CLINICAL PHARMACY & Chapter 3: Practical Pharmacokinetic

PHARMCOTHERAPY 1 Ms. Neri Margaret Fabillo

AY 2022-2023 MM/DD/YYYY
2nd Semester

OUTLINE
I. General Applications: Response, Loading dose, etc.
II. Application to Therapeutic drug
III. Basic Concepts: Volume of distribution, Elimination,
Absorption, peak and toug levels, consent. data, etc.
IV. Clinical Applications: Estimation of creatinine clearance,
Digoxin, theophylline, gentamicin, etc.

KEY NOTES
•Pharmacokinetics can be applied to a range of clinical
situations with or without therapeutic drug monitoring (TDM).
•TDM can improve patient outcomes but is only necessary for
drugs with a low therapeutic index, where there is a good
concentration response relationship, and where there is no
easily measurable physiological parameter.
•Sampling before steady state is reached or before distribution
is complete, leads to erroneous results. B. NEED FOR A LOADING DOSE
• The volume of distribution can be used to determine the ● The same type of information can be used to determine whether
loading dose. the loading dose of a drug is necessary
• The elimination half-life determines the time to steady state → drugs with longer half-lives are more likely to require loading
and the dosing interval. doses for acute treatment.
• Kinetic constants determine the rate of absorption and
elimination.
C. DOSAGE ALTERATIONS
•Clearance determines the maintenance dose.
•Creatinine clearance can be reliably estimated from
● Clinical pharmacokinetics can be useful in determining dosage
population values.
alteration if the route of elimination is impaired through end
• Use of actual blood level data wherever possible to
organ failure (e.g. renal failure) or drug interaction.
assist dose adjustment is advisable. However, population
● Using the fraction that should be excreted unchanged ( fe
pharmacokinetic values can be used for digoxin, theophylline
value), quantitative dosage changes can be estimated.
and gentamicin.
•Once daily dosing of gentamicin is a realistic alternative to
multiple dosing. D. CHOOSING A FORMULATION
•TDM is essential in the dose titration of lithium and
phenytoin, but of little value for valproate, or the newer ● An understanding of the pharmacokinetics of absorption may
anticonvulsants. also be useful in evaluating the appropriateness of particular
Note: If no learning objectives were given during the lecture, either formulations of a drug in a patient.
use the ones in the handout given or delete this portion altogether
II. APPLICATION TO THERAPEUTIC DRUG
I. GENERAL APPLICATIONS MONITORING

● Clinical Pharmacokinetics III. BASIC CONCEPTS

→ may be defined as the study of the time course of the
absorption, distribution, metabolism and excretion of drugs ELIMINATION
and their corresponding pharmacological response.
→ can be applied in daily practice to drugs with a low Drugs may be eliminated from the body by a number of
therapeutic index, even if drug level monitoring is not routes. The primary routes are:
required. → Excretion of the unchanged drug in the kidneys
→ Metabolism (usually in the liver) into a more water soluble
A. TIME TO MAXIMAL RESPONSE compound for subsequent excretion in the kidneys,
→ Combination of both.
● By knowing the half-life of a drug, the time to reach a steady
state may be estimated, and also when the maximal therapeutic ● Clearance (CL)
response is likely to occur, irrespective of whether drug level → The main pharmacokinetic parameter describing elimination.
monitoring is needed. → It is defined as the volume of plasma completely emptied of
drug per unit time.

● Rate of Elimination
Eq. (3)

Where:
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 → A constant rate of elimination irrespective of plasma
▪ Rate of Elimination = Rate of drug disappearing from the
concentration
body (𝑔/ℎ𝑟)
▪ CL = Clearance (𝐿/ℎ𝑟) ● For drugs undergoing first-order elimination, there are two other
useful pharmacokinetic parameters in addition to the volume of
▪ C = Plasma drug concentration (𝑔/𝐿) distribution and clearance. These are the elimination rate
constant and elimination half-life.
● Total Body Elimination
→ Is the sum of the metabolic rate of elimination and the renal ● Elimination Rate Constant (𝐾𝑒)
rate of elimination. → is the fraction of the amount of drug in the body (A)
eliminated per unit time.
Eq. (5)

→ If the fraction eliminated by the renal route is known (𝐹𝑒),

then the effect of renal impairment on total body clearance
▪ Combining Eqs. (3) and (5) gives,
can be estimated.

