Week 1 – Introduction to PK & PD Principles

What are “drugs”?

• FDA defines these agents as being:

o Drugs: “intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease” and
“intended to affect the structure or any function of the body of man or other animals”.
▪ Consists of both “small” and “large” molecule agents”
• Biopharmaceuticals: Viral, toxin, antitoxin, blood/blood product or therapeutic serum intended to prevent, treat
or cure a disease
o Examples include vaccines, insulin, monoclonal antibodies, blood factors
o Sub-set of “drugs” encapsulated above

Breakdown of large vs small molecules

• Small molecules:
o 1204 unique products approved by the FDA
o 803 oral, 421 parenteral, and 275 topical (some have more than one route)
o 227 molecular targets
• Large molecules:
o 166 unique products
o 76 protein targets, only 9 targets are augmented by both small and large molecule agents (example is
tyrosine kinase inhibitors for malignancy)
• Examples of large molecules:
o Insulin products: glargine (Lantus), aspart (Novolog), lispro (Humalog)
o Vaccines: Diphtheria, tetanus and pertussis (Adacel), Influenza (Fluzone), Herpes Zoster (Zostavax)
• Examples of biologic products:
o All end in ‘mab’ (monoclonal antibody)
 o Abciximab (Reopro): antiplatelet inhibitor
o Infliximab (Remicade): used for many GI/arthritis conditions
o Omalizumab (Xolair): asthma
o Trastuzumab (Herceptin): breast cancer
▪ Largest class of drugs used for oncologic diseases

Developmental differences

• Small molecules:
o Produced or synthesized within laboratory settings
o Standardization done within laboratory/development phase
o Minimally impacted by the manufacturing process
▪ Standardization testing done to ensure consistency amongst batches
• Large molecules:
o Produced or developed in living systems
o Bacteria, viral, human cells
o Variability caused by changes in amino acid chains/bonding, environmental factors (heat/cold, lighting)
o Greatly impacted by the manufacturing process
o Variability means differences may be seen even amongst different batches of the same product

Differences in therapeutic targets

• Small molecules often target receptors, enzymes, or cells within the body
o Low level of immunogenicity, typically not recognized as “foreign”
• Large molecules target a gene or protein
o Higher level of immunogenicity, may be quickly recognized as “foreign”

Differences in pharmacokinetics/dynamics

• Biologic agents typically:

o Have shorter half-lives
o Less stable / more prone to degradation
o More sensitive to environmental changes e.g., temperature, light, humidity
o Production costs are higher, as are costs to the consumer/healthcare system

Biosimilar products

• Equivalent of “generic” medications

• Often represents a biologic agent with similar properties/development as the reference product
• Approval and development processes are much more lengthy, involved, and costly compared to small molecule
generics
o May discourage competition
• FDA: Biosimilar products are biologic agents that are “highly similar to the reference product” with regard to
“safety, purity, and potency”
• Currently, the FDA has approved the following:
o Use of the nonproprietary (generic) product name with four additional letters added to the end
▪ Infliximab (Remicade®) vs Infliximab-dyyb
o World Health Organization and the European Medicines Agency have similar language

Real world application

• Currently there are just over 120 biologic agents approved for use in the US
o Only 4 biosimilar agents have been approved with 11 others under investigation / review
 ▪ Many other countries have approved larger numbers
o Cost for these agents can range up to $400,000/year
▪ Average cost has increased over the past decade
▪ Biosimilar agents may provide cost-reductions of up to 30%

Receptors: Definitions and details

• Receptors are often proteins

o Drug effects are determined by the number of receptors that are “bound” at one time
o May have multiple “states” with only one being active/available for binding
o Up and downregulation occurs based on presence of stimuli and homeostatic regulation
▪ For example, the presence of excessive catecholamine's or use of beta agonists, beta receptors
may down-regulate

Receptor binding

• Agonist: receptor activation via binding

o Most binding is reversible, bind via ionic or hydrogen binding
▪ Covalent (chemical/molecular) binding is irreversible
o Partial agonist: binds but produces submaximal response
▪ May also produce antagonistic effects (partial)
• Antagonist: binds to receptor but prevents activation
o Binding is similar as for agonists
o Competitive antagonism: drug actively “competes” for receptor site to prevent agonist from binding
(concentration response)
o Non-competitive antagonism: often seen with agonist that binds covalently

Entrance into the system

• All medications seek to cross lipid bilayer to enter cells to produce receptor effects
• Passive diffusion (95%):
o Non carrier-mediated
o Energy independent
o Mobilizes with concentration gradient (high to low)
o No saturation kinetics
• Active transport (5%):
o Carrier-mediated
o Energy dependent
o ATP → ADP
o Mobilizes against concentration gradient (low to high)
o Saturation kinetics

