Pharmacokinetics (PK):What the body does to the drug?

Most drugs:• Enter the body by crossing barriers • Distributed by the blood to the site of action• Biotransform

• perhaps to several different compounds by enzymes evolved to cope with natural materials

• Excreted• which removes them and/or their metabolites

from the body

Pharmacokinetic Profile of a Plasma Concentration-Time Curve

Why are Pharmacokinetics Important?

If a drug is going to work, it needs to be:in the right placeat the right concentrationfor the right amount of time

Pharmacokinetics tells us:what dose to givehow often to give ithow to change the doseabout drug interactions

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Absorption• How does the drug get into the bloodstream?• How long does it take?• Routes of administration

• IV • no absorption limitations• drug directly into venous blood

• Oral agent• must be soluble • pass across membrane out of stomach or intestines• bioavailability concerns

• Many other routes • Affects on drug absorption

• gastric pH• food

Distribution• How the drug travels in the bloodstream?• Movement of drug throughout the body• Areas of the body are specially protected from

chemicals (including drugs) • Brain• Reproductive organs

• Determine what percentage of the drug in the blood is stuck to proteins (called protein binding)• Only drug that is free of proteins can travel in and

out of other areas of the body to be effective

Metabolism• Biotransformation: How the body chemically

changes a drug?• Mostly in the liver and GI tract

• Break a drug down or add a chemical that makes it easier to pass it into urine or stool• Drug-drug interactions happen because one drug

interferes with the metabolism of another drug (called inhibition). Inhibition causes higher drug levels.

• Drug can also speed up the metabolism of another drug (called induction). Induction causes lower drug levels.

• Factors that affect metabolism

Cytochrome P450 (CYP 450)

• Enzymes that change many drugs into a less toxic form that can be excreted by the body

• Drug metabolism via the CYP 450 system has emerged as an important determinant in:• Occurrence of drug-drug interactions• Reduced pharmacologic effect of drugs• adverse drug reactions.

• Most up-to-date information is from the Division of Clinical Pharmacology at Indiana University• http://medicine.iupui.edu/clinpharm/ddis/

Elimination

• How the body gets the drug and/or drug metabolites out of the body?

• Primarily occurs in kidney with drug being excreted in urine

• Also occurs in liver (elimination into bile feces)

Drug Disposition (ADME)

GI Tract

LiverBlood

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Kidney

How do we learn about the pharmacokinetics of a drug?

• In vitro • Experiments can provide information on:

• Enzymes responsible for metabolism• Solubility

• Preclinical studies• In at least two animal species (one non-rodent)• Experiments can provide information on:

• Absorption, Distribution, Metabolism, Excretion• Clinical studies

• Phase I studies and beyond

Blood sampling…

• PK samples are drawn in order to determine circulating concentrations of drug in the blood

• Blood samples are drawn from the patient at varying intervals

• Timepoints are normally designed based on the drug to ensure the best data without unnecessary bleeding of the patient

…Blood sampling

• Blood for PKs CANNOT be drawn from the same line delivering the drug

• Samples drawn from the incorrect location are often useless

• Can also measure drug levels in urine, feces, CSF

Protocol and PKs• Protocol should contain information related to PKs

• What tube(s) should be used?• When will samples be collected?• How long after collection do samples need to be

processed?• What to do with samples in interim?

• How are samples processed?• Speed and duration of time• Temperature• # of aliquots

• How are samples stored?• Freezer temp

• How/when are samples to be shipped?• PK worksheets

Goal: Concentration-time profile

“Typical” IV Drug “Typical” Oral Drug

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