● Clearance of most drugs remains constant for each individual. 𝐶𝐿 × 𝐶 = 𝐾𝑒 × 𝐴

However, it may alter in cases of drug interactions, changing ▪ And since,
end-organ function or autoinduction. 𝐴
𝐶 = 𝑉𝑑
‘As the plasma concentration changes so will the rate of ▪ Then,
elimination.” 𝐴
𝐶𝐿 × 𝑉𝑑
= 𝐾𝑒 × 𝐴
● Steady state
→ When the rate of administration is equal to the rate of ▪ Therefore,
𝑠𝑠 Eq. (6)
elimination and the plasma concentration is constant (𝐶 ) . 𝐶𝐿 = 𝐾𝑒 × 𝑉𝑑

● Elimination Half-Life (𝑇1/2)

● Rate of administration → Is the time it takes for the plasma concentration to decay by
→ At the beginning of a dosage regimen the plasma half.
concentration is low. Therefore, the rate of elimination from → In five half-lives the plasma concentration will fall to
Eq. (3) is less than the rate of administration, and approximately zero.
accumulation occurs until a steady state is reached. Eq. (7)
−𝑘𝑒×𝑡
Eq. (4) 𝐶2 = 𝐶1 × 𝑒
Where:
▪ C1 and C2 = Plama concentrations
● First-order elimination
→ As the plasma concentration falls (e.g. on stopping treatment ▪ t = time
or after a single dose), the rate of elimination also falls.
→ The plasma concentration time graph follows a non-linear ● Two ways of determining 𝑘 :
curve characteristic. 𝑒
→ Estimating the half-life and applying Eq. (8)
Figure 3.4 First-order elimination → Substituting two plasma concentrations in Eq. (7) and
applying natural logarithms:

In 𝐶 = In 𝐶1 − (𝑘𝑒 × 𝑡)
2

(𝑘𝑒 × 𝑡) =In 𝐶1 − In 𝐶2

𝐼𝑛 𝐶1− 𝐼𝑛 𝐶2
𝑘𝑒 = 𝑡

● It takes approximately five half-lives for a drug to accumulate to

the steady state on repeated dosing or during constant infusion.

Eq. (8)
𝑠𝑠 −𝑘𝑒×𝑡
𝐶 =𝐶 ⎡⎣1 − 𝑒 ⎤
⎦
Where:
▪ C = The plasma concentration at time t after the start of
● Zero-order Elimination
the infusion

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 𝑠𝑠 ● To determine a loading dose:
▪ 𝐶 = the steady state plasma concentration.
Eq. (11)
ABSORPTION

● Intravenous Route
→ In this route all of the administered drug is absorbed.
→ Most efficient; Other routes must be absorbed into the
● to determine maintenance dose or steady state plasma
bloodstream thus it may or may not be 100% efficient.
concentrations at the steady state:
● Bioavailability (𝐹) Eq. (12)
→ The fraction of the administered dose which is absorbed into
the bloodstream
→ For oral administration, the dose or rate of administration
must be multiplied by 𝐹
→ Bioavailability 𝐹 is determined by calculating the area under
Where:
the concentration time curve (AUC). ▪ 𝑇 = the dosing interval.

● Rate of Elimination PEAK AND TROUGH LEVELS

→ The fraction of the administered dose which is absorbed into
the bloodstream.
● For oral dosing and constant intravenous infusions, it is usually
adequate to use the term ‘average steady state plasma
𝑇ℎ𝑒 𝑎𝑚𝑜𝑢𝑛𝑡 𝑒𝑙𝑖𝑚𝑖𝑛𝑎𝑡𝑒𝑑 𝑖𝑛 𝑎𝑛𝑦 𝑜𝑛𝑒 𝑢𝑛𝑖𝑡 𝑜𝑓 𝑡𝑖𝑚𝑒 𝑑𝑡 = 𝐶𝑙 × 𝐶 × 𝑑𝑡
concentration’ (average C ss).
→ However, for some intravenous bolus injections it is
𝑇𝑜𝑡𝑎𝑙 𝑎𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑒𝑙𝑖𝑚𝑖𝑛𝑎𝑡𝑒𝑑 = 𝐶𝑙 𝐶𝐿 × 𝐶 × 𝑑𝑡 sometimes necessary to determine peak and trough levels.

