Clinical Pharmacokinetics

Dr. Norul Badriah Hassan Jabatan Farmakologi

Pusat Pengajian Sains Perubatan Universiti Sains Malaysia

Objectives

1. Drug-Response Relationship

2. Why we need to study pharmacokinetics?

3. Absorption

4. Sites of Drug Administration

5. Bioavailability and factors affecting bioavailability

6. Absorption in children and elderly

7. Distribution

8. Distribution in children and elderly

9. Metabolism

10. Metabolism in children and elderly

11. Excretion

12. Excretion in children and elderly

Pharmacokinetics

• Study of the movement of drugs through the body.

• Pharmacokinetics determine the time course of drug concentrations in serum or plasma as well as in tissues and body fluids

Pharmacokinetics

•Absorption

•Distribution

•Metabolism

• Excretion

Site of

ActionDosage Effects

Plasma

Concen.

Pharmacokinetics Pharmacodynamics

what the body does to the drug

what the drug does to the body

Drug-Response Relationship

Relationship between dose of a drug and response produced by that drug

Generally if there is more dose, then there will be more drug-receptor complex and more response

But when the maximum response is produced by the drug, then there will be no more increase of response even after administration of more dose.

Dose & Response D

rug C

oncentr

ation

Therapeutic Window

Therapeutic Response Adverse Effects

Dose-Response Relationship

• Potency of A is more than B (less dose is needed to produce same response)

• Efficacy of both same (max response same).

Pharmacokinetics

Why we need to study pharmacokinetics?

• Compare and select appropriate drugs

• Mode of administration

• Dosage adjustment

Sites of Drug Administration

• GI tract

• Artery

• Peripheral vein

• Muscle

• Subcutaneous tissue

• Lung

Bioavailability

• Percentage or fraction of

administered dose that reaches systemic circulation of patient.

Bioavailability = AUC (oral)

AUC (intravenous)

Bioavailability

1. Dissolution

2. Absorption

3. Chemical form (e.g. salt)

4. Dosage form (tablet, solution)

5. Route of administration

6. Stability of active ingredient in GI tract

7. Extent of drug metabolism

Oral Bioavailability

Dose

Destroyed

in gut

Not

absorbed

Destroyed

by gut wall

Destroyed

by liver

to

systemic

circulation

Oral bioavailability

Drug Foral (%)

Gentamicin

Verapamil

Lignocaine

Propranolol

Digoxin

Phenytoin

Valproate

< 5

22

35

36

75

98

100

Plasma concentration-time

relationship after a single oral dose

Effect of Food on Bioavailability

Grapefruit juice:

• increases bioavailability:

☻felodipine - 200%

☻nifedipine - 57%

☻verapamil - 36%

Effect of Food on Bioavailability

Grapefruit juice:

• Alter the pharmacokinetics of oral medications by different mechanisms:

☻ inhibit CYP3A4 irreversibly in intestinal apical enterocytes and hepatocytes.

☻ Inhibition of the P-glycoprotein in intestinal enterocytes. ↑ drug amount in systemic circulation.

• This inhibitory effect can last up to 72 hours after final

consumption of the grapefruit juice.

Effect of Food on Bioavailability

• Other fruits which inhibit the CYP3A4 enzyme system:

• Seville orange juice • Pimelo

• common orange juice (30% of the inhibitory

effect compared to grapefruit)

Drugs Known to Have Potentially Serious Interactions with

Grapefruit Products

Antiepileptics Carbamazepine

Antidepressants Sertaline, buspirone,

clomipramine

Benzodiazepines Diazepam

Calcium channel blocker Felodipine, nifedipine,

nimodipine, verapamil

Antiretroviral agents Saquinavir, indinavir

Statins Simvastatin, lovastatin,

atorvastatin

Cytotoxic drugs Cyclosporin, tacrolimus,

Antiarrhythmics Amiodarone

Miscellaneous Methadone, sildenafil

Pillai et al, South Med J. 2009

Absorption in Children

Infant- slower compared to older children and adults:

• Prolong GI emptying time

• Unpredictable gastric peristalsis

• Delayed time to peak concentrations

Absorption in Children

• Gastric pH values: 1 to 3 within 24 hours after birth neutral by 1 week of age slowly decline over 2 to 3 years to adult values.

• These changes may result in: greater absorption of basic drugs, e.g amoxicillin, erythromycin, and penicillin G.

reducing absorption of weak acidic drugs, including phenobarbital.

Cmax

Distribution

• Refers to transport of drugs to body compartment and the time required for the drug to reach those locations.

• Vd : Volume of distribution

(liters or L/kg).

Distribution

Factors affecting drug transport:

• Protein binding

• Body fluids

• Membrane transport/permeability

• Blood and tissue hemodynamics

Distribution

Determinants of drug movement to maintain equilibrium:

• Disease states

• Drug lipid solubility

• Characteristics of body tissues

• Regional pH differences

• Protein binding

Volume of Distribution

A measure of the tendency of a drug to move out of the blood plasma to some other site.

