Transcript No Slide Title

CLEARANCE CONCEPTS
Text:
Applied Biopharm. & PK
L. Shargel, S Wu-Pong & A. Yu;
5th Ed. Chapter 6 (p131-158)
Chapter 11 (p303-348)
Math problems? Call 1-800-[(10x)(13i)^2]-[sin(xy)/2.362x]
Clearance
-Objectives for Today Review of methods to calculate total body
clearance .
• Understand the relative contribution of
specific eliminating pathways on total body
clearance.
• Integration of clearance methods for the
calculation of specific organ clearances
and elimination rates.
Clearance
Def’n: PK term to describe the irreversible
removal of drug from the body (drug
elimination)
• Most important PK parameter because it
determines Dose & Dosing schedule.
– Variable parameter- affected by age, disease,
genetics …
• Can be used to describe drug elimination
from either total body (CLT) or from a
single organ ( ie. CLH ; CLR ; CLbile ; ).
Total Body Clearance (CLT)
• Given in Drug Monographs
• Mechanism of clearance not identified
• Sum total of processes:
CLT = CLM+ CLR+CLBILE +...
• Rather than describing in terms of amount
of drug removed per unit time, Clearance is
described as volume of plasma cleared of
drug per unit time (volume/time)
1000 mg Drug
100 mg/L
L/hr
10 Litres
Simplest case- a beaker…
But the body’s not a beaker- multiple systems involved…..
BODY
Vd
KIDNEY
DRUG
ke
URINE
IV
LIVER
km
Metabolites
kbile
Bile
Calculation of Clearance
METHOD 1.
Clearance calculated using:
Elimination Rate Constants.
CLT = K (V)
Processes
contributing
Beaker- Single
Tap Analogy
CL r (renal) = ke (V)
CL m (metab) = km (V)
CL bile = kbile (V)
Add all processes & cancel out Volume terms …
K = km + ke + kbile + ….
Model Dependent
• 2 compartment model has distribution
& elimination occurring.
K = hybrid value
– Need accurate measurement of K and V
• Assumes First Order Kinetics are
followed.
• In many drug monographs – I can only find
information on the half-life and
distribution. Isn’t this as good as
clearance?
Relationship between CLT and t½
CLT = KV
CLT = 0.693 *V/ t½
K = 0.693/ t½
t½ = 0.693 *V / CLT
• t½ inversely related to CLT
• t½ also dependent on volume of distribution.
• K and t½ are dependent on both CLT &V
Model Dependent
Example:
BODY
Ke = 0.147
Vd = 44 L
DRUG
IV
KIDNEY
LIVER
URINE
Kbile = 0.331
Bile
Km = 0.251
Metabolites
Calculate the CLr, CLT and t ½ for this drug.
Answer:
CLr = ke * V
CLT = K * V
T ½ = 0.693/K
METHOD 2
Clearance calculated using drug concentrations:
CL = (dX/dt) / C
• Clearance is defined as rate of drug loss (from total
body or organ) relative to the concentration of drug in
plasma.
• Model independent
dX/dt = Rate of drug elimination
C = Plasma (or blood) concentration
Rearranging
CL = (dX/dt) / C
dX/dt = CL * C
• Clearance can be calculated by plotting
elimination rate versus drug concentration.
• Slope will be equal to clearance
• Clearance is a constant.
Example : Calculation CLr
Plot of Urinary Excretion Rate (dAe/dt) versus Drug
Conc (mid-point) can be used to calculate CLr
dAe/dt = CLr•C
Slope = CLr
dAe/dt
calculate slope
Plasma Drug Concentration
• minimum of 2 determinations are needed
Rather than plotting, clearance can also be
calculated by integrating the equation over
time.
