The document discusses clinical pharmacokinetics and objectives of clinical pharmacokinetics such as defining terms, calculating dosage regimens, comparing linear and nonlinear pharmacokinetics, and modifying doses for patients with organ dysfunction. It also covers types of drug interactions including pharmacodynamic, pharmacokinetic, and pharmaceutical interactions that can affect drug absorption, distribution, metabolism, and excretion. Specific examples of drug interactions that impact these pharmacokinetic processes are provided.

1. Dr. Rameshwar Dass
Guru Gobind Singh College of Pharmacy, Yamunanagar
Haryana, India
Rmeshwar Dass GGSCOP, YNR 1

2. Introduction
• Pharmacokinetics is the science of the kinetics of drug absorption,
distribution, and elimination (metabolism and excretion)
• Clinical Pharmacokinetics:
• It is the application of pharmacokinetic methods to drug therapy.
• It involves a multidisciplinary approach to individually optimized
dosing strategies based on the patient's disease state and patient-
specific considerations.
• It is also applied to TDM, for very potent drugs such as those with a
narrow therapeutic range, in order to optimize efficacy and to prevent
any adverse toxicity
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3. Objectives of Clinical Pharmacokinetic
• Define the following terms: clinical pharmacokinetics, pharmacodynamics,
and clearance, volume of distribution, half-life, bioavailability, linear
pharmacokinetics, and nonlinear pharmacokinetics.
• Calculate a maintenance dose, loading dose, and dosage interval for a
patient given values of clearance, volume of distribution, and half-life.
• Compare the attributes of linear pharmacokinetics and nonlinear
pharmacokinetics.
• List patient characteristics needed to decide upon the best drug dose for an
individual.
• Discuss the various drug metabolism enzymes and drug transport proteins
and their importance in drug bioavailability and elimination.
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4. Objectives of Clinical Pharmacokinetic
• Recommend when drug doses should be modified for patients with renal
or hepatic dysfunction.
• Calculate a modified drug dosage regimen for an agent that follows linear
pharmacokinetics given a steady-state drug concentration and current drug
dose.
• Identify when a patient would benefit from the determination of
pharmacokinetic constants for the use of dosage adjustment using drug-
specific techniques or bayesian computer dosing programs.
• Calculate an initial dose for a patient for the following medications:
aminoglycoside antibiotics, vancomycin, digoxin, theophylline, phenytoin,
and cyclosporine.
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5. Scope of Clinical Pharmacokinetics
• FDA and other regulatory hurdles
• Absolute Bioavailability
• Dosage form design
• Bioavailability problems (F=5% or 95%)
• Intersubjective Variability (absorption vs
DME)
• Estimate Rate Processes
• Distinguish rate process from rate
constant
• Characterize drug exposure
• time duration
• degree of exposure
• Predict dosage requirements
• how much, how often
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Assess changes in dosage requirement
special populations
drug interactions
Pharmacokinetic - Pharmacodynamic
Relationships
Concentration effect relationships
Use PK to provide concentration
when PD
measurement is performed
Establish safety margins and efficacy
characteristics
Efficient and safe drug utilization

6. Drug interaction
• A modification of the expected drug response in the patient as a
result of exposure of the patient to another drug or substance.
• Unintentional
• Intentional
• Drug interactions may include
• Drug-drug interactions
• Food–drug interactions
• Chemical–drug interactions
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7. Types of Drug Interactions
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Pharmacodynamic
Pharmacokinetic
Pharmaceutical
compounding
ABSORPTION
DISTRIBUTION
METABOLISM
EXCRETION (RENAL/HEPATIC)
Competing drug potentiates
or antagonizes the action of
the first drug
Chemical or physical
incompatibility when two or
more drugs are mixed
together

