Pharmacokinetics Powerpoint

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Pharmacokinetics WebQuest

Kimberly Koon, Pharm. D.

BW733

October 1, 2013

1

Overview

• Introduction

• Absorption

– IV, SubQ, IM

– Oral, SL

– transdermal, rectal, vaginal, inhalation, topical

• Distribution

– models

– % cardiac output

– Vd

• Metabolism

– sites,

– CYP450, first-pass, pro-drugs

– t

1/2 vs duration of action

• Excretion

– kidney

– liver

– enterohepatic recycling

– lungs

• Time vs. concentration graph

2

Introduction

Pharmacokinetics: study of how body processes drugs; think reverse-factory

– Absorption

– Distribution

– Metabolism

– Excretion

Pharmacodynamics: study of drug effects on body

1. Dictionary. Merriam-Webster website. http://www.merriam-webster.com/dictionary/pharmacokinetics. Accessed September 27, 2013.

2. Pharmacokinetics1-introduction [video]. Handwritten Tutorials website. http://www.handwrittentutorials.com/videos.php?is=79.

Accessed September 27, 2013.

3

Absorption

Absorption rate: time from entry to circulation

Bioavailability: percent that reaches circulation

• IV drug infusion rate determined by characteristics of drug compound

• drugs with small volume and can be given as a bolus or push

(< 3 minutes) negate absorption time

• Many IV drugs require slow infusion

Vancomycin ‘red man syndrome’ if drug given rapidly, more than

1 gram/hr Red man syndrome

Absorption

– Subcutaneous

• small volume bolus

• slow absorption rate

• infusions possible

Insulin pump

– Intramuscular rate varies according to drug properties

• absorption rate variable

• no infusions

Services. St Vincent’s Hospital Sydney website. http://www.stvincents.com.au/index.php?option=com_content&task=view&id=751&Itemid=798.

Accessed September 29, 2013.

5

Absorption

Oral absorption rate has wide variation

– drug dissolution time

– presence or absence of food

– transport time across intestine

• passive

• active

Goole J, Lindley DJ, Roth W, et al. The effects of excipients on transporter mediated absorption. Int J Pharm 2010;393(1-2):17-31.

doi:10.1016/j.ijpharm.2010.04.0419. Accessed September 27, 2013.

6

Absorption

• Sublingual – rapid

• Transdermal/topical – slow, systemic or local

• Rectal – unpredictable rate

• Inhalation – rapid absorption, local or systemic

• Other: eye, ear, nose, vaginal – most drugs stay local

• Delayed release delivery systems

– extended-release capsules and tablets

– Depot subcutaneous and IM injections

A first course in pharmacokinetics and biopharmaceutics. Biopharmaceutics and Pharmacokinetics website. http://www.boomer.org/c/pl/index.html. Accessed September 27, 2013.

7

Distribution

Time from circulation to target tissue: factors are rate (cardiac output), volume, diffusion model, drug properties.

• one compartment model (linear kinetics): drug absorbs and distributes quickly, ie bolus IV

– molecules less than 10,000 grams/mole diffuse freely through capillaries

8

Distribution

• two compartment model:

– compartment 1

• central circulatory system

• rapidly perfused tissues and organs

– cardiac muscle

– brain

– lungs

– liver

– compartment 2

• peripheral circulatory sys.

• deep organs and tissues

– skeletal muscle

– adipose tissue

– skin

Two Compartment

Model

A first course in pharmacokinetics and biopjharmaceutics website anesthesiologist book

9

Distribution

• three compartment model: drugs dependent on active transport

– V

1

– V

2

– V

3 circulation and rapidly perfused tissues slowly perfused tissues third much slower equilibrium compartment

10

Woerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things. 1991 http://www.anesthesiaweb.org

Distribution

Example of 3 compartment distribution model for transdermal drug delivery system (patch) linked by 2 sets of rate constants.

