Group Assignment

1. Dosage regimen adjustment in Obesity

Pharmacokinetic drug interactions in combination therapy
2. Therapeutic drug monitoring
Principles and applications
Drugs requiring therapeutic drug monitoring
Lithum, theophylline

3. Antibiotics – Aminoglycosides and vancomycin

Anticonvulsants – Phenytoin, carbamazepine, valproic acid,
Phenobarbital/primidone, ethosuximide

4. Cardiovascular drugs – Digoxin, lidocaine, procainamide and N-

acetyl procainamde and quinidine
Immunosuppressants – cyclosporine and tacrolimus

1
Clinical
pharmacokinetics

BY: Natanim Degefu (B. Pharm, MSC. In

Pharmaceutics)

2
Introduction

3
Outline
 Definitions of pharmacokinetics
 Applications of pharmacokinetics
 Types of pharmacokinetics
 Pharmacokinetic and Pharmacodynamic relationships

4
Introduction
 The term pharmacokinetics comes from two Greek words;
 Pharmakon - “drug”
 Kinetikos - “moving or in motion”

 is the science of the kinetics of drug absorption, distribution, and

elimination (i.e. excretion and metabolism).

 It is the study of how a drug behaves in the body.

 In other words, PK is the study of “what the body does to a drug”.

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Cont. . .
 The acronym ADME to refer to four processes relevant to
pharmacokinetics,
 A standing for absorption (how the drug gets into the body),

 D for distribution (where the drug goes once inside the body),

 M for metabolism (what enzymes metabolize what drugs, and

how rapidly drugs are metabolized) and
 E for excretion (how drugs are removed from the body).

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Cont. . .

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Cont. . .
 Absorption: is defined as the process by which a drug proceeds
from the site of administration to the site of measurement (usually
blood, plasma)
 Distribution: is the process of reversible transfer of drug to and
from the site of measurement (usually blood or plasma).
 Elimination: is the irreversible loss of drug from the site of
measurement (blood, plasma).
 Elimination of drugs occur by one or both of:
 Metabolism
 Excretion.

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Cont. . .
 Metabolism: is the process of conversion of one chemical species
to another chemical species.
 Usually, metabolites will possess little or none of the activity of
the parent drug.
 However, there are exceptions with active metabolites.

 Procainamide  N-acetyl procainamide

 Propranolol  4-hydroxypropranolol

 Excretion: is defined as the irreversible loss of a drug in a

chemically unchanged or unaltered form.

 Disposition: processes that occur subsequent to the absorption of

the drug.
 Encompasses distribution and elimination phase

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Cont. . .
 Despite the common place use of “ADME” as a definition of
“pharmacokinetics”, the two terms are not truly equivalent.

 Pharmacokinetics is more accurately described by the acronym

“ITE”.
 I for input into the body, since some routes of administration do

not have absorption components (e.g., intravenous

administration),
 T for transfer of drug within the body, and

 E for elimination from the body (which includes metabolism,

since metabolism is a major route of drug elimination).

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Cont. . .
 Pharmacokinetics encompasses
 the fate of a drug after administration to the body, with respect
to the drug’s (or metabolite’s) time course of
 input into the body,

 transfer within the body, and

 elimination from the body.

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Cont. . .
 Application of pharmacokinetic study
 Bioavailability measurements

 Correlation of pharmacological responses with administered

doses
 Evaluation of drug interactions

 Effects of physiological and pathological conditions on drug

disposition and absorption
 Dosage adjustment of drugs in disease states, if and when

necessary
 Clinical prediction: using pharmacokinetic parameters to
individualize the drug dosing regimen and thus provide the most
effective drug therapy.

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Clinical Pharmacokinetics
 is the application of pharmacokinetic methods to drug therapy.

 Is application of pharmacokinetic principles to safe and effective

management of drugs in an individual patient.

 involves a multidisciplinary approach

 to individually optimized dosing strategies based on

 the patient's disease state and patient-specific considerations.

 Primary goals of clinical PK are enhancing efficacy & decreasing

toxicity of a patient's drug therapy

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Cont. . .