D

V

C = D/V

V = D/C

Concentration of

a drug in the

plasma

Total amount of

the drug in the

body

Volume of Distribution

D

V

Average population Vd = 1 L/kg Desired

Plasma concentration = 15 mg/L

Required loading dose = 15 mg/kg.

Volume of Distribution

Vd (L/Kg) =Amount of drug (mg)

Css (mg/L)

Drugs with extensive extraplasma

distribution seem to have large Vd values.

D

V

D = 50 mg

C = 2.5 mg/L

V = D/C

= 50mg /

2.5mg/L

= 20 Litres

Volume of Distribution

Vd (L/Kg) =Amount of drug (mg)

Css (mg/L)

Loading Dose As with infusions, a loading dose may be required to produce

therapeutically effective blood levels without delay.

With loading dose (extra large initial dose)

Immediately effective treatment

Divided doses

Volumes of distribution (In litres for average 70 Kg adult)

Warfarin 7

Gentamicin 16

Theophylline 35

Cimetidine 140

Digoxin 510

Mianserin 910

Quinacrine 50,000

Small vol. Mainly in

plasma little in

tissues.

Medium volume.

Similar concent in

plasma and tissues

Large volume.

Mainly in tissues,

little in plasma.

36

Amount

eliminated << 1

dose

Amount

eliminated < 1

dose

Amount

eliminated = 1

dose

Steady state

Css,max = “Peak”

Css (Average)

Css,min = “Trough”

Concentrations at

Steady State

Free Vs Bound Drug

• Drug bound to protein is inactive

• Only unbound or free drug is pharmacologically active.

Free Versus Bound Drug

Major drug binding proteins in serum:

• Albumin,

• 1-acid glycoprotein

• Lipoproteins

In uremia

↑ free drug concentration

liver disease

hypoalbuminemia

Protein Binding of Commonly Monitored

Therapeutic Drugs

Drug Protein Binding

(%)

Protein Type

Amikacin <5 No

Kanamycin <5 No

Ethosuximide 0 No

Procainamide 10–15 Albumin

Theophylline 40 Albumin

Phenobarb 40 Albumin

Phenytoin 90 Albumin

Carbamazepine 80 Albumin

Valproic acid 90–95 Albumin

Primidone 15 Albumin

Digoxin 25 Albumin

Quinidine 80 1-acid glycoprotein

Lidocaine 60–80 1-acid glycoprotein

Cyclosporine 98 Lipoproteins

A. Dasgupta Handbook of Drug Monitoring Methods © Humana Press Inc., Totowa, NJ

Pathophysiological Conditions that Reduce

Albumin Concentration Leading to an Increase in Free Fraction of Acidic Drugs

Uremia

Pregnancy

Intensive care unit patients

Trauma patients

Liver disease

Hyperthyroidism

Burn patient

Elderly (> 75years)

Cirrhosis

Malnutrition

AIDS patients

Reduced Albumin Concentrations

A. Dasgupta Handbook of Drug Monitoring Methods © Humana Press Inc., Totowa, NJ

Distribution in Elderly

Fat soluble (lipophilic)

Increased Vd in older persons because they have greater fat stores.

Longer time to reach a steady-state

Longer elimination from the body.

Examples of fat-soluble drugs: diazepam, thiopental

Distribution in Elderly

• Vd also influenced by protein binding.

• Albumin is often decreased in older patients

• Higher proportion of drug is unbound (free) and pharmacologically active.

• eg. ceftriaxone, diazepam, lorazepam, phenytoin, valproic acid, and warfarin.

Distribution in Children

Total Body Water and Extracellular Fluid Volume • Expanded total body water values relative to body weight are

observed in newborns,infants, and children compared with adults: 80% total body weight in premature infants 70 to 75% in newborns 50 to 60% in adults

• Neonates and young infants also have a greater extracellular fluid

compartment relative to body weight compared with adults.

• For watersoluble drugs demonstrating distribution through total body water, larger doses will be required in infants to achieve comparable serum concentrations to those achieved in adults.

• e.g aminoglycosides, penicillins, and cephalosporins,

Metabolism

• Defined as chemical modification of a drug in a biologic environment.

• Also referred as drug biotransformation or drug detoxification.

Metabolism

• Liver - most common site of drug metabolism

• Metabolic conversion also can take place in:

intestinal wall lungs skin kidneys other organs

Metabolism

• Most drugs undergo metabolism.

• Only few excreted unchanged in urine.

e.g. Acetazolamide Penicillin G

First-Pass Effect

• Some drugs may be extensively metabolised by the liver before reaching systemic circulation

• First pass refers to metabolism by the liver as a drug passes through the liver via portal vein following absorption

Metabolism in Children

• Both Phase I and II reactions mature over time.

• Phase I reactions generally mature by 1 year of age.

