Clinical Pharmacokinetics

Janice E. Sullivan, M.D.

Brian Yarberry, Pharm.D.

Why Study Pharmacokinetics (PK) and Pharmacodynamics (PD)?

• Individualize patient drug therapy

• Monitor medications with a narrow therapeutic index

• Decrease the risk of adverse effects while maximizing pharmacologic response of medications

• Evaluate PK/PD as a diagnostic tool for underlying disease states

Clinical Pharmacokinetics

• The science of the rate of movement of drugs within biological systems, as affected by the absorption, distribution, metabolism, and elimination of medications

Absorption• Must be able to get medications into the

patient’s body

• Drug characteristics that affect absorption:– Molecular weight, ionization, solubility, &

formulation

• Factors affecting drug absorption related to patients:– Route of administration, gastric pH, contents of GI

tract

Absorption in the Pediatric Patient

• Gastrointestinal pH changes

• Gastric emptying

• Gastric enzymes

• Bile acids & biliary function

• Gastrointestinal flora

• Formula/food interaction

Time to Peak Concentration

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Distribution• Membrane permeability

– cross membranes to site of action

• Plasma protein binding– bound drugs do not cross membranes– malnutrition = albumin = free drug

• Lipophilicity of drug– lipophilic drugs accumulate in adipose tissue

• Volume of distribution

Pediatric Distribution

• Body Composition total body water & extracellular fluid adipose tissue & skeletal muscle

• Protein Binding– albumin, bilirubin, 1-acid glycoprotein

• Tissue Binding– compositional changes

Metabolism

• Drugs and toxins are seen as foreign to patients bodies

• Drugs can undergo metabolism in the lungs, blood, and liver

• Body works to convert drugs to less active forms and increase water solubility to enhance elimination

Metabolism

• Liver - primary route of drug metabolism

• Liver may be used to convert pro-drugs (inactive) to an active state

• Types of reactions– Phase I (Cytochrome P450 system)– Phase II

Phase I reactions• Cytochrome P450 system

• Located within the endoplasmic reticulum of hepatocytes

• Through electron transport chain, a drug bound to the CYP450 system undergoes oxidation or reduction

• Enzyme induction

• Drug interactions

Phase I reactions types

• Hydrolysis

• Oxidation

• Reduction

• Demethylation

• Methylation

• Alcohol dehydrogenase metabolism

Phase II reactions

• Polar group is conjugated to the drug

• Results in increased polarity of the drug

• Types of reactions– Glycine conjugation– Glucuronide conjugation– Sulfate conjugation

Elimination

• Pulmonary = expired in the air

• Bile = excreted in feces– enterohepatic circulation

• Renal – glomerular filtration– tubular reabsorption– tubular secretion

Pediatric Elimination

• Glomerular filtration matures in relation to age, adult values reached by 3 yrs of age

• Neonate = decreased renal blood flow, glomerular filtration, & tubular function yields prolonged elimination of medications

• Aminoglycosides, cephalosporins, penicillins = longer dosing interval

Pharmacokinetic Principles

• Steady State: the amount of drug administered is equal to the amount of drug eliminated within one dosing interval resulting in a plateau or constant serum drug level

• Drugs with short half-life reach steady state rapidly; drugs with long half-life take days to weeks to reach steady state

Steady State Pharmacokinetics

• Half-life = time required for serum plasma concentrations to decrease by one-half (50%)

• 4-5 half-lives to reach steady state0

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Loading Doses

• Loading doses allow rapid achievement of therapeutic serum levels

• Same loading dose used regardless of metabolism/elimination dysfunction

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Linear Pharmacokinetics

• Linear = rate of elimination is proportional to amount of drug present

• Dosage increases result in proportional increase in plasma drug levels

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Nonlinear Pharmacokinetics

• Nonlinear = rate of elimination is constant regardless of amount of drug present

• Dosage increases saturate binding sites and result in non- proportional increase/decrease in drug levels

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Michaelis-Menten Kinetics

• Follows linear kinetics until enzymes become saturated

• Enzymes responsible for metabolism /elimination become saturated resulting in non-proportional increase in drug levels

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Special Patient Populations

• Renal Disease: same hepatic metabolism, same/increased volume of distribution and prolonged elimination dosing interval

• Hepatic Disease: same renal elimination, same/increased volume of distribution, slower rate of enzyme metabolism dosage, dosing interval

• Cystic Fibrosis Patients: increased metabolism/ elimination, and larger volume of distribution dosage, dosage interval

Pharmacogenetics

• Science of assessing genetically determined variations in patients and the resulting affect on drug pharmacokinetics and pharmacodynamics

• Useful to identify therapeutic failures and unanticipated toxicity