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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
– t1/2 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
Red man syndrome. Daily EM website. http://www.dailyem.wordpress.com/2013/08/06/red-man-syndrome/. Accessed September 27,4 2013.
Absorption
– Subcutaneous
Insulin pump
• small volume bolus
• slow absorption rate
• infusions possible
– 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. 6
doi:10.1016/j.ijpharm.2010.04.0419. Accessed September 27, 2013.
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
– V1 circulation and rapidly perfused tissues
– V2 slowly perfused tissues
– V3 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
Gopferich A, et al. Int J Pharm. 1991.
Compartment 1
Compartment 3
x space coordinate
-L outer edge of matrix
t time
c(x,t) drug concentration
m(t) drug mass
p diffusivity
k12, k21, k23, k32 microconstants
ke elimination rate constant
11
c0 initial drug concentration in matrix
Distribution
Rate of Distribution and Volume of Physiological Compartments
Compartment
% Cardiac Output* (L/h)
% Body Weight (body volume, L)**
Lung
100 (335)
0.8 (0.6)
Venous blood
100 (335)
5.57 (3.9)
Arterial blood
100 (335)
2.43 (1.7)
Other rapidly
perfused tissue
(brain)
38 (127)
83 (58.1)
Kidney
19 (64)
0.44 (0.3)
Slowly perfused tissue
(skin, muscle, fat, etc)
18 (60)
5.16 (3.6)
*Average cardiac output 335 L/h
**Average body weight = 70kg; average body density = 1 L/kg = body volume = 70L
http://2012.igem.org/Team:Slovenia/ModelingPK
12
Distribution
Circulation Times
From where to where
Time (seconds)
Arm vein to lung
5-8
Arm vein to left ventricle
6-8
Arm vein to tongue
12-15
Arm vein to brain
13-20
Foot vein to tongue
37-47
Right heart ventricle to ear (at level of
brain stem)
8
Arm to foot
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.
14
Buxton IL, Benet LZ. Chapter 2. Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, Metabolism, and Elimination. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman
& 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
http://epharmacology.hubpages.com/hub/Pharmacological-Effects-Prodrugs-Definition-Examples-and-Sources-of-Drug-Information
17
Metabolism
• Half-life: t1/2
– describes rate drug disappears from plasma
– helpful with dosing parameters
– exponential decline
• Example: drug with 11 minute t1/2
–
–
–
–
1st 11 minutes concentration drops to 50%
2nd 11 minutes concentration drops to 25%
3rd 11 minutes concentration drops to 12.5%
4th 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 t1/2
• drugs that bind irreversibly
– omeprazole
• t1/2 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
• t1/2 20 days
http://www.prilosecotc.com/LocaleData/enUS/Assets/Documents/Monograph.pdf
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http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000582/WC500029271.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
http://www.boomer.org/c/p4/c16/c1604.html
22
Excretion
• Hemodialysis
Hemodialysis Schematic
– small molecules
– water soluble drugs
– drugs with low protein binding
• Lungs
– excretion of gases
– anesthesia
– alcohol
http://www.boomer.org/c/p4/c16/c1604.html
http://www.medbroadcast.com/test_and
_procedure_info_details.asp?TPid=8&Type
=1#.Ukxyuoasim4
23
Putting It All Together
Pharmacokinetic parameters
describing a typical plasma
concentration time profile after
an oral administration.
• Cmax maximum concentration
• tmax 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;252009.
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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