Transcript Document

Pharmacy 732
Winter 2003
Instructors
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William Hayton
James Coyle
Cari Brackett
Kristin Lugo
Juhyun Kim
Pharmaceutics
PPAD
PPAD
PPAD
Pharmaceutics
Contact Information
E-mail
[email protected]
Phone
292-
Office
Parks
Hall
Hayton
WebCT
-1288
232
Coyle
[email protected]
-7103
A208
Brackett
[email protected]
-5718
A216
-5335
425
247-6469
243
Lugo
Kim
[email protected]
.1452 @osu.edu
Exams
• 3 Exams, 100 points each
– Exam 1: Tues. Jan. 28,
– Exam 2: Tues. Feb. 18,
– Exam 3: Tue. March 18, 9:30 – 11:18
• Quizzes,
– seven total, 15 points each, drop the lowest
score 90 points
• Workshop participation 10 points
• Total:---------------------------------- 400 points
Grading
Total Points  4
88.0
A
78.0
B-
86.0
A-
75.0
C+
83.0
B+
71.0
C
80.0
B
67.0
C-
Remediation and Make-Up
• Exams 1 & 2 will be offered again during the 10th
week class.
• Remediation
– Open to all students; manditory for students scoring
<67.
– Scoring: 0.2 x first score + 0.8 x second score
• (0.2)(65) + (0.8)(85) = 81
• Make-Up
– If exam was missed for a qualified reason, full score
will count; if not, remediation scoring will be used
with the first score being zero.
Post-Course Remediation
• Course average between 60.0 and 66.9
– Eligible to take a comprehensive exam over
Pharmacy 732 during workshop of the first
week of Pharmacy 733.
• 67.0: C- for the course
• <67.0: E for the course
• Course average <60
– No post-course remediation allowed and E
grade stands.
Workshops
• Monday Afternoon, 1:30 – 3:18
– Rm. 550
– Rm. 257
• Wednesday Afternoon 1:30 – 3:18
– Rm. 550 Parks Hall
– Rm. 257 Parks Hall
Course Materials
• Clinical Pharmacokinetics, Rowland and
Tozer, third edition
• Calculator
• Semilog graph paper
• Course Pack
Cp [mg/L]
10
1
0
5
10
15
Time [hr]
20
25
Classroom Conduct
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Quiet is appreciated
Cell phones turned off
Pagers in quiet mode
Refrain from exiting and re-entering
Academic Misconduct: Exams
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No caps
No use of memory in calculators
No PDAs, laptops, etc.
No exchanging information with others
No cell phones or pagers in “on” mode
No crib notes, cheat sheets, etc.
Pharmacy 732
Winter 2001
Dosing Regimen Design
One compartment model
Infusion
Multiple dosing
Two compartment
model
Nonlinear kinetics
Dosing Regimen Individualization
Principles
Patient Specific
Variables
Body Size
Age
Gender
Pharmacogenomics
Environment
Drug Interactions
Disease
Therapeutic
Drug Monitoring
WebCT
• Course Materials
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Slides from class
Narrated slides from class
Reference materials; e.g., PK parameters
Exam Keys old and current
Quiz Keys old and current
Bulletin board
Email
Quiz and exam scores; i.e., grade book
Self tests
Student home page - optional
WebCT Logon
(1) Open a web browser and go to: http://class.osu.edu
(2) Log on:
Enter your “username” and “password.”
Username = lastname.123 (all lowercase, No CAPITAL
LETTERS!)
Example: If your E-mail address is [email protected] =
Username is “smith.303”
Password = same one you use to check your OSU e-mail,
to register online for classes, and to enable Internet
access in OIT student computer labs.
Dosing Regimen Design
Infusion regimen
Why is a dosing regimen
necessary?
• To replace the drug that the body
eliminates.
How can drug be replaced?
• Continuously or intermittently.
Continuous Input
• Learning Objectives
– input rate to achieve a desired plasma
concentration.
– kinetics of accumulation; i.e., how long to
steady state.
– loading dose.
– determination of CL, V, KE and t1/2.
Examples of continuous input
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i.v. drip
i.v. infusion
transdermal patch
sustained release oral dosage forms
Ocusert
Norplant
Kinetics of continuous input
dA/dt = rate in - rate out
A = amount of drug in body
Cp = plasma concentration
dA/dt = Ko - KEA
Ko = input rate (amt/time)
A = V x Cp and KEV = CL
KE = elimination rate
constant, (CL/V)
dA/dt = Ko - CL•Cp
Ko
dA/dt = 0 at a plateau Cp
Rate In = Rate Out
Ko
= CL •Cp,ss
Cp,ss
= Ko/CL
v
CL
Example: Diazepam
Cp,t profile in young and old:
Ln Cp
young
What’s different?
old
Time
DR adjustment?
Vss
CL
t1/2
fup
[L/kg]
[L/h/kg]
[h]
[%]
0.88
0.0174
44.5
2.49
1.39
0.0156
71.5
2.76
Herman and Wilkinson. Br. J. Clin.
Pharmacol. 42:147,1996. #2919
Principles
• When infused at the same rate (one
compartment model assumed):
– all drugs with the same half life will have the
same steady-state amount of drug in the body.
– all drugs with the same clearance will have the
same steady-state plasma concentration.
Accumulation Kinetics
Ko
KEt
KEt
1  e   Ass 1  e 
Ainf 
KE
C p ,inf
Ko
KEt
KEt
1  e   C p,ss 1  e 