Drug Transporters

• Specific transporters may aid influx, or efflux, of a drug

• P-glycoprotein (permeability glycoprotein) is a membrane-associate protein in the ATP binding cassette
transporter superfamily
o Transport drugs back out of the gut wall and into the gut lumen, thus reducing absorption
o Transports drugs out of the kidney and into the urine

Pharmacology Terms // Two major branches impacting patient care

• Pharmacodynamics:
 o Study of the biochemical and physiological effects of drugs and their mechanisms of action (what the
drug does to the body)
• Pharmacokinetics:
o Study of how absorption, distribution, metabolism (biotransformation), and excretion determine the
concentration of a drug at its site of action (what the body does to the drug)
• Pharmacognosy:
o Study of the natural sources of drugs: animals, minerals and plants
o Also encompasses “herbal” or “natural” medicine products
o Up to 50% of approved drugs from 1982-2012 were (in)directly derived from natural products
▪ Up to 70,000 different plant sources have been screened
• Toxicology:
o Study of the effects of poisons including adverse drug events
• Pharmacotherapeutics:
o Study of how drugs are used to diagnose, prevent, and treat disease

Pharmacokinetics: ADME

• A: Absorption
• D: Distribution
• M: Metabolism
• E: Elimination/Excretion

Absorption

• Defined as shift of drug from the site of administration to serum

• Dependent on route of administration as previously discussed
o Oral: stomach and intestines into portal system
o Rectal: rectum into systemic circulation
o Intramuscular/topical: muscles into systemic circulation
o Sublingual/IV: directly into systemic system
• Rate of absorption: Fick’s law
o Predicts rate of absorption
o Highest with larger surface area and thin

Alteration of Absorption

• Lipid solubility:
o Higher the lipophilicity, greater the absorption (can be measured)
▪ Non-polar drugs are ionized and are lipophilic (NaCl vs Na+ and Cl-)
o Blood flow:
▪ Receipt of greater blood flow increases absorption rates
o Available surface area:
▪ Presence of greater surface area increases absorption rates
o Contact time:
▪ Alterations in contact time (diarrhea decreases, medical conditions can increase) including
presence of food can alter absorption

Bioavailability

• Defined as percentage (fraction) of unchanged drug that reaches systemic system

o Example: 1000 mg tablet that has 85% bioavailability would yield 850 mg of unchanged drug
 o Determined by comparison of plasma concentrations for oral vs. intravenous routes of administration

Alteration of Bioavailability

• First-pass metabolism:
o Metabolism of parent (unchanged) drug after it leaves the GI tract but prior to reaching the systemic
system via the liver
o Many classes of drugs including β-blockers and tricyclic amines undergo first-pass metabolism
o Significantly decreases the amount of parent drug that reaches the systemic system
• Solubility:
o Extremely hydrophilic (water loving) and lipophilic (fat loving) drugs are poorly absorbed
o Due to their affinity for water or fat these drugs possess decreased solubility and thus decreased
bioavailability
• Stability:
o Due to their chemical composition products such as insulin are rapidly degraded by enzymes

Distribution

• Defined as the process of the drug enters the extracellular fluid and/or tissues from the serum
o Enters the ‘central compartment’ and immediately becomes dilute
o Rapidly absorption into the blood volume but complete distribution to body tissues may take hours (or
days)
o Many drugs will distribute into tissues, becoming ‘multicompartment’
• Polarity: measured by amount of drug that dissolves in oil and water
o Polar drugs are drawn into water and have lower Volume of distribution; non-polar are drawn into fat
and have higher Volume of distribution

Distribution: Volume of Distribution

• Volume of distribution (Vd) is the theoretical volume of fluid required to “dilute” a drug within the body
o Vancomycin (antibiotic): 0.4 to 1 Liter/kg
o Propofol (sedative): 60 L/kg
• Three major compartments of water within the body:
o Plasma: 6% of the body weight
o Extracellular: 20% of the body weight
o Total body water: 60% of the body weight

Factors influencing distribution

• Blood flow: areas receiving greater blood flow have great distribution, and the opposite is true
• Structure:
o Lipid soluble drugs can cross the blood-brain barrier, whereas lipid-insoluble drugs cannot
o Hydrophobic (water hating) drugs readily move across cell membranes whereas hydrophilic (water
loving) cannot readily cross
• Binding: the higher the protein binding the lower the free drug concentration
o Albumin is the most common protein; α1-acid glycoprotein
o Age, liver/renal disease and pregnancy can all decrease plasma proteins

