Download Lecture 10 (Bioavailability and Absorption)

Bioavailability & Absorption
Objectives
 Factors affecting Bioavailability
 The calculation of Bioavailability (F)
 Absolute vs. Relative Bioavailability
 The effect of ka on [ ]-time profiles
 What happens if the dose does not
begin to be absorbed immediately?
 What is the difference between
an SR and an EC product?
Bioavailability & Absorption
400 mg of moxifloxacin is administered orally to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Time
Plasma Conc
Parameter Estimates
(hr)
(mg/L)
ka = 2.365 hr-1
0.0
0.00
K = 0.06899 hr-1
0.25
0.88
0.5
1.40
T½ = 10.04 hr
1
1.86
AUCI =33.0 mg*hr/L
1.5
1.98
V/F = 175.69 when F=1
2
1.99
4
1.77
But does F=1 in this patient?
8
1.34
CPS says F = 0.9 …?
12
24
1.02
0.44
Definitions:
Bioavailability:
relative amount
of an administered dose
which reaches the general circulation
and the rate at which this occurs.
Relative to either and IV dose
(Absolute bioavailability)
or to another formulation of unknown F
(Relative bioavailability).
Definitions:
Bioequivalence:
The term applied to
generic formulations
of the same active ingredient and dose
are said to be bioequivalent
when the profiles of
drug or metabolite(s) or both are similar.
(considers both rate & extent)
Definitions:
Bioequivalence:
Similar pharmacokinetic profiles of
drug or metabolite(s) or both
The degree of similarity
between profiles is established statistically
using Cmax and AUC as endpoints.
Bioequivalence implies that with similar profiles,
two bioequivalent drug products
can be expected to have
the same systemic effect
(both therapeutic and adverse)
Conducting a Bioavailability Study
1000
Test
Reference
Concentration (ng/mL)
Test and Reference given
in a minimum
number of subjects (12)
generally young males
Controlled Conditions
on separate occassions
Assumption:
Products shown to be
bioequivalent in young males
are assumed to be
bioequivalent
in the population
that will use them,
regardless of age, sex, and
ethnic background.
100
10
1
0.1
0
2
4
6
Hours
8
10
12
Conducting a Bioavailability Study
Test and Reference in a
2-way cross-over design
in a minimum
number of subjects (12)
under controlled conditions
Measure drug concentration
with a specific and
sensitive method
Estimate AUC and CMAX
Test
Reference
Concentration (ng/mL)
Sample to capture CMAX
and 80% of AUC
(~4 half-lives  90% and
generally > 80% in all)
1000
100
10
1
0.1
0
2
4
6
Hours
8
10
12
Parameters for Estimating Bioavailability
Measures of Rate:
Maximum concentration [Cmax],
absorption rate constant [ka]
Cmax
Concentration (mg/L)
6.0
5.0
4.0
Tmax
2.0
1.0
0.0
0.0
2.0
4.0
Hours
6.0
Is Cmax
a good measure
of absorption rate?
Answer: No ! ….
Cmax is not a
pure measure of rate …
if we double the dose,
Cmax will change
(ka might not)
But it is easy to estimate
7.0
3.0
Estimating Rate
8.0
10.0
and in a profile
there is no argument
about the
highest measured
concentration.
Parameters for Estimating Bioavailability
Estimating Extent
Measures of Extent:
Area Under the Curve [AUC]
Is AUC
a good measure
of the extent
of absorption?
AUC
7.0
Concentration (mg/L)
6.0
5.0
Answer: Yes ! ….
4.0
3.0
2.0
1.0
0.0
0.0
2.0
4.0
Hours
6.0
8.0
10.0
Even based on
trapezoidal rule
AUC is a
good measure
of extent
Calculating Bioavailability
Mean Data based on 23 subjects
Data from Yacobi, J Clin Pharmacol 2000; 40: 826-35
Test
Reference
90
Concentration (ng/mL)
Then calculate the
Relative ratio of AUC
Test / reference
80
Test
70
Reference
60
50
40
30
20
10
0
AUC0-∞
27.0 ± 5.9
(ng x hr / mL)
Relative Ratio:
26.3 ± 5.3
0
102.66
Questions:
What does 27.0 ± 5.9 mean?
What does 102.66 mean?
5
10
Hours
15
20
Factors Affecting Bioavailability
Physiologic factors
1.
2.
3.
4.
5.