8. Pharmacokinetic Absorption
• It can affect the rate and the extent of systemic drug absorption
(bioavailability) from the absorption site
• Increased bioavailability
• Decreased bioavailability
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9. Rmeshwar Dass GGSCOP, YNR 9
Pharmacokinetic Drug Interactions
Drug Interaction Examples (Precipitant Drugs) Effect (Object Drugs)
Bioavailability
Complexation/chelation Calcium, magnesium, or aluminum and iron
salts
Tetracycline complexes with divalent cations,
causing a decreased bioavailability
Adsorption binding/ionic interaction Cholestyramine resin (anion-exchange resin
binding)
Decreased bioavailability of thyroxine, and
digoxin; binds anionic drugs and reduces
absorption
Adsorption Antacids (adsorption) Decreased bioavailability of antibiotics
Charcoal, antidiarrheals Decreased bioavailability of many drugs
Increased GI motility Laxatives, cathartics Increases GI motility, decreases bioavailability
for drugs which are absorbed slowly; may also
affect the bioavailability of drugs from
controlled-release products
Decreased GI motility Anticholinergic agents Propantheline decreases the gastric emptying of
acetaminophen (APAP), delaying APAP
absorption from the small intestine
Alteration of gastric pH H-2 blockers, antacids Both H-2 blockers and antacids increase gastric
pH; the dissolution of ketoconazole is reduced,
causing decreased drug absorption
Alteration of intestinal flora Antibiotics (eg, tetracyclines, penicillin) Digoxin has better bioavailability after
erythromycin; erythromycin administration
reduces bacterial inactivation of digoxin
Inhibition of drug metabolism in intestinal cells Monoamine oxidase inhibitors (MAO-I) (eg,
tranylcypromine, phenelzine)
Hypertensive crisis may occur in patients
treated with MAO-I and foods containing
tyramine

10. Pharmacokinetic Distribution
• It may be altered by displacement of the drug from plasma protein or
other binding sites due to competition for the same binding site
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Distribution
Protein binding Warfarin–phenylbutazone Displacement of warfarin from
binding
Phenytoin–valproic acid Displacement of phenytoin from
binding

11. Pharmacokinetic Hepatic elimination
• Drug-metabolized by same enzymes have a potential for a drug
interaction.
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Hepatic elimination
Enzyme induction Smoking (polycyclic aromatic
hydrocarbons)
Smoking increases theophylline clearance
Barbiturates Phenobarbital increases the metabolism of warfarin
Enzyme inhibition Cimetidine Decreased theophylline, diazepam metabolism
Mixed-function oxidase
Fluvoxamine Diazepam t 1/2 longer
Quinidine Decreased nifedipine metabolism
Fluconazole Increased levels of phenytoin, warfarin
Other enzymes Monoamine oxidase inhibitors,
MAO-I (eg, pargyline,
tranylcypromine)
Serious hypertensive crisis may occur following ingestion
of foods with a high content of tyramine or other pressor
substances (eg, cheddar cheese, red wines)
Inhibition of biliary
secretion
Verapamil Decreased biliary secretion of digoxin causing increased
digoxin levels

12. Pharmacokinetic Renal clearance
• Drugs that compete for active renal secretion may decrease renal
clearance of the first drug.
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Renal clearance
Glomerular filtration rate
(GFR) and renal blood
flow
Methylxanthines (eg,
caffeine,
theobromine)
Increased renal blood flow and GFR will decrease time
for reabsorption of various drugs, leading to more rapid
urinary drug excretion
Active tubular secretion Probenecid Probenecid blocks the active tubular secretion of
penicillin and some cephalosporin antibiotics
Tubular reabsorption and
urine pH
Antacids, sodium
bicarbonate
Alkalinization of the urine increases the reabsorption of
amphetamine and decreases its clearance
Alkalinization of urine pH increases the ionization of
salicylates, decreases reabsorption and increases its
clearance

13. Pharmacodynamic
• It occurs at the receptor site in which the competing drug potentiates
or antagonizes the action of the first drug
• Example: Alcohol (ethanol) with Antihistamines, opioids may
cause Increased drowsiness
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14. Pharmaceutical compounding
• They are caused by a chemical or physical incompatibility when two
or more drugs are mixed together
• Example: An IV solution of aminophylline has an alkaline pH and
should not be mixed with such drugs as epinephrine which
decompose in an alkaline pH
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15. Food–Drug Interaction
• Theophylline disposition is influenced by diet. A protein-rich diet will
increase theophylline clearance.
• Grapefruit juice increases average felodipine levels about threefold,
increases cyclosporine levels, and increases the levels of terfenadine,
a common antihistamine
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