 Pharmacokinetics is also applied to therapeutic drug monitoring

(TDM) for very potent drugs such as those with a narrow
therapeutic range,
 in order to optimize efficacy and to prevent any adverse toxicity.

 For these drugs, it is necessary to monitor the patient,

 either by monitoring plasma drug concentrations (eg,

theophylline) or
 by monitoring a specific pharmacodynamic endpoint such as
prothrombin clotting time (eg, warfarin).
 Some drugs frequently monitored are the aminoglycosides and
anticonvulsants.
 Other drugs closely monitored are those used in cancer
chemotherapy, in order to minimize adverse side effects.

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Cont. . .
 Clinical pharmacokinetics
 is the application of pharmacokinetic principles to

 the safe and effective therapeutic management of drugs in an

individual patient.

 With an understanding of pharmacokinetics, pharmacists, doctors

and other health-care professionals can
 increase the effectiveness,

 decrease the toxicity, or

 increase patient compliance with a therapeutic regimen.

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Cont. . .
 The majority of the adverse drug reactions seen in the clinic are
dose-related,
 thus an understanding of pharmacokinetics can help to minimize
these problems.

 Application of pharmacokinetic principles can enhance patient

compliance by
1. allowing establishment of patient friendly dosing regimens or
2. enabling formulation of controlled- or extended-release
products, reducing dosing frequency.

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Cont. . .
 The goal of pharmacokinetics is
 to obtain the desired drug concentration in the body by
optimizing the dosage regimen and dosage form.

 The problem with attaining this goal lies

 in the determination of the optimum target concentration.

 The solution to this problem is found in

 the field of pharmacodynamics (PD),

 the study of the relationship between the drug concentration

at the site of action and the pharmacologic response.
 Unfortunately, we typically do not know the drug concentration at
the site of action,
 so we estimate it based upon plasma concentrations.

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Cont. . .
 As mentioned, since we often do not know concentrations at the
site of action (i.e. concentrations surrounding the receptor in a
given tissue),
 plasma levels are frequently used as indicators of tissue
concentration.

 Thus, blood concentrations are used to optimize the dose of

the drug
 that is, to maximize therapeutic effect and minimize
adverse effects.

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Drug Concentrations in Blood, Plasma, or
Serum
 Measurement of drug concentration (levels) in the blood, serum, or
plasma is the most direct approach to assessing the
pharmacokinetics of the drug in the body.

 Whole blood contains cellular elements including

 red blood cells, white blood cells, platelets, and various other
proteins, such as albumin and globulins.

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Cont. . .
 In general, serum or plasma is most commonly used for drug
measurement.
 Plasma perfuses all the tissues of the body, including the cellular
elements in the blood.
 Assuming that a drug in the plasma is in dynamic equilibrium
with the tissues, then changes in the drug concentration in
plasma will reflect changes in tissue drug concentrations.

20
Cont. . .

Figure: Generalized plasma level–time curve after oral administration of a

drug.

21
Cont. . .
 MEC and MTC represent
 the minimum effective concentration and minimum toxic
concentration of drug, respectively.
 Assuming the drug concentration in the plasma is in equilibrium
with the tissues,
 the MEC reflects the minimum concentration of drug needed at

the receptors to produce the desired pharmacologic effect.

 Similarly, the MTC represents the drug concentration needed to

just barely produce a toxic effect.

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Cont. . .
 The onset time corresponds to
 the time required for the drug to reach the MEC.

 The intensity of the pharmacologic effect is proportional to the

number of drug receptors occupied,
 which is reflected in the observation that higher plasma drug
concentrations produce a greater pharmacologic response, up to
a maximum.

 The duration of drug action is

 the difference between the onset time and the time for the drug
to decline back to the MEC.

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Cont. . .
 In contrast, the pharmacokineticist can also describe the plasma
level–time curve in terms of such pharmacokinetic terms as
 peak plasma level,

 time for peak plasma level, and

 area under the curve, or AUC.

 The time of peak plasma level is

 the time of maximum drug concentration in the plasma and

 is a rough marker of average rate of drug absorption.

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Cont. . .
 The peak plasma level or maximum drug concentration is
 related to the dose, the rate constant for absorption, and the
elimination constant of the drug.