Patch Compartment 2 Compartment 1 Compartment 3

Gopferich A, et al. Int J Pharm. 1991 .

x space coordinate

-L outer edge of matrix t time c(x,t) drug concentration m(t) drug mass p diffusivity k

12, k e k

21, k

23, k

32 microconstants elimination rate constant c

0

11 initial drug concentration in matrix

Distribution

Rate of Distribution and Volume of Physiological Compartments

Compartment

Lung

Venous blood

Arterial blood

% Cardiac Output* (L/h)

100 (335)

100 (335)

100 (335)

% Body Weight (body volume, L)**

Other rapidly perfused tissue

(brain)

Kidney

Slowly perfused tissue

(skin, muscle, fat, etc)

38 (127)

19 (64)

18 (60)

*Average cardiac output 335 L/h

**Average body weight = 70kg; average body density = 1 L/kg = body volume = 70L

0.8 (0.6)

5.57 (3.9)

2.43 (1.7)

83 (58.1)

0.44 (0.3)

5.16 (3.6) http://2012.igem.org/Team:Slovenia/ModelingPK

12

Distribution

Circulation Times

From where to where

Arm vein to lung

Arm vein to left ventricle

Arm vein to tongue

Arm vein to brain

Foot vein to tongue

Right heart ventricle to ear (at level of brain stem)

Arm to foot

Time (seconds)

5-8

6-8

12-15

13-20

37-47

8

21-35

Woerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things. 1991 http://www.anesthesiaweb.org

13

Distribution

Volume of distribution (VD)

– quantifies extent to which drug is present in tissues (extravascular)

– hypothetical volume required to contain all drug in tissues at consistent concentration

– does not reflect actual plasma or blood volume

Absorption of Fluorescent Chemotherapy Drug by

Murine Tumor Cells

Image from: Thurber GM, Yang KS, Reiner T, et al.

Single-cell and subcellular pharmacokinetic imaging allows insight into drug action in vivo. Nat Commun. 2013;4:1504.

doi:10.1038/ncomms2506.

& Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com/content.aspx?aID=16658120. Accessed October 2, 2013.

Metabolism

Metabolism starts as soon as drug reaches enzymes capable of metabolizing.

liver

kidney

no metabolism

proteolytic catabolism

– large protein biotech drugs http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000582/WC500029271.pdf

https://elcaminogmi.dnadirect.com/grc/patient-site/psychiatric-drug-response/what-affects-psychiatric-drug-response.html

15

Metabolism

CYP450 – cytochrome

P450 enzyme system

– liver and intestines most common sites

– P450 enzymes can be inhibited (slowed), induced (sped up)

– drugs often compete for same enzyme subgroup http://www.boomer.org/c/p4/c07/c0702.html

http://www.thebody.com/content/art875.html

16

Metabolism

First-pass metabolism

occurs before drug reaches circulation drugs with larger oral vs IV dose

– propranolol

– morphine

Prodrugs

enhanced bioavailability avoids first-pass metabolism

Metabolism

Half-life: t

1/2

– describes rate drug disappears from plasma

– helpful with dosing parameters

– exponential decline

• Example: drug with 11 minute t

1/2

– 1 st 11 minutes concentration drops to 50%

– 2 nd 11 minutes concentration drops to 25%

– 3 rd 11 minutes concentration drops to 12.5%

– 4 th 11 minutes concentration drops to 6.25%

Not to be confused with duration of action

Woerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things. 1991 http://www.anesthesiaweb.org

18

Metabolism

Drug effect does not necessarily relate to t

1/2

• drugs that bind irreversibly

– omeprazole

• t

1/2

30-60 minutes

• binds irreversibly and inactivates proton pumps on gastric parietal cells

• body must build new proton pumps before effects of omeprazole completely gone

• 14 days average time to build a proton pump

• drugs with atypical metabolism

– bevacizumab binds endothelial cells

• metabolism thought to be proteolysis at endothelial cell

• t

1/2

20 days http://www.prilosecotc.com/LocaleData/enUS/Assets/Documents/Monograph.pdf