Metabolism

• Four major pathways:

o Oxidation; Reduction; Hydrolysis; Conjugation
• Phase I: Oxidation, reduction, hydrolysis
 o Goal is to make the medication more polar
• Phase II: Conjugation via covalent binding to carbohydrate/amino acid
o Goal is to make the medication hydrophilic for elimination
• Kinetics of metabolism:
o First-order: drug metabolism is proportional to drug dose
▪ These reactions typically follow Michaelis-Menten kinetics
o Zero-order: drug metabolism is independent of drug dose

Phase I metabolism

• Oxidation, reduction, and hydrolysis occurs via CYP (cytochrome) isoenzymes

o Primarily hepatic in nature, catalyze metabolism
o Grouped based on shared characteristics e.g. CYP 2, CYP 3
▪ Further grouped into sub-families e.g. CYP 2D6
▪ CYP 3A4 responsible for up to 50% of all metabolism
o May be increased (induced) or decreased (inhibited) by medications that act on the liver

Phase II conjugation

• Primarily occurs via transferases, making medication more water soluble

o Conjugation of phase I medications/metabolites with endogenous substances yielding more polar
molecules
▪ Yields highly polar and often therapeutically inactive molecules
o Glucuronidation is important pathway of anesthesia medications (propofol, benzodiazepines, opioids)

CYP Inducers and inhibitors

• Common inducers:
o NNRTIs – e.g. Efavirenz (Sustiva)
o Rifampin
o Anticonvulsants – e.g. Carbamazepine (Tegretol), Phenytoin (Dilantin)
• Common inhibitors:
o Protease inhibitors
o Azole antifungals: Keto-, Fluconazole
o Macrolide antibiotics: Erythromycin

Pharmacokinetic substrates

• Substrate: medications that are metabolized by CYP isoenzymes

• Common CYP450 substrates:
o HMG-CoA reductase inhibitors
o Omeprazole
o Angiotensinogen-receptor blockers
o Benzodiazepines
o Beta blockers

Elimination

• Defined as the elimination of drug from the body

• Largely done via the kidneys
o Also internally via bile (enterohepatic), lungs and within breast milk or externally via dialysis
• Glomerular filtration:
o Unbound drug enters glomerulus where it becomes ‘filtered’ into glomerular filtrate
 o Typical rates are 100-120 milliliters/min
o Decreases with age or kidney dysfunction

• Most metabolism/elimination is proportional to the amount of drug present in the system

o However, this is not an infinite process, and limits may be reached, which is referred to as “saturation”
o Majority of agents follow linear kinetics; proportionate amount of drug entering the system to the
amount being metabolized/removed

Zero and first order processes

• Zero order: rate of metabolism/elimination is constant/fixed per time

o A constant amount of drug is eliminated over a given time, regardless of any other factors
o Consumption of oxygen is one real-world example, methanol, fluoxetine, omeprazole, phenytoin are
other examples
o Toxicity is more concerned with time of administration/ingestion
• First order: rate of metabolism/elimination is proportional to the amount of drug
o The amount of drug eliminated shifts based on remaining percentage
o Most medications follow this pathway for elimination
o Toxicity is more concerned with amount administered/ingested

Pharmacology related terms

• Half-life (t1/2):
o Time necessary for the amount of drug in the body to decrease by one-half
• Time to steady state (tss)
o Typically requires 3-5 half lives
o Will impact:
▪ Times that blood levels are drawn
▪ Whether or not a loading dose is needed

Therapeutic definitions

• Therapeutic range:
o Serum concentration range between the minimum effective and minimum toxic concentrations
 • LD50 (lethal dose):
o Median lethal dose or smallest dose needed to kill half of a the population
• ED50 (effective dose):
o Median effective dose needed to produce the stated effect in half the population
o Example: 10 mg of lisinopril will reduce SBP by 7-8 mmHg
• Therapeutic Index:
o Margin of safety for a drug as measured by the ratio between LD50 and ED50
o The larger the ratio, the ‘safer’ the drug

Oral Route

• Easiest to use, and thus most common

o Most complicated in terms of reliable bioavailability (percent of drug that reaches systemic system)
o Various modalities are employed:
o Tablets/capsules
▪ Sublingual vs. buccal vs. regular release vs. sustained/extended release vs. enteric coated
o Liquids (solutions, suspensions, emulsions)
o Inhalations

Oral Route: Tablets/capsules

• Why are there so many delivery methods?

o Variable bioavailability and reliability exist
o Time-action profile differences exist
▪ Differences in half-life (therapeutic action)
▪ Dosing considerations exist
• Once daily versus four times daily
o Financial considerations exist