As previously explained, CL is constant. Therefore , ● At the steady state,

→ the change in concentration due to the administration of an
𝑇𝑜𝑡𝑎𝑙 𝑎𝑚𝑜𝑢𝑛𝑡 𝑒𝑙𝑖𝑚𝑖𝑛𝑎𝑡𝑒𝑑 = 𝐶𝐿 × Σ𝐶 × 𝑑𝑡 from start until 𝐶 intravenous dose will be equal to the change in concentration
is zero due to elimination over one dose interval:

● Σ𝐶 × 𝑑𝑡 from start until zero is the area under the plasma

concentration–time curve (Fig. 3.5)
● Within one dosing interval,
𝑠𝑠
→ the maximum plasma concentration (𝐶 ) will decay to the
𝑚𝑎𝑥
𝑠𝑠
minimum plasma concentration (𝐶 ) as in any first-order
𝑚𝑎𝑥
process.
𝑠𝑠 𝑠𝑠
→ Substituting 𝐶 for 𝐶 and 𝐶 for 𝐶 in Eq. (7):
𝑚𝑎𝑥 1 𝑚𝑖𝑛 2

𝑠𝑠 𝑠𝑠 −𝑘𝑒×𝑡
𝐶𝑚𝑎𝑥 = 𝐶𝑚𝑎𝑥 × 𝑒
Where:
▪ 𝑡 = the dosing interval.

− If this is substituted into the preceding equation:

𝑆 × 𝐹 × 𝑑𝑜𝑠𝑒 𝑠𝑠 𝑠𝑠 −𝑘𝑒×𝑡
𝑉𝑑
= 𝐶𝑚𝑎𝑥 − (𝐶𝑚𝑎𝑥 × 𝑒 )
DOSING REGIMENS

● To determine the change in plasma concentration ΔC Therefore,

immediately after a single dose:
Eq. (13)
Eq. (10) 𝑠𝑠 𝑆 × 𝐹 × 𝑑𝑜𝑠𝑒
𝐶𝑚𝑎𝑥 = −𝑘𝑒×𝑡
𝑉𝑑 ⎡⎣1−𝑒 ⎤
⎦
Eq. (14)
𝑠𝑠 𝑆 × 𝐹 × 𝑑𝑜𝑠𝑒 −𝑘𝑒×𝑡
Where: 𝐶𝑚𝑎𝑥 = −𝑘𝑒×𝑡 ×𝑒
𝑉𝑑 ⎡⎣1−𝑒 ⎤
⎦
▪ F = bioavailability

▪ S = salt factor (fraction of active drug when the dose is INTERPRETATION OF DRUG CONCENTRATION
administered as a salt) DATA