6.
pH Stomach ~ 1 and intestine ~ 6
Surface area of the of the intestine – microvilli
Presence of carrier proteins for absorption & exsorption (Pgp)
Enzymes; endogenous and bacterial
GI blood flow
Gastric Emptying & intestinal transit (Pgp or MDR1)
Physicochemical Properties of the Drug
1.
2.
3.
4.
5.
pKa
Water & lipid solubility
Molecular size
Stability in GI environment (pH)
Specificity for carrier proteins and enzymes (Pgp or MDR1)
Factors Affecting Bioavailability
Physiologic factors
1.
2.
3.
4.
5.
6.
Factors
which
change
pH Stomach ~ 1 and intestine ~ 6
Surface area of the of the intestine
microvilli
the –environment.
Presence of carrier proteins for absorption & exsorption (Pgp)
Enzymes; endogenous and bacterial FOOD
GI blood flow
Affects pH,
Gastric Emptying & intestinal transit (Pgp
MDR1)
Bloodorflow
Gastric emptying
Interactions
enzymes
Physicochemical Properties
of thewith
Drug
1.
2.
3.
4.
5.
pKa
Water & lipid solubility
DRUGS
Molecular size
Affect Blood flow
Stability in GI environment (pH) Gastric emptying
Specificity for carrier proteinsInteractions
and enzymeswith
(Pgpenzymes
or MDR1)
Factors Affecting Bioavailability
Food can affect both rate (ka)
and extent (AUC) of absorption.
No general statement
of the effect of food can be made.
Effect depends on the drug
and the nature of the meal.
Food can
increase / decrease or have no effect
on either rate (ka) or extent (AUC).
Factors Affecting Bioavailability
DRUGS, & Alternative Medicines can affect
both rate (ka) & extent (AUC) of absorption
No general statement
of the effect of drugs can be made.
Effect depends on the two drugs
involved in the interaction
and the mechanism of interaction…if known!
inhibition of MDR1, change in pH, GI transit, blood flow…
Calculating Bioavailability
400 mg of moxifloxacin is administered orally to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Time
Plasma Conc
Parameter Estimates
(hr)
(mg/L)
ka = 2.365 hr-1
0.0
0.00
K = 0.06899 hr-1
0.25
0.88
0.5
1.40
T½ = 10.04 hr
1
1.86
AUCI =33.0 mg*hr/L
1.5
1.98
V/F = 175.69 when F=1
2
1.99
4
1.77
But does F=1 in this patient?
8
1.34
CPS says F = 0.9 …?
12
24
1.02
0.44
Calculating Bioavailability
To estimate absolute bioavailability in Mr BB, 400 mg of
moxifloxacin is administered as an IV bolus. Blood samples were
drawn following the dose and the plasma concentration determined.
It is known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Time
(hr)
0
2
6
12
24
36
48
Plasma Conc
(mg/L)
Questions to Solve
2.32
1.76
1.16
0.5
0.22
BLOQ
1.
2.
3.
What model best describes profile?
Calculate AUC, K, T½, V & Cl
Calculate F for Mr BB
Graph Patient Data
Using semi-log paper, or Excel
graph the data following
IV bolus administration of
400 mg of moxifloxacin
10
6
3
Time
(hr)
0
2
6
12
24
36
48
1
0.6
Concentration (mg/L)
10.0
0.4
0.2
1.0
0.1
0
0.1
0
4
4
8
8
12
10
16 20
Hours
24
28
14 18
32
36
22 24
Plasma Conc
(mg/L)
2.32
1.76
1.16
0.5
0.22
BLOQ
Graph Patient Data
What model best
describes this profile?
Concentration (mg/L)
10.0
1.0
0.1
0
4
8
12
16 20
Hours
24
28
32
36
Terminal elimination
phase is log-linear…
1 Compartment
Model
with first order
elimination (K)
Calculating Bioavailability
To estimate absolute bioavailability in Mr BB, 400 mg of
moxifloxacin is administered as an IV bolus. Blood samples were
drawn following the dose and the plasma concentration determined.
It is known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Time
(hr)
0
2
6
12
24
36
48
Plasma Conc
(mg/L)
Questions to Solve
2.32
1.76
1.16
0.5
0.22
BLOQ
1. What model best describes profile?
2. Calculate AUC, K, T½, V & Cl
3.
F for Mr
YouCalculate
should solve
thisBB
problem on your own.
This will not be covered in Class.