• Phase II processes mature at a slower rate,

• E.g - glucuronidation activity by 3 to 4 years of age.

• CYP activity is present at 30 to 60% of adult values in infancy.

Metabolism in Elderly

• Aging affects the liver by decreasing liver blood flow, liver size & mass.

• Consequently, in the older patient the metabolic clearance of drugs by the liver may be reduced.

Excretion

• Excretion refers to a drug’s final route(s) of exit from the body.

• For most drugs, this involves elimination by the kidney as either the parent compound or as a metabolite or metabolites.

• Terms used to express excretion are drug’s half-life (t1/2) and its clearance.

Half-Life

• A drug’s half-life is the time it takes for its plasma or serum concentration to decline by 50%,

e.g. from 20 µg/mL to 10 µg/mL.

• Expressed in hours.

• Steady state is reached when the amount of drug entering the systemic circulation is equal to the amount being eliminated.

• For a drug administered on a regular basis, 95% of steady state in the body is achieved after five half-lives of the drug.

Half-Life

Linear vs non-linear pk

• First order kinetics = linear

Rate of change in drug concentration is

proportional to drug concentration

• Zero order kinetics = non-linear

Michealis-Menten Equation- capacity limited

kinetics

For most drugs [Expansion of the relevant part of the graph]

Drug concentration

Elimination

rate Graph would start to curve if

we went to much higher

concentrations and began to

saturate the enzyme.

For CERTAIN drugs

Drug concentration

Elimination

rate

Highest concentrations actually seen in

real therapeutic use.

Too little to saturate the enzyme.

Almost no curvature.

Rate of

eliminat’n

Rate of

eliminat’n

Blood drug conc Blood drug conc

Linear kinetics

(most drugs)

Non-linear

kinetics

(e.g. phenytoin)

NON-LINEAR KINETICS

There are a small number of drugs where

concentrations seen in real life use are high

enough to saturate the eliminating enzymes.

Phenytoin - The only case of real clinical

significance

•Salicylates

•Ethanol

Theophylline may approach saturation but, in

practice, it can be treated as following linear

kinetics.

Factors Causing Non-Linear Kinetics

Absorption

• Poor aqueous solubility/slow dissolution

(griseofulvin)

• Site specific absorption along GI tract (phenytoin)

• Carrier mediated absorption (riboflavin)

Factors Causing Non-Linear Kinetics

Absorption

• P-glycoprotein efflux in intestinal epithelial cells (cyclosporin A)

• Saturable first pass effect by the intestine and/or liver (propranolol).

• Dose/time-dependent changes in GI physiology including gastric emptying, GI motility & GI blood flow rate.

Factors Causing Non-Linear Kinetics

Distribution

• Non-linear plasma protein binding (valproic

acid)

• Carrier-mediated membrane transport (thiamine)

• Non-linear tissue binding (prednisolone)

Factors Causing Non-Linear Kinetics

Metabolism

• Saturable metabolism (ethanol)

• Product inhibition (dicoumarol)

• Co-substrate depletion (acetaminophen)

• Nonlinear plasma protein binding (prednisolone)

• Autoinduction

Factors Causing Non-Linear Kinetics

Excretion

• Nonlinear protein binding and/or glomerular

filtration (naproxen)

• Carrier-mediated tubular excretion (cimetidine)/reabsorption (riboflavin)

• Carrier-mediated biliary excretion (iodipamide)

Excretion in Children

• Glomerular filtration function is dramatically reduced in newborns

• Greater immaturity in premature infants when compared with full-term infants

• Increases in glomerular filtration rate (GFR) occur in the first weeks of life, reaching 50 to 60% of adult function by the third week of life, and adult values by 8 to 12 months of age.

• By 3 to 6 years of life, GFR values exceed adult values.

• Therefore, drugs dependent on glomerular filtration will show reduced drug clearance through early infancy, more evident in premature infants, and likely require dosage reduction.

• During early childhood, higher daily doses are likely when corrected for weight and in comparison with adult doses because of increased GFR.

Clearance in the Elderly

• Decline in renal function with age, even in the absence of renal disease

• Increased Vd

• Larger drug storage reservoirs

• Decreased drug clearance

• Prolong drug half-lives and lead to increased plasma drug concentrations in older people.

Creatinine in Elderly

• Serum creatinine - not accurate reflection of creatinine clearance in elderly patients.

• Decline in lean muscle mass cause reduced production of creatinine.

Acknowledgements

• Dr. Mohd Suhaimi Ab Wahab

• Dr. Ruzilawati Abu Bakar

Suggested Readings

• Michael E. Winter, Basic Clinical Pharmacokinetics,

4th ed. Lippincott Williams & Wilkins, Philadelphia

• Thomas N. Tozer & Malcolm Rowland, Introduction to Pharmacokinetics and pharmacodynamics:

The quantitative basis of drug therapy.

Lippincott Williams & Wilkins, Philadelphia