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The following are the criteria that should be fulfilled before
undertaking therapeutic drug monitoring:
→ the drug should have low therapeutic index
→ there should be a good concentration-response relationship
→ there are no easily measurable physiological parameters
● Monitor Adherence or Confirm Toxicity
→ other justification for undertaking TDM in the absence of the
criteria
Factors needed to be considered when interpreting TDM data:
● Sampling Times
→ TDM as an aid to dose adjustment: concentration should be
at steady state
→ approximately five half-lives should elapse after initiation
before sampling
→ EXCEPTION OF THE RULE: toxicity is suspected
→ Steady state has reached: sample at the correct time
Dosage Adjustment
- simple
- linear relationship exists between the dose and
concentration if a drug follows first-order elimination
● Capacity limited clearance
→ If a drug is eliminated by the liver, it is possible for the
metabolic pathway to become saturated.
→ Initial elimination: first-order
→ Elimination of a saturated system: zero-order
→ Majority of drugs eliminated by the liver, the chracteristic
dose-concentration (seen in the graph Fig. 3.6B) is not seen
at normal therapeutic doses. It only occurs at very high
supratherapeutic levels.
→ EXCEPTION: Phenytoin - the saturation of the enzymatic
pathway occurs at therapeutic doses.
● Increasing Clearance
→ First-order elimination: clearance increases as the plasma
concentration increases (Fig. 3.6C)
→ Under normal circumstances, the plasma protein binding
sites available to a drug far outnumber the capacity of the
drug to fill those binding sites.
→ Valproate and Disopyramide: as the concentration
increases, the plasma protein binding sites become
saturated and the ratio of unbound drug to bound drug
increases
- elimination of these drugs are dependent on the
unbound concentration
Figure 3.6 Dose-concentration relationships: (A) first-order elimination, (B),
capacity-limited clearance, (C) increasing clearance.
● Therapeutic range
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1
→ usually used as a guide to the optimum concentration
→ limits of these ranges should not be takes an absolute
→ these ranges are only adjuncts to dose determination, which
should always be done in the light of clinical response
IV. CLINICAL APPLICATION
A. ESTIMATION OF CREATININE CLEARANCE
● 24-h urine collection couped with a plasma creatinine
measurement
→ usual method in estimating creatinine clearance
The rate of elimination is calculated from the measurement of the
total amount of creatinine contained in the 24-h urine sample
divided by 24, that is,
𝑎𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒
= 𝑟𝑎𝑡𝑒 𝑜𝑓 𝑒𝑥𝑐𝑟𝑒𝑡𝑖𝑜𝑛 (𝑚𝑔/ℎ)
24
→ whole process is cumbersome and there is an inevitable
delay in obtaining results
→ biggest problem is the inaccuracy of the 24-h urine collection
● Estimate the rate of production of creatinine
→ alternative approach and has advantages
→ does not involve 24-h urine collections and requires only a
single measure of plasma creatinine
Equations have been produced which are rearrangements of
equation 4, that is,
𝑟𝑎𝑡𝑒 𝑜𝑓 𝑝𝑟𝑜𝑑𝑢𝑐𝑡𝑖𝑜𝑛
𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 = 𝐶𝑠𝑠
→ rate of production is replaced by a formula which estimates
this from physiological parameters of age, weight and sex
● Cockcroft and Gault (1976) Equation
→ appears to be the most satisfactory
→ modified version using SI units
where F = 1.04 (females) or 1.23 (males)
→ used in patients with moderate to severe renal failure
● Modification of Diet in Renal Disease (MDRD) Formula
→ can be used to estimate glomerular filtration rate (eGFR)
→ uses plasma creatinine, age, sex and ethnicity
eGFR = glomerular filtration rate (mL/min per 1.73 m2).
→ should be used with care when calculating doses of drugs
Digoxin
● Action and uses
→ most widely used of the digitalis glycosides.
→ primary actions on the heart: ↑ the force of contraction and ↓
conduction through the atrioventricular node.
→ treatment of atrial fibrillation
→ also used in the treatment of heart failure in the presence of
sinus rhythm.
● Plasma concentration–response relationship:
• <0.5 μcg/L: no clinical effect
• 0.7 μcg/L: some positive inotropic and conduction
blocking effects
• 0.8–2 μcg/L: optimum therapeutic range (0.5–0.9 μcg/L in
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 patients >65)
• 2–2.5 μcg/L: increased risk of toxicity, although tolerated
in some patients
• >2.5 μcg/L: gastro-intestinal, cardiovascular system and
central nervous system toxicity.
● Distribution
→ widely distributed; extensively bound in varying
degrees to tissues throughout the body.
= high apparent volume of distribution