Use the associated Excel File to
check your answers
1-Compartment IV Dosing
AUC
38.38 mg*hr/L
K
0.0694 hr-1
T½
9.98 hr
Cl
10.42L/hr
Calculating Bioavailability
To estimate absolute bioavailability in Mr BB, 400 mg of
moxifloxacin is administered as an IV bolus. Blood samples were
drawn following the dose and the plasma concentration determined.
It is known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Time
(hr)
0
2
6
12
24
36
48
Plasma Conc
(mg/L)
2.32
1.76
1.16
0.5
0.22
BLOQ
Parameter Estimates
K = 0.0694 hr-1
T½ = 9.98 hr
AUCI =38.38 mg*hr/L
V = 150.12 L
Calculating Bioavailability
To estimate absolute bioavailability in Mr BB, 400 mg of
moxifloxacin is administered as an IV bolus. Blood samples were
drawn following the dose and the plasma concentration determined.
It is known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Time
(hr)
0
2
6
12
24
36
48
Plasma Conc
Questions to Solve
(mg/L)
2.32
1.76
1.16
0.5
0.22
BLOQ
1.
2.
3.
What model best describes profile?
Calculate AUC, K, T½, V & Cl
Calculate F for Mr BB
In order to calculate the absolute
bioavailability for moxifloxacin in this patient
we will need to give Mr. BB an IV dose (data
on left) and compare it to the oral data.
Calculating Bioavailability
Why are we comparing AUC’s?
What happens to AUC if we change the dose?
If I give the same patient the same dose of a drug
(400 mg) will the AUC always be the same? … if
NOT when NOT?
Change volume
Change half-life
Change clearance
Calculating Bioavailability
Concentration (mg/L)
2.5
Oral
2
IV
1.5
1
0.5
0
0
10
20
30
40
Hours
AUCORAL = 33.000 mg*hr/L – from previous Slide Pak
AUCIV = 38.386 mg*hr/L – Just calculated
F=?
Calculating Bioavailability
Oral Data
IV Data
L
F
= AUCORAL / AUC IV
= 33.00 / 38.39
= 85.97%
F = 85.97%
CPS: F = 90%
Is it wrong?
Bioavailability (F) & Other parameters
IV Data
Oral Data
L
Inspect other data:
Should Clearance and Volume change
as a result of a change in the route of administration?
Clearance is calculated as Dose / AUC.
Is the Dose really 400 mg if F is 85.97%?
Bioavailability (F) & Other parameters
IV Data
Oral Data
L
Ratio of Clearance (Cl IV and ClORAL)
Cl IV= 10.42 L/hr and ClORAL = 12.12 L/hr
Ratio = 10.42 / 12.12
= 0.8597
(Same ratio as ratio of AUC (F))
How should Clearance following and oral dose be calculated?
Bioavailability (F) & Other parameters
IV Data
Oral Data
L
Clearance following an Oral Dose (ClORAL)
Cl ORAL= (F x Dose)/AUC
= 0.8597 x 400 mg / 33.00 mg * hr/L
= 10.421 L/hr
Bioavailability (F) & Other parameters
IV Data
Oral Data
L
Clearance following an Oral Dose (ClORAL)
Clearance is constant. It should not change when route changes.
If clearance is calculated to be different than ClIV,
it is because F is not known or F is different than expected.
When F is not known, F is commonly assumed to be 1 (or left out
of the equation) and then Clearance is best described as
Apparent Oral Clearance.
Bioavailability (F) & Other parameters
IV Data
Oral Data
L
Inspect other data:
Should Volume change
as a result of a change in the route of administration?
Clearance is calculated from K x V and Dose / AUC.
Is the Volume really 175.69 L if F is 85.97%?
Bioavailability (F) & Other parameters
IV Data
Oral Data
L
Ratio of Volumes (V IV and VORAL)
VIV= 150.12 L and VORAL = 175.69 L
Ratio = 150.12 / 175.69
= 0.8597
(Same ratio as ratio of AUC (F) and ratio of clearances)
How should Volume be calculated following and oral dose?
Bioavailability (F) & Other parameters
IV Data
Oral Data
L
Volumes following an Oral Dose (V IV and VORAL)
Since Cl = K x V and Cl = F x Dose / AUC
then: K x V = F x Dose / AUC
and
VORAL = F x Dose / K x AUC
= ((0.8597)(400)) / ((0.0694)(175.69))
= 150.159 L
Bioavailability (F) & Other parameters
IV Data
Oral Data
L
Volume following an Oral Dose (VORAL)
Volume should remain constant. It should not change when route
changes. If the volume following and oral dose is different than
the volume following an IV dose, it is because F is not known
or F is different than expected. When F is not known, F is
commonly assumed to be 1 and then Volume is best described as
Apparent Oral Volume of Distribution.
