Patozone

Pharmacokinetics

 

Mathematically describes the fate of the drug after administration in a given dosage form and a given route of administration.

Compares a drug with other drugs or compares a drug dosage form with other dosage forms

Predicts blood levels of a drug with different dosage regimens or predicts blood levels of a drug with different disease states

 

Factors affecting pharmacokinetics

 

Age

Gender

Genetics

Diet

Health habits

Pathology

 

CLADME Process

 

Compliance

Take the drug appropriately

Responsibility lies with:

Physician, Pharmacist, Patient

Non-compliance includes:

Taking drug more or less prescribed

Skipping doses

Taking for shorter lengths of time

Steady state must be achieved and maintained

Adolescence, genetics, complications from other drugs, metabolism

 

Administration

Enteral

Oral – most common route of administration

Sublingual – Placement under the tongue

Rectal – 50% of the drainage in the rectal region bypasses the liver which will prevent the destruction of the drug by intestinal enzymes.

Perenteral - used for drugs that are poorly absorbed from the GI tract

IV – most common parenteral route

IM – used for drugs that dissolve slowly

SC – absorption is slower than the IV route

 

Liberation

Oral doses must be released from the dosage form and made soluble

Rate of release depends on:

Drug formulation

Dosage

Ionization state

Un-ionized form readily pass membranes

pH of the environment

Protein binding

Proteins have the ability to bind drugs

Non-protein bound drugs

The degree of protein binding varies from drug to drug

It is consistent between individuals for a given drug

Varies with age

Drugs will exist in blood in equilibrium between the bound and the free form

Free form drugs are the active form

Conditions altering the binding protein concentrations, such as albumin, greatly affects the amount of free drug

Endogenous substances may also compete with binding sites on proteins and displace a given drug

 

Absorption

Describes the rate and degree to which a drug leaves the site of administration and enters the circulation

EXCEPTION: IV administration of drugs

Here the rate depends on

Physical & chemical characteristics of the drug (solubility & pKa)

Local physiology (pH, perfusion rate, GI motility)

Polarity

Oral administration

Mouth – stomach – intestinal lumen – portal circulation for “first pass metabolism”

 

Distribution

Delivery of drug via circulation

Depends on:

Binding of protein

Transportation

Ability to cross cellular membranes

Rate of tissue perfusion

Lung

Skeletal muscle

 

Metabolized

Most takes place in the liver

Uses Cytochrome P450

Primary purpose is to transform drug into its polar or water soluble form

Metabolites are formed

Occurs in phases

Phase 1

Phase 2

 

First-order (linear)

The amount of metabolite produced steadily increases in proportion to an increasing amount of parent drug in the system

The rate of metabolite is a constant percentage of parent drug eliminated per unit of time

Examples: antibiotics and most other drugs

 

Zero-order (non-linear)

The rate of metabolism approaches Vmax

The rate of metabolite formed is constant and independent of the amount of parent drug eliminated per unit of time

Example: alcohol

 

 

 

Excreted

Elimination occurs in a variety of ways

• Filtration
• Secretion
• Reabsorption

How a drug is eliminated dictates:

Monitoring drug

Monitoring metabolite

 

 

Volume of Distribution

 

A hypothetical volume of fluid into which the drug is disseminated

Relates the volume of drug in the body to the concentration of drug in the blood

Process takes between 30 minutes and 2 hours

C = D/Vd or Vd = D/C, where

• C = plasma concentration of drug
• D = Total amount of drug in the body

Example:

If 25 mg of a drug (D=25mg) is administered and the plasma concentration is 1.0 mg/L, then Vd = 25 mg/1.0 mg/L = 25 L

 

Half-life

 

Definition:

time needed for the serum concentration to decrease by one-half

Formula for calculating:

t½ = 0.0.693 Vd/total body clearance (TBC)

TBC = clearance rate /mass

Example:

What is the half-life of a drug, which had a Vd of 1.1 L/kg and a clearance of 15 ml/min in a patient weighing 34 kg?

t½ = 0.0.693 Vd x 1/TBC

t½ = 0.693 (1.1 L/kg x  1min/15mL x 1000mL/L x 34 kg)

t½ = 1728 min or 29 hrs

 