→ VD can be estimated using the equation:
7.3L/kg (ideal body weight (BWt))
→ VD in patient with renal impairment:
Vd = 3.8 x ideal BWt + (3.1 x creatinine clearance
(mL/min))
→ distribution time: 6–8h
→ Clinical effects are seen earlier after intravenous doses
● Elimination
→ eliminated primarily by renal excretion of unchanged drug
(60–80%); some hepatic metabolism occurs (20–40%)
→ population average value for digoxin clearance:
digoxin clearance (mL/min) = 0.8 BWt + (creatinine
clearance (mL / min))
→ patients with severe congestive heart failure have a reduced
hepatic metabolism and a slight reduction in renal excretion of
digoxin:
digoxin clearance (mL/min) = 0.33 BWt + (0.9 x
creatinine clearance (mL / min))
● Absorption
→ poorly absorbed from the gastro-intestinal tract
→ dissolution time affects the overall bioavailability.
→ Bioavailabilities of two oral formulations:
F (tablets) 0.65
F (liquid) 0.8
● Practical Implications
→ congestive heart failure, hepatic and renal diseases: ↓
elimination of digoxin.
→ hypothyroidism: ↑ plasma concentration, ↑ sensitivity of the
heart to digoxin
→ Hyperthyroidism: Opposite of hypothyroidism
→ Hypokalaemia, hypercalcaemia, hypomagnesaemia and
hypoxia: ↑ sensitivity of the heart to digoxin.
Theophylline
● is an alkaloid related to caffeine.
● Clinical effects:
→ mild diuresis
→ central nervous system stimulation
→ cerebrovascular vasodilatation
→ ↑ cardiac output
→ bronchodilatation (major therapeutic effect)
● Plasma concentration–response relationship:
• <5mg/L: no bronchodilatation1
•5–10mg/L: some bronchodilatation and possible
anti-inflammatory action
• 10–20 mg/L: optimum bronchodilatation, minimum side
effects
• 20–30mg/L: increased incidence of nausea, vomiting2
and cardiac arrhythmias
• >30mg/L: cardiac arrhythmias, seizures.
● Distribution
→ extensively distributed throughout the body
→ average VD: 0.48L/kg.
→ does not distribute very well into fat
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→ distribution time: approximately 40 min.
● Elimination
→ first-order process primarily by hepatic metabolism to
relatively inactive metabolites.
→ population average clearance: 0.04L/h/kg
→ Neonates: 50% of theophylline is converted to
caffeine.
→ treatment of neonatal apnoea of prematurity range:
lower therapeutic range (usually 5–10 mg/L)
● Product formulation
Aminophylline
→ the ethylenediamine salt of theophylline
→ 80% theophylline
● Practical Implications
→ IV bolus doses of aminophylline
- need to be given slowly (preferably by short
infusion) to avoid side effects
→ Oral doses (sustained release preparations)
- may be assumed to provide 12h cover
Gentamicin
● Clinical use
➔ The spectrum of activity of gentamicin is similar to other
aminoglycosides but its most significant activity is against
Psuedomonas aeruginosa.
● Therapeutic range
➔ Gentamicin has a low therapeutic index, producing dose
related side effects of nephro- and ototoxicity.
➔ The use of TDM to aid dose adjustment is essential
➔ It is generally accepted that the peak level should not
exceed 12 mg/L and the trough level should not exceed 2
mg/L.
● Distribution
➔ Gentamicin is relatively polar and distributes primarily
into extracellular fluid.
➔ the apparent volume of distribution is only 0.3 L/kg.
➔ it follows a two-compartment model with distribution
being complete within 1 h.
● Elimination
➔ Elimination is by renal excretion of the unchanged drug.
➔ Gentamicin clearance is approximately equal to
creatinine clearance.
● Practical implications
Initial dosage.
➔ This may be based on the patient's physiological
parameters.
➔ Gentamicin clearance may be determined directly from
creatinine clearance, and the volume of distribution may
be determined from ideal body weight.
Changing dosage
➔ This is not as straightforward as for theophylline or
digoxin, since increasing the dose will increase the peak
and trough levels proportionately.
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Once daily dosing.
➔ Aminoglycosides accumulate in the kidneys, and once
daily dosing could reduce renal tissue accumulation.
➔ clinical trials comparing once daily administration of
aminoglycosides with conventional administration have
shown less nephrotoxicity, no difference in ototoxicity,
and similar efficacy with once daily administration.
➔ Initial dosage for a once daily regimen is 5–7 mg/kg/day
for patients with a creatinine clearance of >60 mL/min,
and this is subsequently adjusted on the basis of blood
levels.
➔ Once daily dosing has not been well studied in pregnant
or breastfeeding women, patients with major burns, renal
failure, endocarditis or cystic fibrosis; therefore, it cannot
be recommended in these groups and multiple daily
dosing should be used.
Lithium