Oral Route: Tablets/Capsules

• Bioavailability:
o Many drugs are metabolized/inactivated prior to reaching site of action
▪ Nitroglycerin is a great example
▪ Buprenorphine/naloxone is another
• First-pass metabolism severely decreases bioavailability and renders swallowed tablets useless, thus
sublingual/buccal dosage forms help to alleviate this problem
o Metabolism in the liver causes drug loss/inactivation

Oral Route: Sustained & Extended Release

• Sustained, extended, delayed, continuous, long-acting…

o No major difference from immediate-release counterparts concerning bioavailability
o Major difference: time-action profile
▪ Half-life of the drug is longer with sustained release products than immediate release

Oral Route: Enteric coated tablets

• Enteric coated tablets:

o Shell/coating the surrounds active drug to minimize dissolution via stomach and maximize bioavailability
o Aspirin: done to prevent irritation to stomach
o Erythromycin/Naproxen: done to prevent degradation of active drug
Oral Route: Liquids

• Liquid available products:

o Bypasses stomach breakdown of dosage form, thus entering systemic system at a quicker rate
o Various “forms” of liquids available
▪ Solution: drug dissolved in a liquid
▪ Suspension: drug suspended in a liquid
▪ Emulsion: liquid drug globules suspended in another liquid

Oral Route: Inhalation

• Inhaled dosage forms:

o Aerosolized: albuterol (Proair®) HFA inhaler
o Dry powder: tiotropium (Spiriva®) inhaler
• Medication is rapidly absorbed via lungs
• Bioavailability varies based on technique

Rectal Route

• Rectal absorption has less variability than the oral route

o Approx. 50% of rectal drainage avoids hepatic breakdown, increasing bioavailability
o Utilized primarily for:
▪ Direct action at the site e.g. enemas for constipation
▪ When oral route is not possible e.g. vomiting
o Any oral tablet may be administered rectally
▪ Special formulations enhance retention, tolerability, and comfort

Parenteral Route

• Parenteral refers to the administration of a drug via direct injection (intravenous, intramuscular, subcutaneous,
intrathecal)
• Utilized for:
o Drugs that are poorly absorbed
o Times when the oral route is non-preferred
• Introduction of foreign organisms is always a concern

Parenteral Route: Intravenous

• Intravenous (IV) is the most common parenteral route

o Utilized predominately for hospitalized patients who:
▪ Oral route is unavailable (ventilated patients)
▪ Cannot tolerate oral route (vomiting)
▪ Oral route is otherwise contraindicated (certain medical procedures require this)
• With IV route:
o Drug is administered directly into the body via serum (blood)
o 100% absorption/bioavailability as there is no GI tract interference
o Rapid onset of action (time to effect)

Parenteral Route: Intramuscular

• Intramuscular (IM) route is utilized for specific drug preparations:

o Drug is administered directly into the body via muscle tissue
o IM route typically utilized for long-acting preparations e.g. haloperidol, olanzapine
▪ “Depot” drugs
 o Many vaccines are given via IM route

Intrathecal administration

• An injection into the spinal canal (intrathecal space surrounding the spinal cord)
o Often used for spinal anesthesia, chemotherapy, antimicrobial, or pain management applications

Oral vs Parenteral

• Oral bioavailability depends on both absorption and first pass metabolism

• Parenteral avoids the GI tract, thus bioavailability is 100%

Pregnancy Risk Categories

• Categories A-X will no longer be used

• New categories have gone into place:
o Pregnancy: Labor and Delivery
o Lactation
o Females and Males of Reproductive Potential
• Each category will contain the following types of info:
o Risk summary for respective medication
o Clinical considerations for use
o Data (provided it is available)

Sources of Drug Information

• Primary literature:
o Medical journals e.g. NEJM, JAMA
o Meeting posters/abstracts
• Secondary literature:
o Textbooks/edited works
o UpToDate
• Tertiary literature:
o Wikipedia, guidebooks, manuals, handbooks
o Micromedex/Lexicomp
• Alternative sources:
o Internet sites
o E.g. FDA, CDC, NIH
o Drug manufacturers
o Professional organizations
o Drug Information Centers, Poison Control Centers

Summary

• Significant differences exist between the small and large molecule products
o Most deal with production and development
• Large molecules are commonly seen in the management of diabetes and preventative strategies (vaccines)
• Biologic agents are commonly used for oncologic or rheumatologic disorders
o Biosimilar agents are not “generic” copies of the reference product
• Numerous pharmacokinetic differences exist between agents, including half-life, dosing, bioavailability
o True for oral vs injectable products