Vd = 7.3 L/kg, is decreased in CRF (4-5 L/kg)

 Vd is larger in children and neonates

 Protein binding: 20-30%

 In patients with severe renal dysfunction, digoxin is only 18%

protein bound

 Elimination
 Major route of elimination is renal; 75-85% excreted
unchanged by the kidney
 Considerable biliary excretion of digoxin is also evident

Page 59 of 68
Need for Digoxin monitoring

 Studies show digoxin concentration in serum and in heart

muscle to be correlated

 In spite if this correlation, the plasma concentration

required for similar responses vary widely between patients

 Some patients elicit toxic manifestations at low or what are

considered therapeutic plasma concentrations; while others
show suboptimal responses at what are considered toxic levels

 An absolute standard for a therapeutic window for the

overall population cannot be defined

Page 60 of 68
 The uncertainty with regard to ideal digoxin plasma levels
makes concentration-based predictions unreliable

 Most patients exhibit a satisfactory inotropic effect at

steady-state digoxin levels of 0.7 - 1.5 ng/ml

 Monitoring steady-state digoxin levels can be combined with

clinical observations to identify patients who are either
ultrasensitive or resistant to digoxin

 Two of the most prominent features of digoxin are its

narrow therapeutic index and an endpoint of therapy
which is difficult to define and measure

Page 61 of 68
 When should Digoxin levels be monitored?

 When standard doses would not be expected to produce

satisfactory effect without toxicity, e.g. renal
insufficiency, hypokalaemia, hyper- or hypothyroidism

 When toxicity is suspected, e.g. anorexia, nausea,

vomiting, confusion in the elderly, visual disturbances or
arrhythmias

 When compliance is in doubt

 When a Digoxin-drug interaction is known or suspected

Page 62 of 68
Other drugs: Theophylline

Pharmacokinetics

 Following IV injection, theophylline blood concentration is

described by a two-compartment open model

 The α-phase (distribution phase) is completed within

roughly 30min and is very rapid relative to the β-phase
(post-distribution phase)

 For clinical decisions, theophylline may be regarded

practically as monoexponential disposition

Page 63 of 68
 Absorption

 Theophylline is quickly and completely absorbed (>90%) from

solution and rapidly releasing tablet

 Distribution

 Unlike elimination, distribution and absorption parameters are

relatively stable

 55-63% plasma protein bound

 The apparent Vd is approximately 0.5 L/kg; Vd is relatively

constant and displacement from bound protein is insignificant

Page 64 of 68
 Elimination

 Show variability

 Diseases that affect liver blood flow, such as cirrhosis

and heart failure, may reduce theophylline clearance

Page 65 of 68
Need for Theophylline Monitoring

 Inter-subject variability in biological half-life, despite its

linear pharmacokinetics

 In spite of normally linear kinetics, the t1/2 varies from 3 to

20.7 hr in healthy adults and 1.4-7.9hr in asthmatic
children

 This may be attributed to genetic factors, since only 7%

of the IV dose is excreted intact in the urine

 Theophylline also has a narrow therapeutic index

Page 66 of 68
Dosage considerations

 Since absorption is rapid and complete, loading dose

equation for IV administration;

DL = C x Vd

Can be used without individualization

 But, initial estimation of maintenance dose is dependent on

t1/2

 Variability in plasma clearance is so great that no constant

infusion can be recommended that can reasonably predict
both therapeutic efficacy and safety

Page 67 of 68
 The clearance of theophylline is affected by many variables
which necessitate carefully individualized dosage

 Age, smoking, congestive heart failure, other diseases

and drug interactions all contribute to a change in the
metabolism of theophylline

 So wide is the variation in clearance rates that no dose

which will produce effective levels of theophylline in most
patients will produce toxic levels in a few

 In patients having no residual theophylline levels prior to

therapy, the loading dose may range 5-7.5 mg/kg

Page 68 of 68