● Lithium is effective in the treatment of acute mania and in the
prophylaxis of manic depression.
● Lithium is toxic, producing dose-dependent and dose-
independent side effects; thus, TDM is essential in assisting in
the management of the dosage.
● Dose-dependent effects
● <0.4 mmol/L: little therapeutic effect
● 0.4–1.0 mmol/L: optimum range for prophylaxis
● 0.8–1.2 mmol/l: optimum range for acute mania
● 1.2–1.5 mmol/L: causes possible renal impairment
● 1.5–3.0 mmol/L: causes renal impairment, ataxia,
weakness, drowsiness, thirst, diarrhoea
● 3.0–5.0 mmol/L: causes confusion, spasticity,
dehydration, convulsions, coma, death. (Levels above
3.5 mmol/L are regarded as a medical emergency.)
● Dose-independent effects
➔ These include tremor, hypothyroidism, nephrogenic
diabetes insipidus, gastro-intestinal upset, loss in bone
density, weight gain and lethargy.
● Distribution
➔ Lithium is unevenly distributed throughout the body, with
a volume of distribution of approximately 0.7 L/kg.
➔ Lithium follows a two-compartment model with a
distribution time of 8 h
● Elimination
➔ Lithium is excreted unchanged by the kidneys.
➔ Lithium clearance is approximately 25% of creatinine
clearance, since there is extensive reabsorption in the
renal tubules.
➔ changes in renal function, dehydration, diuretics
(particularly thiazides), ACE inhibitors and NSAIDs
(except aspirin and sulindac) all decrease lithium
clearance.
➔ aminophylline and sodium loading increase lithium
clearance
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1
➔ there is a wide interindividual variation in clearance, and
the lithium half-life in the population varies between 8
and 35 h with an average of approximately 18 h.
● Practical implications
➔ lithium should not be prescribed unless facilities for
monitoring plasma lithium concentrations are available.
➔ Blood samples should be drawn 12 h after the evening
dose, since this will allow for distribution and represent
the slowest excretion rate.
➔ Population pharmacokinetic data (particularly the volume
of distribution) cannot be relied upon to make initial
dosage predictions, although renal function may give an
approximate guide to clearance.
➔ Blood level measurements are reported in SI units and
therefore it is useful to know the conversion factors for
the various salts.
● 100 mg of lithium carbonate is equivalent to 2.7
mmol of lithium ions
● 100 mg of lithium citrate is equivalent to
1.1 mmol of lithium ions.
Phenytoin
● used in the treatment of epilepsy
● associated with dose-independent side effect:
- hirsutism, acne, coarsening of facial features, gingival
hyperplasia, hypocalcaemia and folic acid deficiency
● has a narrow therapeutic index and has serious
concentration-related side effects
● Plasma concentration–response relationship
•<5mg/L: generally no therapeutic effect
• 5–10mg/L: some anticonvulsant action with approximately
50% of patients obtaining a therapeutic effect with
concentrations of 8–10mg/L
• 10–20mg/L: optimum concentration for anticonvulsant effect
• 20–30mg/L: nystagmus, blurred vision
• >30mg/L: ataxia, dysarthria, drowsiness, coma.
● Distribution
- follows a two-compartment model with a distribution time
of 30–60min
- apparent volume of distribution is 1L/kg
● Elimination
- main route of elimination is via hepatic metabolism
- can be saturated at normal therapeutic doses
- results in the characteristic non-linear dose/concentration
curve
- instead of the usual first-order pharmacokinetic model, a
Michaelis– Menten model, used to describe enzyme
activity, is more appropriate
- Using this model, the daily dosage of phenytoin can be
described by
- (insert equation)
- Km is the plasma concentration at which metabolism
proceeds at half the maximal rate.
- varies greatly with age and race
- Vmax is the maximum rate of metabolism of phenytoin
and is more predictable at approximately 7mg/kg/day.
- clearance changes with blood concentration, the halflife
also changes
- as a rule of thumb, 1–2 weeks should be allowed to
elapse before sampling after a dosage change.
- In overdose, it can be assumed that metabolism of the
drug is occurring at the maximum rate of Vmax
● Practical implications
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 - Care is needed when interpreting TDM data and making
dosage adjustments
- phenytoin is approximately 90% protein bound
- in patients with a low plasma albumin/ uraemia, the free
fraction increases and therefore an adjusted total
phenytoin should be calculated or a free salivary level
taken.
- To adjust the observed concentration in
hypoalbuminaemia the following equation can be applied:
- (insert equation)
- Albumin concentration is in g/L.
- In ureamic patients with severe renal failure, the unbound
