Clinical pharmacokinetics and its application

Clinical pharmacokinetics and its application--
1)definition
2) APPLICATIONS OF CLINICAL PHARMACOKINETICS
 Design of dosage regimens:
a) Nomograms and Tabulations in designing dosage regimen,
b) Conversion from intravenous to oral dosing,
c) Determination of dose and dosing intervals,
d) Drug dosing in the elderly and pediatrics and obese patients.

 Pharmacokinetics of Drug Interaction:
a) Pharmacokinetic drug interactions
b) Inhibition and Induction of Drug metabolism
c) Inhibition of Biliary Excretion.
 Therapeutic Drug monitoring:
a) Introduction
b) Individualization of drug dosage regimen (Variability – Genetic, Age and Weight, disease, Interacting drugs).
c) Indications for TDM. Protocol for TDM.
d) Pharmacokinetic/Pharmacodynamic Correlation in drug therapy.
e) TDM of drugs used in the following disease conditions: cardiovascular disease, Seizure disorders, Psychiatric conditions, and Organ transplantations

 Dosage adjustment in Renal and Hepatic Disease.
a. Renal impairment
b. Pharmacokinetic considerations
c. General approach for dosage adjustment in renal disease.
d. Measurement of Glomerular Filtration rate and creatinine clearance.
e. Dosage adjustment for uremic patients.
f. Extracorporeal removal of drugs.
g. Effect of Hepatic disease on pharmacokinetics.

 Population Pharmacokinetics.
a) Introduction to Bayesian Theory.
b) Adaptive method or Dosing with feedback.
c) Analysis of Population pharmacokinetic Data

1. CLINICAL PHARMACOKINETICS &
PHARMACOTHERAPEUTIC DRUG
MONITORING





ASSIGNMENT ON CLINICAL
PHARMACOKINETICS AND ITS
APPLICATIONS









SUBMITTED BY:
PAVITHRA .V
V- PHARM D

2. CLINICAL PHARMACOKINETICS :

DEFINITION:
PHARMACOKINETICS: It involves the stidy of absorption ,
distribution , metabolism ( biotransformation) and drug excretion
over time.
CLINICAL PHARMACOKINETICS: It is the application of
pharmacokinetic principles to the safe and effective therapeutic
management of drugs in an individual patient.
- It is the discipline that describes the absorption , distribution ,
metabolism and elimination of drugs in patients requiring drug
therapy.
AIMS OF CLINICAL PHARMACOKINETICS:
Primary goals of clinical pharmacokinetics include enhancing
efficacy and decreasing toxicity of a patient's drug therapy
The development of strong correlations between drug
concentrations and their pharmacologic responses has enabled
clinicians to apply pharmacokinetic principles to actual patient
situations.
A drug's effect is often related to its concentration at the site of
action, so it would be useful to monitor this concentration.
Receptor sites of drugs are generally inaccessible to our
observations or are widely distributed in the body, and therefore
direct measurement of drug concentrations at these sites is not

3. practical. For example, the receptor sites for digoxin are
believed to be within the myocardium, and we cannot directly
sample drug concentration in this tissue.
However, we can measure drug concentration in the blood or
plasma, urine, saliva, and other easily sampled fluids.
new concepts and principles in pharmacokinetics
application of therapeutic drug monitoring to optimize therapy
prediction and avoidance of drug interactions
new methodology in drug development and advances in drug
delivery systems
optimization of treatment for particular patient populations

APPLICATIONS OF CLINICAL
PHARMACOKINETICS
 Design of dosage regimens:
a) Nomograms and Tabulations in designing dosage regimen,
b) Conversion from intravenous to oral dosing,
c) Determination of dose and dosing intervals,
d) Drug dosing in the elderly and pediatrics and obese
patients.

 Pharmacokinetics of Drug Interaction:
a) Pharmacokinetic drug interactions
b) Inhibition and Induction of Drug metabolism
c) Inhibition of Biliary Excretion.

4. Therapeutic Drug monitoring:
a) Introduction
b) Individualization of drug dosage regimen (Variability –
Genetic, Age and Weight , disease, Interacting drugs).
c) Indications for TDM. Protocol for TDM.
d) Pharmacokinetic/Pharmacodynamic Correlation in drug
therapy.
e) TDM of drugs used in the following disease conditions:
cardiovascular disease, Seizure disorders, Psychiatric
conditions, and Organ transplantations

Dosage adjustment in Renal and hepatic Disease.
a. Renal impairment
b. Pharmacokinetic considerations
c. General approach for dosage adjustment in Renal
disease.
d. Measurement of Glomerular Filtration rate and
creatinine clearance.
e. Dosage adjustment for uremic patients.
f. Extracorporeal removal of drugs.
g. Effect of Hepatic disease on pharmacokinetics.

Population Pharmacokinetics.
a) Introduction to Bayesian Theory.
b) Adaptive method or Dosing with feed back.
c) Analysis of Population pharmacokinetic Data

5.  DESIGN OF DOSAGE REGIMENS:
Several methods may be used to design a dosage regimen.
Generally, the initial dosage of the drug is estimated using average
population pharmacokinetic parameters.
Which is obtained from the literature and modified according to
the patient’s known diagnosis, pathophysiology, demographics,
allergy, and any other known factor that might affect the
patient’s response to the dosage
The dosing strategies are based generally on pharma- cokinetic
calculations that were previously performed manually.
Computer automation and pharmacokinetic software packages
improve the accuracy of the calculation, make the calculations
“easier,” and have an added advantage of maintaining proper
documentation
regimen
NOMOGRAM :
Nomograms or equations, which describe the
relationships between patient characteristics (e.g. Age, weight,
gender, disease states, interacting drugs, environmental factors-
smoking & food) and pharmacokinetic parameters in a population,
are often used to estimate the initial pharmacokinetic parameters for
drug dosing in individual patients for whom patient-specific
parameters are not known.
TABULATION:
 The tables may include loading and maintenance doses that
are modified for the demographics of the patient (eg, age,

6. weight) and for certain disease states (eg, renal
insufficiency).