CL
Time to steady state
3.3 t1/2 is time to 90% of Cp,ss
t = nt1/2 where n = no. of half lives that have passed
e
KEt
e
  ln 2 t1/ 2 nt1/ 2
C p ,inf  C p , ss 1  e
1

 
2
KEt
n
  C 1  1 2 
n
p , ss
Example
This drug has a V = 45 L and a CL = 12 L/h. What
infusion rate is needed to achieve a Cp,ss of 25 mg/L?
Ko = CL x Cp,ss = 12 L/h x 25 mg/L = 300 mg/h
How long will it take to get to 90% of steady state?
t1/2 = ln 2 V/CL = (0.693)(45)/(12) = 2.6 h
t90% = 3.3 t1/2 = (3.3)(2.6) = 8.6 h
How much drug is in the body at steady state?
Ass = Cp,ssV = 45 L x 25 mg/L = 1,125 mg
Summary
Cp,ss
Ass
Time to SS
 Ko



 CL



V



Diagram
VP, VE, VR
RE/I, fur, fup
V
Ass
Ko
t90%
CL
Css
QH, fup, CLint,u
GFR, etc.
Review
With a constant rate of input, Ko
Rate In = _______
Rate Out
Rate In = Css x ___
CL
Rate In = Ass x ___
KE
All drugs with same CL will have same ____
Css
All drugs with same t1/2 will have same ____
Ass
Post-Infusion Cp Profile
Infusion
0.035
0.030
0.025
0.020
0.015
0.010
0.005
0.000
0
20
40
60
Time
80
100
120
Post-Infusion Cp Profile
Infusion
0.10000
0.01000
0.00100
0.00010
0.00001
0
20
40
60
Time
80
100
120
Changing to a new Cp,ss
CL by
25%
Cp
V by
25%
Ko by
25%
Time
Bolus and Infusion
A “loading dose” may be used to start at steady
state immediately.
Loading Dose = Ass = Ko/KE = CssV
Rowland and Tozer, Figure 6-5. p. 74
Time to Steady State
3.3 t1/2 is time to 90% of Cp,ss.
When Cp,0 is 0, this is within ±10% of Cp,ss.
When Cp,0 is  0, the time to ±10% of Cp,ss differs from
the t90%.
What is the appropriate endpoint for calculation of the
time to steady state?
Calculation of time to ±10%
Cp,ss
Plasma concentration at any time after bolus + infusion:
C p  C p ,0 e
KEt
 Css 1  e
KEt

Given Cp,0 and Css, the time to reach any Cp can be
calculated from:
C
C
ss
ss
 Cp 
 C p ,0 
e
KEt
1

 
2
n
Example
Cp,0 = 500 mg/L and Css = 100 mg/L, how long does it
take to reach 110 mg/L? (i.e., 110% of Css)
C
C
ss
ss
 Cp 
 C p ,0 
e
KEt
1

 
2
n
(1/2)n = (100 – 110)/(100 – 500) = -10/-400 = 0.025
(n)[ln (0.5)] = ln (0.025)
n = ln (0.025) / ln (0.5) = 5.32 half lives
What would be the Cp after 3.3 half lives?
140 mg/L
Assessment of PK parameters
1. CL = Ko / Cp,ss
Log (Cp,ss - Cp)
2. Get KE from the
slope of a semilog
plot of (Cp,ss – Cp)
vs. t.
-2.3 slope = KE
Time
3. V = CL / KE
C p ,inf  C p ,ss 1  e  K E t 