fraction is approximately doubled, so the target
concentration needs to be half the normal concentration
or apply the adjusted concentration equation if albumin
level is known.
- oral formulations of phenytoin show good bioavailability.
However, tablets and capsules contain the sodium salt (S
= 0.9), whereas the suspension and infatabs are
phenytoin base (S = 1).
- Intramuscular phenytoin is slowly and unpredictably
absorbed, due to crystallisation in the muscle tissue, and
is therefore not recommended.
- Fosphenytoin, a prodrug of phenytoin, is better absorbed
from the intramuscular site. Doses should be expressed
as phenytoin equivalent. Fosphenytoin sodium 1.5mg is
equivalent to phenytoin sodium 1mg
→ Detail
▪ Smaller Detail
- ▪ Metabolized by the the liver (80%), excreted (20%)
● unchanged in the urine
Carbamazepine
● Carbamazepine is in a class of medications called
anticonvulsants. It works by reducing abnormal electrical
activity in the brain
. → Practical Implications:
→ Indication:
▪ Used for treatment of partial and secondary generalized
tonic-clonic seizures, primary generalized tonic-clonic
seizures, trigeminal neuralgia, and prophylaxis
(Prevention) of bipolar disorder unresponsive to lithium
→ Side effects
▪ Different dermatologic reactions (e.g. rashes)
▪ Aplastic anemia (bone marrow cannot make new RBC’s)
▪ Stevens–Johnson syndrome (disorder of the skin and
mucous membranes)
→ Distribution:
▪ Distributed widely, most concentrated in the kidneys
▪ A highly protein bound drug (70%-80%)
▪ Ave. VD is (0.8–1.9L/kg)
→ Elimination:
▪ Metabolized by the body, excreted 2% unchanged in the
urine
▪ Induces own metabolism or auto-induction
▪ First order Elimination (Elimination proportional to
concentration)
▪ Half-Life = 35 hrs
→ Absorption:
▪ Slow (oral absorption)
▪ Incomplete absorption
▪ Bioavailability = 80%
→ Practical Implications:
CLINPHARM Practical Pharmacokinetics
1
▪ Blood samples should be taken after 2-4 weeks (steady
steat must be achieved first)
▪ trough level must be measure when sampling
▪ Rule of thumb: each 100mg dose will increase the plasma
concentration at the steady state by approximately 1mg/L
in adults
▪ Interactions: Other drugs (e.g. Phenytoin) given at the
same wime with carbamazepine affects metabolism and
blood concent.
Phenobarbital
● Phenobarbital is in a class of medications called barbiturates. It
works by slowing activity in the brain.
.
→ Indication:
▪ Used for treatment of all forms of epilepsy except
absence seizures.
→ Side effects
▪ Sedation with continuous therapy
▪ Tolerance can happen (Impartant to monitor plasma
concent.)
→ Distribution:
▪ Distributed most into body tissues
▪ protein bound drug (50%)
▪ Ave. VD is (0.7–1L/kg)
→ Elimination:
▪ Induces own metabolism or auto-induction
▪ First order Elimination (Elimination proportional to
concentration)
▪ Clearance in children (Faster) is twice the adult clearance
▪ Long half-life, given as single dose
▪ The pharmacokinetics of phenobarbital may be altered by
liver and (less markedly) renal disease
▪ not affected by the simultaneous administration of other
anticonvulsants.
Primidone
● Primidone is in a class of medications called barbiturates. It
works by slowing activity in the brain.
.
→ Indication:
▪ Used for treatment of tonic–clonic and partial seizures.
These are siezures that involve both tonic (stiffening) and
clonic (twitching or jerking) phases of muscle activity.
→ Side effects
▪ sedation
▪ nausea
▪ ataxia (clumsy voluntary movements due to poor muscle
control. It may impair walking, balance, speech,
swallowing, and eye movement.)
Valproate
● Sodium valproate as valproic acid is an anticonvulsant used to
control complex partial seizures and both simple and complex
absence seizures.
.
→ Indication:
▪ broad spectrum of anticonvulsant activity, being useful in
generalised absence, generalised tonic–colonic and
partial seizures
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→ Plasma concentration–response relationship
▪ Valproate has no concentration–response relationship, but
a range of 50–100mg/L is recommended, with 50% of
patients responding at levels above 80mg/L.
▪ Above 100mg/L has no therapeutic value.
→ Toxic Effects
▪ Valproate's rare hepatotoxicity is linked to plasma levels
over 150mg/L.
→ Distribution:
▪ Highly protein bound bound drug (90-95%)
▪ saturates protein binding sites at concentrations above
50mg/L
▪ Ave. VD varies (0.1 to 0.5L/kg)
→ Elimination:
▪ Elimination by the the liver/hepatic, excreted (5%)
eliminated by the kidneys.
▪ At higher concentrations, drug clearance increases due to
protein binding site saturation and increased free fraction.
▪ Plasma concentration changes non-linearly with dose.
→ Practical Implications:
▪ Valproate levels should not be measured due to the lack