Bioavailability (F) & Other parameters
IV Data
Oral Data
L
Apparent
Clearance (FDose/AUC)
Volume (F= 85.97)
L/hr
L
10.42
150.1
Absorption Rate - ka
Objectives

 Factors affecting Bioavailability

 The calculation of Bioavailability (F)
 Absolute vs. Relative Bioavailability

 The effect of ka on [ ]-time profiles
 What happens if the dose does not
begin to be absorbed immediately?
 What is the difference between
an SR and an EC product?
Absorption Rate - ka
400 mg of moxifloxacin is administered orally to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Time
Plasma Conc Parameter Estimates
(hr)
(mg/L)
ka = 2.365 hr-1
0.0
0.00
K = 0.06899 hr-1
0.25
0.88
T½ = 10.04 hr
0.5
1.40
AUCI =33.0 mg*hr/L
1
1.86
ka? 2.365 hr-1 ?
1.5
1.98
V/F = 175.69
when F=1
What would
happened to ka if we
2
1.99
administered Moxi with food ?
4
1.77
8
1.34
or increased the dose?
12
24
1.02
0.44
Absorption Rate - ka
ka is the absorption rate
constant. It has units of hr-1.
mg/L
10.00
Values of ka
can <theoretically>
range from 0 to ,
1.00
but in reality the ka would
never be less than 0.001 hr-1
or greater than 30 hr-1.
0.10
0
4
8
12
Hours
16
20
24
What is the difference
between a value of
0.5 hr-1 vs. 2.3 hr-1?
Absorption Rate - ka
What is the difference
between a value of
0.5 hr-1 vs. 2.3 hr-1?
A larger ka value indicates
faster absorption.
Here both drugs have
a 2 hour half-life
(parallel terminal phase)
Which profile is produced
with a ka of 2.3 hr-1?
Absorption Rate - ka
What is the difference
between a value of
0.5 hr-1 vs. 2.3 hr-1?
Here both drugs have
a 2 hour half-life.
Which profile is produced
with a ka of 2.3 hr-1?
Dose 1 has a ka of 2.3 hr-1 and a Tmax of ~1 hr.
Dose 2 has a ka of 0.5 hr-1 and a Tmax of ~2.4 hr.
Absorption Rate - ka
A ka value of 100 hr-1
is so fast that it
resembles IV bolus
injection.
ka appears to
determine Tmax…?
ka= 100 Tmax = 0.05 hr
ka= 2.3 Tmax = 0.98 hr
ka= 0.5 Tmax = 2.39 hr
… any other factors??
Dose 1 has a ka of 2.3 hr-1 and a Tmax of ~1 hr.
Dose 2 has a ka of 0.5 hr-1 and a Tmax of ~2.4 hr.
Dose 3 has a ka of 100 hr-1 and a Tmax of ~0.05 hr (3 minutes).
Absorption Rate - ka
K or Half-life
also determines
Tmax following
the first dose.
Formula:
ln [ ka/k]
TMAX = --------------ka - k
Dose 1 has a ka of 1 hr-1 and a T-half 1 hr and T max of 1.2 hr.
Dose 2 has a ka of 1 hr-1 and a T-half of 2hr and T max of 1.6 hr.
Dose 3 has a ka of 1 hr-1 and a T-half of 10 hr and T max of 2.9 hr.
Absorption Rate - ka
Absorption
from many
formulations
is usually
first order …
But
does absorption
occur
at other
rates????
Absorption Rate - ka
Some modified release
or sustained release
formulations display
zero-order absorption.
A zero-order
absorption rate
concentration-time
profile will appear
different. The peak
will be abrupt, not
smooth and rounded.
These profiles are shown
with the same half-life (4 hr)
but a different volume
so that the profiles
are separated.
Absorption Rate - ka
Zero-Order Rate
200 mg/hr
Tmax = 2 hours
A zero – order rate is
Constant Each hour
the same amount of
drug (mg) is absorbed
(or released)
from the formulation.
The entire dose of a
400 mg tablet that is
absorbed at the
zero-order rate of
200 mg/hr will all be
absorbed in 2 hours.