 The AUC is related to the amount of drug absorbed systemically.

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Cont. . .

Plasma level–time curve showing peak time and concentration.

• The shaded portion represents the AUC (area under the
curve).

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Drug Concentrations in Tissues
 Tissue biopsies are occasionally removed for diagnostic purposes,
such as the verification of a malignancy.

 Usually, only a small sample of tissue is removed,

 making drug concentration measurement difficult.

 Drug concentrations in tissue biopsies may not reflect drug

concentration
 in other tissues nor the drug concentration in all parts of the
tissue from which the biopsy material was removed.

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Cont. . .
 In fact, for many tissues, blood flow to one part of the tissues
 need not be the same as the blood flow to another part of the
same tissue.
 The measurement of the drug concentration in tissue biopsy
material may be used to ascertain
 if the drug reached the tissues and reached the proper

concentration within the tissue.

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Drug Concentrations in Urine and Feces
 Measurement of drug in urine is an indirect method to ascertain
the bioavailability of a drug.

 The rate and extent of drug excreted in the urine

 reflects the rate and extent of systemic drug absorption.

 Measurement of drug in feces may

 reflect drug that has not been absorbed after an oral dose or
may reflect drug that has been expelled by biliary secretion after
systemic absorption.

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Drug Concentrations in Saliva

 Saliva drug concentrations have been reviewed for many drugs for
therapeutic drug monitoring.

 Because only free drug diffuses into the saliva,

 saliva drug levels tend to approximate free drug rather than total
plasma drug concentration.

 The saliva drug concentrations taken after equilibrium with the

plasma drug concentration generally provide more stable indication
of drug levels in the body.

 The use of salivary drug concentrations as a therapeutic indicator

should be used with caution and preferably as a secondary
indicator.

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Forensic Drug Measurements
 Forensic science is the application of science to personal injury,
murder, and other legal proceedings.

 Drug measurements in tissues obtained at autopsy or in other

bodily fluids such as saliva, urine, and blood may be useful
 if a suspect or victim has taken an overdose of a legal

medication, has been poisoned, or has been using drugs of abuse

such as opiates (eg, heroin), cocaine, or marijuana.

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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 = 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 (Figure 1-2).

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Cont. . .

FIGURE 1-2 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. 33
Cont. . .
 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.

 This repeating pattern continues and eventually drug

concentrations for each dosage interval become superimposable
 when the amount of cyclosporine absorbed into the body from

the GIT equals the amount removed by hepatic metabolism over

each dosage interval.

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Cont. . .
 Regardless of the mode of drug administration, when the rate of
drug administration equals the rate of drug removal,
 the amount of drug contained in the body reaches a constant
value.
 This equilibrium condition is known as steady state and
 is extremely important in clinical pharmacokinetics because

 usually steady-state serum or blood concentrations are used

to assess patient response and compute new dosage
regimens.

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Cont. . .
 If a patient is administered several different doses until steady state
is established, and
 steady-state serum concentrations are obtained from the patient
after each dosage level, it is possible to determine a pattern of
drug accumulation (Figure 1-3).
 If a plot of steady state concentration versus dose yields a straight
line, the drug is said to follow linear pharmacokinetics.
 In this situation, steady-state serum concentrations increase or
decrease proportionally with dose.

36
Cont. . .

FIGURE 1-3 When doses are increased for most drugs, steady-state concentrations increase
in a proportional fashion leading to linear pharmacokinetics (solid line). However, in some
cases proportional increases in steady-state concentrations do not occur after a dosage
increase. When steady-state concentrations increase more than expected after a dosage
increase (upper dashed line), Michaelis-Menten pharmacokinetics may be taking place. If
steady-state concentrations increase less than expected after a dosage increase (lower
dashed line), saturable plasma protein binding or autoinduction are likely explanations. 37
Cont. . .
 Therefore, if a patient has a steady-state drug concentration of 10
 g/mL at a dosage rate of 100 mg/h,
 the steady-state serum concentration will increase to 15 g/mL
if the dosage rate is increased to 150 mg/h (e.g., a 50% increase
in dose yields a 50% increase in steady-state concentration).

 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.

38
Cont. . .
 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 phenytoin and salicylic acid follow Michaelis-Menten
pharmacokinetics.