of a concentration–response relationship and variable
pharmacokinetics.
▪ Clinical response determines dosage in most cases.
▪ Valproic acid takes weeks to become fully active, so dose
adjustments should be made slowly.
Lamotrigine, vigabatrin, gabapentin, tiagabine,
topiramate, pregabalin, lacosamide and
levetiracetam
● These medications are calles called anticonvulsants..
. → Practical Implications:
● Indication:
→ indicated for multiple epilepsy types and some with
additional indications. All are adjunctive (Another
treatment used together with the primary treatment) to
other anticonvulsants, and some are monotherapy.
● Plasma concentration–response relationship
→ These newer anticonvulsants have no clear plasma
concentration-response relationship.
→ These preparations are usually added to other
anticonvulsants, which complicates theplasma
concentratio-response relationship.
● Practical Implications
→ These agents have narrow therapeutic indices and inter-
and intra-individual pharmacokinetic variation, but there is
not enough evidence to support routine TDM (minitoring).
→ Dosage should be titrated to clinical response.
Ciclosporin
● . Immunosuppressive agent
.
→ Indication:
▪ Tolypocladium inflatum gams produces the neutral
lipophilic cyclic endecapeptide cyclosporin.
▪ It reduces graft rejection after organ and tissue
1. Which of the following anti-convulsants is contraindicated in
transplantation as a potent immunosuppressant.
▪ Has low therapeutic index (causes various toxicities)
▪ Concentration affects graft rejection and nephro- and
hepatotoxicity.
CLINPHARM Practical Pharmacokinetics
1
→ Toxic Effects
▪ nephrotoxicity
▪ hepatotoxicity
▪ gastro-intestinal intolerance
▪ hypertrichosis
▪ neurological issues.
→ Plasma concentration–response relationship
▪ Therapeutic ranges are not absolute for all monitored
drugs.
▪ Since there are many factors, defining a ciclosporin
therapeutic range is even harder.
1. sampling matrix affects concentration (i.e.
whole blood or plasma).
2. it depends on whether the assay includes
metabolites or is ciclosporin-specific.
▪ Target concentrations vary by center, but are typically
100–200 ng/mL in the first 6 months after transplantation
and 80–150 ng/mL after 6 months onwards.
▪ Graft rejection increases below this window.
▪ Above-limit levels increase nephrotoxicity and
hepatotoxicity.
→ Distribution:
▪ Highly lipophilic
▪ protein binding (98%)
▪ Ave. VD varies (4–8L/kg)
→ Elimination:
▪ Elimination by the the liver/hepatic
▪ Clearance (0.1–2L/h/kg)
▪ The milligram per kilogram dosage is 40% higher in
children. Elderly and hepatic patients have lower
clearance rates.
▪ In normal subjects, ciclosporin absorption is variable and
incomplete (F = 0.2–0.5).
▪ Bioavailability varies even more in transplant patients,
especially in the first few months after transplant.
▪ Numerous drugs interact with ciclosporin.
▪ Due to wide inter-patient variation, population averages
are not useful for dose prediction, but therapeutic drug
monitoring will help select the best dose.
▪ TDM (monitoring) with ciclosporin requires practical
considerations:
− whole blood should be the sampling matrix for
ciclosporin varies between blood and plasma
− • Draw samples at steady state, 2–3 days after starting
or changing dosage, to represent trough levels
(average half-life is 9 h).
− Postoperative ciclosporin concentration monitoring
should be done every 2–3 days until the patient's
clinical condition is stable. Monitoring can continue
every 1–2 months.
− Since ciclosporin brands differ in bioavailability, TDM
should be done when switching brands.
REVIEW QUESTIONS (optional)
patients with a history of Tricyclic antidepressants
hypersensitivity?
A. Ethosuximide
B. Carbamazepine
C. Phenobarbital
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 D. Phenytoin
E. Gabapentin
2. What are the most common adverse effects of anticonvulsive
drugs?
I. Alteration in cognition and mentation
II. Headaches and dizziness
III. Gastrointestinal symptoms
A. II only
B. II and III only
C. I, II and III only
D. III only
E. I and II only
3. Which of the following drugs may increase the level of
carbamazepine due to its ability to decrease carbamazepine
metabolism?
A. Valproic acid
B. Primidone
C. Phenytoin
D. Phenobarbital
E. Topiramate
4. Which of the following is/are known side effects of phenytoin?
I. Steven-Johnson Syndrome
II. Gingival hyperplasia
III. Ataxia
IV. Lupus erythematosus

A. II and III only

B. I, II and III only
C. II and IV only
D. II only
E. I, II, III and IV

Aswers: b, c, a, e

REFERENCES

Roger Walker and Cate Whittlesea Clinical Pharmacy and

Therapeutics Fifth Edition

CLINPHARM Practical Pharmacokinetics 9 of 9

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