The peak will occur
at 2 hours, regardless
of the elimination rate
Absorption Rate - ka
Zero-Order Rate
200 mg/hr
Tmax = 2 hours
A first order rate is a
constant percentage
(not amount) per unit
of time. A drug with
ka = 0.693 hr-1,
will peak at about
2.6 hours when the
T½ = 4 hours.
But when does
absorption for this
formulation stop?
(i) At the Tmax – 2.6 hrs
(ii) Prior to the peak
(iii) ~ 1 hr after the peak
(iv) Technically – never
(v) It depends
Absorption Rate - ka A first order rate
Zero-Order Rate
200 mg/hr
Tmax = 2 hours
6.25 mg/hr
25 mg/hr
100 mg/hr
Such as 0.693 hr-1,
will peak at about
2.6 hours when the
T½ = 4 hours.
If we deal with ka as
we would K, since
ka = 0.693,
then T½ka = 1 hour.
This means that following
a 400 mg dose, rates/hr =:
Time Amount
1
200
2
100
Peak
3
50
4
25
5
12.5
6
6.25
Absorption Rate - ka
Zero-Order Rate
200 mg/hr
Tmax = 2 hours
A first order rate
Such as 0.693 hr-1,
will peak at about
2.6 hours when the
T½ = 4 hours.
But when does
absorption for this
formulation stop?
(i) At the Tmax – 2.6 hrs
(ii) Prior to the peak
(iii) ~ 1 hr after the peak
(iv) Technically – never
(v) It depends
Absorption Rate - ka
K and ka are
independent processes
Factors which affect K
Drug
Patient
Other drugs …
Factors with affect ka
Drug
Patient
Formulation
Physiologic factors
Food, GI environment
Enzymes
Absorption Rate - ka
K and ka are
independent processes
Factors which affect K
Drug
Patient
Other drugs …
Factors with affect ka
Drug
Patient
Formulation
Physiologic factors
Food, Water
GI environment
Enzymes
Factors Affecting Bioavailability
Physiologic factors
1.
2.
3.
4.
5.
6.
pH Stomach ~ 1 and intestine ~ 6
Surface area of the of the intestine – microvilli
Presence of carrier proteins for absorption & exsorption (Pgp)
Enzymes; endogenous and bacterial
GI blood flow
Gastric Emptying & intestinal transit (Pgp or MDR1)
Physicochemical Properties of the Drug
1.
2.
3.
4.
5.
pKa
Water & lipid solubility
Molecular size
Stability in GI environment (pH)
Specificity for carrier proteins and enzymes (Pgp or MDR1)
Factors Affecting Bioavailability
Physiologic factors
1.
2.
3.
4.
5.
6.
Factors
which
change
pH Stomach ~ 1 and intestine ~ 6
Surface area of the of the intestine
microvilli
the –environment.
Presence of carrier proteins for absorption & exsorption (Pgp)
Enzymes; endogenous and bacterial FOOD
GI blood flow
Affects pH,
Gastric Emptying & intestinal transit (Pgp
MDR1)
Bloodorflow
Gastric emptying
Interactions
enzymes
Physicochemical Properties
of thewith
Drug
1.
2.
3.
4.
5.
pKa
Water & lipid solubility
DRUGS
Molecular size
Affect Blood flow
Stability in GI environment (pH) Gastric emptying
Specificity for carrier proteinsInteractions
and enzymeswith
(Pgpenzymes
or MDR1)
Absorption Rate - ka
In the Excel® workbook
‘10 Bioavailability & Absorption Moxifloxacin’
in ‘Effect of ka or Dose’ sheet,
you can enter in the
vary the Dose, F,
Half-life or ka in
3 different profiles
(shaded green area)
and a single dose
profile out to 20 hours
will be generated.
Parameters are
calculated below.
Absorption Rate - ka
What is a
sustained release
(SR, CD…) product?
… what is different
about these
formulations
compared to an
immediate release
formulations?
What is their purpose
or advantage?
Absorption Rate - ka
A sustained release
(SR, CD…) product,
generally has a
much slower
absorption rate
(smaller ka value).
Slowing the absorption
rate is useful for drugs
which are rapidly
eliminated.(short T½)
What does this
do to the
Cmax and Tmax
of the product?
Absorption Rate - ka
T½ = 2 hours
ka = 2.0 hr-1;
0.5 hr-1 & 0.1 hr-1
As ka is reduced
and absorption slowed,
Tmax increases
& Cmax decreases.