Excretion

• Most common routes

– kidney

• diffusion

• active transport

– liver

• through bile duct into feces

• Enterohepatic recycling

– drug excreted into feces

– metabolized in intestine and reabsorbed

• oral contraceptives http://www.boomer.org/c/p4/c16/c1604.html

20

Excretion

Enterohepatic recycling

http://www.boomer.org/c/p4/c16/c1604.html

21

Excretion

• Kidney

– some drugs pass through by diffusion (passive transport)

– some drugs pass by active transport into kidney tubule

– many renally excreted drugs require dose adjustments based on renal function

• creatinine clearance (CrCl) or glomerular filtration rate (GFR) used to evaluate renal function

– declines naturally with age

– helpful online calculator: www.globalrph.com

22 http://www.boomer.org/c/p4/c16/c1604.html

Excretion

Hemodialysis

– small molecules

– water soluble drugs

– drugs with low protein binding

Lungs

– excretion of gases

– anesthesia

– alcohol

Hemodialysis Schematic http://www.medbroadcast.com/test_and

_procedure_info_details.asp?TPid=8&Type

=1#.Ukxyuoasim4

23 http://www.boomer.org/c/p4/c16/c1604.html

Putting It All Together

Pharmacokinetic parameters describing a typical plasma concentration time profile after an oral administration

.

• C max

• t max maximum concentration time to maximum concentration

• Duration of action for this hypothetical drug: time above the minimum effective concentration (MEC)

• Therapeutic range: concentration above MEC but below maximum tolerated concentration (MTC)

• Area under curve (AUC) is a function of concentration and time that describes total body exposure to drug

Figure 1. International Journal of Impotence Research website. www.nature.com/ijir/journal/v19/n3/fig_tab/3901522f1.html.

Accessed September 27, 2013.

24

Phase 1 Clinical Trials

• Phase 1 trials determine pharmacokinetics in humans

– using animal data extrapolate to humans

• LD50: dose required to kill 50% of the non-human population

• no-observed-adverse-effect level

(NOAEL) for animals

• human equivalent dose (HED) of

NOAEL is calculated using body surface area (BSA)

– dose escalation studies

• max tolerated dose (MTD)

• time to max tolerated

– other factors determined:

• frequency

• route

• food/drug interactions

– healthy volunteers if risk:benefit acceptable

Ivy SP, Siu LL, Garrett-Mayer E, Rubinstein L. Clin

Cancer Res. 2010

Wood LF, Foote M eds. Targeted Regulatory Writing

Techniques. Basel, Switzerland:Birkhauser Verlag; 2009.

Phase 1 Clinical Trials

• Traditional phase 1 trial design

• dose escalated until 33% patients exhibit predetermined toxicity parameter

– dose dropped down once to pre/toxic dose and this is called maximum tolerated dose (MTD)

– study continues with MTD to determine recommended phase 2 dose (RP2D) and schedule

• Molecularly targeted agents (MTAs) and non-cancer agents ie biotech

– often do not have DLTs

– start safe dose according to animal data

– escalate until toxicity or molecular-targeted effects seen

– this dose is called max administered dose and sets RP2D

Ivy SP, Siu LL, Garrett-Mayer E, Rubinstein L. Clin Cancer Res. 2010

26

Resources

• For more information on pharmacokinetics:

– Hand Written Tutorials: http://www.handwrittentutorials.com/

– Biopharmaceutics and Pharmacokinetics

• David W.A. Bourne, B.Pharm., Ph.D. of the University of

Colorado

• Free online textbook http://www.boomer.org/c/p4/#topics

– Woerlee GM. Gerry’s Real World Guide to

Pharmacokinetics & Other Things. 1991 http://www.anesthesiaweb.org

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