 

Steady state

 

Occurs when ?:

 the rate of drug elimination is equal to drug administration

Occurs how ?:

multiple doses are given to an individual

Drug accumulates in the body until

drug elimination = drug administered

Multiple doses given at the intervals equal to the drug’s half-life  will result in Steady state

This is usually achieved after 6 or 7 half-lives after initial dosing

 

Therapeutic Drug Monitoring

 

Serial, routine testing for dose optimization

Blood (plasma, serum, whole blood)

The drug(s) to test for is known

 

Related and often predictable

Blood concentrations

Pharmacokinetics: What the body does to the drug

Pharmacodynamics: What the drug does to the body

 

 

TDM Medications: meet 1+ of these criteria

Narrow therapeutic index

Used for long-term therapy

Correlation between serum concentration and clinical response

Wide variability in individual patient PK

Absence of a biomarker associated with a therapeutic outcome

Administered with other, potentially interacting compounds

 

When is TDM needed??

Suspected drug overdose

Unknown medication in comatose patient

Dose optimization in critically ill patient

Toxic effects look like disease symptoms

Disease state alters pharmacokinetics

Lack of therapeutic effect

Compliance issues

Prophylactic drug

Drug interaction/multidrug therapy

High does Methotrexate (Leucovorin rescue)

 

When to measure free drug concentration??

Highly protein bound drugs (>90% bound)

Recognize what has been dosed is far greater then what is immediately available

Protein concentration is very IMPORTANT

 

CAUTION:

Albumin < 2.5 g/dL

Renal Failure

Pregnancy

Age Extremes

 

ANY TIME PROTEIN STATUS IS ABNORMAL BE CAUTIOUS

 

When to measure metabolites???

Metabolically active metabolites

Primidone

Phenobarbital

Carbamazepine

Procainamide

 

Total concentration of drug and active metabolites important

TCA’s (Amitriptyline and Nortriptyline)

 

CAUTION:  Immunoassays may cross react with    inactive metabolites

 

Avoid gel separator tubes for collection of specimens intended for drug analysis

Why? - because the drug may diffuse from the serum into the gel, causing a reduction in measured drug level.

Evaluate other conditions of specimen collection and handling

Preservatives

Heat

Light

Freeze/thaw

Establish critical values

Report results with therapeutic ranges

Report toxic thresholds

 

Methods for TDM

Automated Assays

Primarily immunoassays

Limited to common drugs

LC-MS/MS

 

Reference Labs

Assays and TAT vary widely

 

Troubleshooting - what can go wrong

Is the value accurate

Test properly validated

QC appropriate

 

Does the value make sense

Is it compatible with life?

Is it unexpected?

 

Reasons for spuriously high or low values

Phlebotomy error

Specimen mix up

Change in patient status

Drug history

Change in formulation or manufacturer

 

TDM in organ evaluation

Drug is metabolized by a particular organ

 

Requires specific metabolism

 

Decreased production of metabolite:

Organ not functioning

OR

Blood flow to organ is interrupted

 

ex:

Lidocaine to measure liver function

Method used after transplant or in critically ill patient to check liver function

- P450 in liver turns lidocaine into Monoethylglycinexylidide (MEGX)

 

Method:

 1.  Measure MEGX level

 2.  Bolus lidocaine

 3.  Measure MEGX level

 

Low MEGX production suggests:

Diminished blood flow

Metabolism decreased

Liver failure

P-450 system not working

 

 

Methotrexate: Dose detemines function

Immunosuppression  <10nM

Psoriasis

Refractory Rheumatoid arthritis

 

Cancer Chemotherapy    50nM

Ordinary dosing

Very High dosing

500 times ordinary dosing

 

Inhibits dihydrofolate reductase

Shuts down DNA synthesis

 

Leukovorin rescue

In cases of very high methotrexate dosing

Leukovorin

N-5-formyltetrahydrofolate

Product of dihydrofolate reductase

Leukovorin infused 18-36 hours after methotrexate

Methotrexate levels must be monitored