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Cont. . .
 When steady-state concentrations increase less than expected after
a dosage increase, there are two typical explanations.
 Some drugs, such as valproic acid, 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, 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.

 In either case, the relationship between steady-state concentration

and dose for drugs that follow nonlinear pharmacokinetics is
fraught with significant inter subject variability.

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Cont. . .
 Drugs that exhibit nonlinear pharmacokinetics are oftentimes very
difficult to dose correctly.

 Steady-state serum concentrations/dose plots for medications are

determined in humans early during the drug development process.

 Because of this, by the time a new drug is available for general use
it is usually known if the drug follows linear or nonlinear
pharmacokinetics, and it is not necessary to determine this
relationship in individual patients.

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Cont. . .
 Thus, the clinician treating a patient knows whether to anticipate
linear or nonlinear pharmacokinetics and can assume the
appropriate situation when adjusting drug doses.
 Dealing with drugs that follow linear pharmacokinetics is more
straightforward and relatively easy.

 If a patient has been taking a medication long enough for steady

state to have been established, and it is determined that a dosage
adjustment is necessary because of lack of drug effect or the
presence of drug toxicity,
 steady-state drug concentrations will change in proportion to
dose for drugs that follow linear pharmacokinetics.

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Cont. . .
 For example, if a patient is taking sustained-release procainamide
1000 mg every 12 hours for the treatment of a cardiac arrhythmia,
but is still having the arrhythmia, a clinician could obtain a steady-
state procainamide serum concentration.
 If the procainamide concentration was too low (e.g., 4 μg/mL
before the next dose), a dosage increase could help suppress the
arrhythmia.
 Using linear pharmacokinetic principles, one could determine that a
dosage increase to 1500 mg every 12 hours would increase
 the steady-state procainamide serum concentration to 6 μg/mL

 (e.g., new steady-state concentration = (new dose/old dose)

× old steady-state concentration;
 new steady-state concentration = (1500 mg/1000 mg) ×4
μg/mL = 6 μg/mL).

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Pharmacodynamics
 refers to the relationship between the drug concentration at the
site of action (receptor) and pharmacologic response,
 including biochemical and physiologic effects that influence the
interaction of drug with the receptor.

 The interaction of a drug molecule with a receptor causes the

initiation of a sequence of molecular events resulting in a
pharmacologic or toxic response.

 Pharmacokinetic-pharmacodynamic models are constructed to

relate plasma drug level to drug concentration in the site of action
and establish the intensity and time course of the drug.

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Pharmacokinetics and pharmacodynamics
relationships
 Pharmacodynamics
• study of therapeutic and or toxic effects of a drug.
• drug effect on the body; major concern of pharmacology.
 Receptor
• site in the biophase to which drug molecules can be bound.
• Drug + Receptor = Effect
• usually a protein or proteinaceous material.

45
Cont. . .

Figure: Relationship of PK and PD and factors that affect each.

46
Cont. . .
 For most drugs, there is a correlation between drug response
and drug concentration in the plasma.
 This correlation is not, however, a linear one.
 In fact, for most drugs, a sigmoidal (S-shaped) relationship
exists between these two factors.
 therapeutic effect reaches a plateau, where increase in drug
concentration will have no further increase in effect.
 In contrast, the toxic effects of a drug show no such plateau.
 Toxic effects start at the minimum toxic concentration and
continue to rise, without limit, as drug concentration
increases.

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 Cont. . .
E.g. therapeutic effects of Albuterol reach a plateau while its toxic
effects continue to rise with increasing drug concentration (Cp).

N.B: Albuterol therapeutic effect is measured by the forced expiratory volume in 1s

(FEV1); while its toxic effects are mainly cardiovascular.
48
Cont. . .

 For the large majority of drugs whose effect is not quantifiable, the
plasma drug concentration remains the best marker of effect.

 Pharmacokinetics allows us to:

 determine a drug dose and dosing interval to achieve and maintain a

plasma drug concentration within the therapeutic range.

 predict the time course of plasma drug concentration over time,

observing fluctuations and deciding when a declining concentration
becomes low enough to require the administration of another
dose.

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