 PHARMACOKINETIC DRUG INTERACTION:

It is the modification of the effect of one drug (the object drug ) by
the prior concomitant administration of another (precipitant drug).

INDUCTION AND INHIBITION:
Metabolism based drug-drug and other interactions can have a
significant influence on the use and safety of many drugs.
Induction of drug metabolism can lead to unexpected drops in
drug concentration or the build-up of metabolites. The reverse
can occur when there is inhibition of drug metabolism.
The major organ involved in metabolism is liver and the major
enzyme system involved in drug metabolism is CYP 450, the
well-known family of oxidative hemo-proteins. Induction CYP
450 enzymes at the liver is responsible for induction of
metabolism of many drugs.
Inhibition:
The phenomenon of decreased drug metabolizing ability of the
enzymes by several drugs and chemicals is called as enzyme
inhibition.
The process of inhibition may be of two types:
[1]. Direct Inhibition
[2]. Indirect Inhibition
Induction:

7. The phenomenon of increased drug metabolizing ability of the
enzymes by several drugs and chemicals is called as enzyme
induction.
A number of drugs can cause an increase in liver enzyme
activity over time. This in turn can increase the metabolic rate
of the same or other drugs. Phenobarbitone will induce the
metabolism of itself, phenytoin, warfarin, etc.

THERAPEUTIC DRUG MONITORING :
The usefulness of plasma drug concentration data is based on the
concept that pharmacologic response is closely related to drug
concentration at the site of action. For certain drugs, studies in
patients have provided information on the plasma concentration
range that is safe and effective in treating specific diseases Within
this therapeutic range, the desired effects of the drug are seen.
Below it, there is greater probability that the therapeutic benefits
are not realized above it, toxic effects may occur.
Therapeutic drug monitoring is defined as the use of assay
procedures for determination of drug concentrations in plasma, and
the interpretation and application of the resulting concentration data
to develop safe and effective drug regimens. If performed properly,
this process allows for the achievement of therapeutic
concentrations of a drug more rapidly and safely than can be
attained with empiric dose changes. Together with observations of
the drug's clinical effects, it should provide the safest approach to
optimal drug therapy.

8. Individualization of Drug Dosage Regimens:
Not all drugs require rigid individualization of the dosage regimen.
Many drugs have a large margin of safety (i.e., exhibit a wide
therapeutic window), and strict individualization of the dose is
unnecessary. The U.S. Food and Drug Administration (FDA) has
approved an over-the-counter (OTC) classification for drugs that the
public may buy without prescription. In the past few years, many
prescription drugs, such as ibuprofen, loratidine, omeprazole,
naproxen, nicotine patches, and others, have been approved by the
FDA for OTC status. These OTC drugs and certain prescription
drugs, when taken as directed, are generally safe and effective for
the labeled indications without medical supervision.
For drugs with a narrow therapeutic window, such as digoxin,
aminoglycosides, antiarrhythmics, anticonvulsants, and some
antiasthmatics, such as theophylline, individualization of the dosage
regimen is very important.
DOSAGE ADJUSTMENT IN UREMIC PATIENTS:
Nomograms are charts available for use in estimating dosage
regimens in uremic patients The nomograms may be based on
serum creatinine concentrations, patient data (height, weight, age,
gender), and the pharmacokinetics of the drug.

 As discussed by Chennavasin and Brater (1981), each
nomogram has errors in its assumptions and drug database.

Most methods for dose adjustment in renal disease assume

9. that nonrenal elimination of the drug is not affected by renal
impairment and that the remaining renal excretion rate constant
in the uremic patient is proportional to the product of a constant
and the Clcr:
ku = knr + αClcr

where knr is the nonrenal elimination rate constant and α
is a constant.

Equation is similar to next Equation,
where 1/VD, and it can be used for the construction of a
nomogram.

POPULATION PHARACOKINETICS:
Population pharmacokinetics (PopPK) is the study of variability in
plasma drug concentrations between and within patient populations
receiving therapeutic doses of a drug.
BAYESIAN THEORY

Bayesian theory was originally developed to
improve forecast accuracy by combining subjective prediction with
improvement from newly collected data. In the diagnosis of disease,
the physician may make a pre- liminary diagnosis based on
symptoms and physical examination.
Later, the results of laboratory tests are received. The
clinician then makes a new diagnostic forecast based on both sets of
information. Bayesian theory provides a method to weigh the prior

10. informa- tion (eg, physical diagnosis) and new information (eg,
results from laboratory tests) to estimate a new probability for
predicting the disease.

ADAPTIVE METHOD OR DOSING WITH FEEDBACK:

 In dosing drugs with narrow therapeutic ratios, an initial dose is
calculated based on mean population pharmacokinetic
parameters.
 After dosing, plasma drug concentrations are obtained from the
patient.
As more blood samples are drawn from the patient, the calculated
individualized patient pharmacokinetic parameters become
increasingly more reliable. This type of approach has been referred
to as adaptive or Bayesian adaptive method with feedback when a
special extended least-squares algorithm is used

11. REFERENCE:

Shargel and yu’s “APPLIED BIOPHARMACEUTICS AND
PHARMACOKINETICS” – Seventh Edition by leon shargel
and Andrew B.C . YU