What happens
to AUC?
Absorption Rate - ka
T½ = 2 hours
ka = 2.0 hr-1;
0.5 hr-1 & 0.1 hr-1
As ka is reduced
and absorption slowed,
Tmax increases
& Cmax decreases.
AUC is not changed.
(~28.9 mg*hr/L)
What about T½ ?
Absorption Rate - ka
T½ = 2 hours
ka = 2.0 hr-1;
0.5 hr-1 & 0.1 hr-1
As ka is reduced
and absorption slowed,
Tmax increases
& Cmax decreases.
AUC is not changed.
(~28.9 mg*hr/L)
What about T½ ?
Should a formulation
be able to affect
the volume, clearance
or half-life of a drug?
Absorption Rate - ka
T½ = 2 hours
ka = 2.0 hr-1;
0.5 hr-1 & 0.1 hr-1
As ka is reduced
and absorption slowed,
Tmax increases
& Cmax decreases.
AUC is not changed.
(~28.9 mg*hr/L)
What about T½ ?
Look at Dose 3 - T½ = 2 hr?
Has reducing the
ka to 0.1 hr-1
changed the half-life
of the drug?
Absorption Rate - ka
Input:
T½ = 2 hours
ka = 2.0 hr-1;
0.5 hr-1 & 0.1 hr-1
but K from profile
is 0.098 hr-1
for dose 3!..??
… the observed
half-life
has changed!
Absorption Rate - ka
T½ = 2 hr
K= 0.34 hr-1
ka = 0.1 hr-1
T½ = 2 hr
K= 0.34 hr-1
ka = 2 hr-1
A formulation
change cannot
modify the
half-life,
elimination rate
or clearance
of a drug,
… only the
appearance of
the profile.
A profile will always
have the slowest
(smallest)
exponential in the
terminal phase.
Absorption Rate - ka
T½ = 2 hr
K= 0.34 hr-1
ka = 0.1 hr-1
A profile
will always
have the slowest
(smallest)
exponential in the
terminal phase.
Terminal phase rate constant: 0.1 hr-1
Rate constant from residual analysis: 0.34 hr-1.
This is sometimes called the Flip-Flop model
… but how does this occur… how does ka appear in the terminal phase?
Absorption Rate - ka
Rate limiting the Elimination Rate
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When absorption occurs quickly
drug enters the body and ‘waits’
to be eliminated.
Drug is observed to accumulate
in the body and only when absorption
is complete and the “tap” is turned off
is the body finally able to clear drug
and produce a declining concentration.

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The elimination rate is
slower than the absorption rate.
Absorption Rate - ka
Rate limiting the Elimination Rate
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When absorption is very slow, drug
can be eliminated from the body more
quickly than it enters.
This is like a bath tub. When the tap
is on full, even when the plug is out,
water begins to fill the tub. But when
the tab is only dripping, water does
not fill up the tub. In fact very little
water would ever be in the tub
(Cmax is lower) and the rate that
water is leaving the tub is virtually
equal to the rate that
water enters the tub.
Absorption Rate (ka) Summary
K and ka determine
Tmax in a single dose profile.
As ka becomes smaller
(slower), [at constant K]
Tmax generally occurs later
and the Cmax is lower.
Changes in ka do not affect
AUC, T½, Volume or Clearance.
If ka is smaller than K,
the rate constant observed
in the terminal phase is ka.
Absorption Rate (ka) Summary
But what is an
Enteric Coated formulation
… Is ka affected?
ka is the rate of absorption.
At time zero the entire dose
is in the stomach. The
tablet or capsule must
disintegrate and the
drug dissolve before
absorption can begin.
Absorption Rate (ka) Summary
But what is an
Enteric Coated formulation
Is ka affected?
An Enteric Coated product delays
initiation of absorption, generally
by preventing disintegration.
When does absorption begin?
Gastric emptying time?
ka may not be affected
(all things being equal)
The delay in the initiation
of absorption is called a lag-time,
… here about 3.75 hrs
Absorption Rate (ka) Summary
An Enteric Coated formulation
delays the initiation of absorption
by preventing disintegration
and induces a lag time (TLAG)
generally, to avoid gastric pH.
A Sustained Release Formulation
reduces the absorption rate (ka),
generally to make a once daily
or twice daily product.
Both may be considered
“Modified Release Formulations”