- This can be any time period, including time
zero (t0) to infinity (t∞ )
Example : Calculating CLr
Based on previous equation:
dAe/dt = (Clr)C
Integrated to time (t1):
Ae 0-t1 = (Clr) AUC 0-t1
CLr = Ae 0-t / AUC 0-t
Integrated to infinity:
CLr = Ae  / AUC
Can be any time
period 0-t; t1-t2
 should collect
urine for 5 t½:
*Usually just calculated could also plot intervals
Example:
Drug X- administered IV. Plasma and urine collected for
12 hours. A total of 7.5 mg of Drug X was collected
in urine during the 12 hour PK study.
Plasma concentrations determined and AUCs
calculated:
AUC 0-12 = 2500 g*hr/L
AUC 0- = 3400 g*hr/L
CLr = ?
Answer:
7.5 mg of Drug X was collected in urine
during the 12 hour PK study.
Therefore Ae 0-12 = 7.5 mg
 Have to use AUC 0-12
Total body clearance can be obtained by integrating this
equation from time zero (t0) to infinity (t ). All drug
eliminated by t 
dX/dt 0-∞ = DOSE
After IV Dose:
CLT = DOSEiv/ AUC 
Systemic clearance reflects total amount of
time that drug resides in the body.
* Model independent
What if the patient is given an oral dose of
the drug!!
How can I calculate clearance?
Non-IV (Extravascular) Doses
• ** Need to account for bioavailability
• After Oral dose:
CLT= Fpo * DOSEpo/ AUC 
Systemic clearance based on amount of drug
which gets into the systemic circulation and
residence time of drug in body.
METHOD 3
Clearance calculated using:
Physiological parameters of individual organs.
CL organ = Q (ER)
NB. Can only be
used for single
organs not CLT
Q = Blood or plasma flow to organ
ER = Extraction Ratio. The efficiency of organ to
clear drug from blood/plasma.
ER= 0 – 1. Can be calculated from differences between
amount of drug entering and leaving organ. The
proportion of drug entering organ that is
eliminated/converted upon each pass through the
organ.
ER = (Cin - Cout )/
Cin
Liver
Blood IN
Blood OUT
Bile
Example: The hepatic extraction ratio (ER) for
morphine is 0.65 and has a distribution volume of
4 L/kg. Assuming a hepatic flow rate (Q) of 90
L/hr, what would be the expected hepatic
clearance for morphine in a 70 kg man after an IV
dose.
CL H = Q (ER)
CL H = 90 L/hr *(0.65)
= 58.5 L/hr
Will cover in more detail with more examples in hepatic lectures
• You will often need to use a combination of
these three methods to calculate clearance.
• Look at the information provided and
determine which approach you should use
for calculations.
Reporting Clearance
• Organ Clearance often reported in different
ways.
• Individual processes/ Organ Clearance may
be described and calculated from Total body
clearance
.
– Addition/Subtraction of Clearance Routes
– Fraction of Total Body Clearance
To Ilustrate : Renal Clearance (CLr)
Renal Clearance (CLr) is one Component of CLT
• Fraction of drug eliminated renally (fe) describes
relationship between Renal Clearance (CLr) and Total
Clearance (CLT). Also describes the relationship between
ke to total body K
fe =
CLr
CLT
=
ke
K
fraction excreted in urine = Ae/ DOSEIV
(Ae = Total amount of drug excreted in urine)
Sample Problem.
• New Immunosuppressant- Noreject is cleared by
both renal (60%) and non-renal excretion and has
a V of 150L. In healthy patients, AUC of 1530
g.hr/L is obtained after a 100 mg IV dose.
a) What is the half-life of Noreject?
b) What is the predicted renal and non-renal
clearance of Noreject?
c) What is the urinary elimination rate constant
(ke) of Noreject ?
Solution- A.
What is the Half-life?
CLT = Dose/ AUC
Solution- B.
What is CLr and CLnr?
Solution C.
What is ke ?
Where are we now?
• Can determine clearance based on:
– Plasma concentrations (Cp or AUC)
– Elimination rate constants
– Extraction efficiency of organ
• Can calculate relative contribution of
individual clearance routes from total body
clearance.
Sample Problems to work on at home
Applied Biopharm & PK, 5th edition
p 158 # 3, 4, 5, 6, 9
P 348-50 # 1, 2, 11