Transcript PK/PD and cardiovascular drugs: case of ACEI

NATIONAL
VETERINARY
SCHOOL
TOULOUSE
PK/PD and cardiovascular drugs:
the case of ACE inhibitors
P.L. Toutain
EAVPT/ECVPT Workshop
London, July 2005
PKPD ACEI London 05 - 1
PK/PD for cardiovascular drugs
• There may be more information on PK/PD
relationships of cardiovascular drugs than any
other group of drugs
–
–
–
–
Digoxine
Beta-blockers
Anti-arrhythmic
ACE inhibitors
• Why?
– PK/PD relationship easy to establish with surrogates
PKPD ACEI London 05 - 2
Pharmacodynamic biomarker,
surrogate and endpoint
• Many biomarkers / surrogates
– Heart rate
– Blood pressure
– Electro-cardiographic parameter (QT)
Only surrogate
May be not validated !!
PKPD ACEI London 05 - 3
ACE inhibitors
Pharmacokinetics and
PK/PD
See Toutain PL. & Lefebvre H.P, JVPT 2004, 27: 515-525
PKPD ACEI London 05 - 4
Goals of heart failure therapy in the
symptomatic patient
• Relieve HF symptoms
– i.e. make patients feel better
– Improve overall clinical status
• Decrease morbidity and mortality
– Slow and/or reverse disease progression
– Identify and treat reversible causes of LV
dysfunction
PKPD ACEI London 05 - 5
How do we make heart failure
patients live longer?
• With neurohormonal interventions
– ACE inhibitors
– Angiotensin receptor antagonists (in ACEinhibitor intolerant patients)
– Aldosterone antagonists
– Beta-blockers
PKPD ACEI London 05 - 6
Neurohormonal blockade for the
cardiovascular diseases
 Angiotensin II
(Renin-Angiotensin System [RAS])
RAS Inhibition
 Norepinephrine
(Sympathetic Nervous System [SNS])
-Blockade
Disease Progression
PKPD ACEI London 05 - 7
Angiotensin converting enzyme
inhibitors (ACEI)
• Drugs considered as first-line treatment
for several cardiovascular and renal
conditions
Rev: Toutain PL. & Lefebvre H.P, JVPT 2004, 27: 515-525
PKPD ACEI London 05 - 8
ACE inhibitors
•
•
•
•
Enalapril
Benazepril
Ramipril
Imidapril
Enacard®
Fortekor®
Vasotop®
Prilium®
Merial
Novartis
Intervet
Vetoquinol
Are coboxylalkyl di- or tri-peptide drugs
PKPD ACEI London 05 - 9
Major effects of Angiotensin II
PKPD ACEI London 05 - 10
Circulating and local (tissue) RAS influence
on the cardiovascular system
Circulating RAS
Short-term effects
Local RAS
Long-term effects
Sodium/water reabsorption
via aldosterone secretion
Intraglomerular
hypertension
ANGIOTENSIN II
Vasoconstriction
Heart
Vascular hypertrophy
Positive
chronotropic
effects/
arrhythmogenic
effects
Myocardial
hypertrophy
Heart
PKPD ACEI London 05 - 11
Angiotensin II
Altered peripheral
resistance
Altered renal
function
• Vasoconstriction
• Release of CA
• ...
• Increase Na+
reabsorption
• release of
aldosterone
• ...
• Increase production of
growth factors
• increase synthesis of
extracellular matrix
Rapid
pressor
response
Slow
pressor
response
Vascular and cardiac
hypertrophy and
remodeling
Goodman Gillman, p.741
Altered cardiovascular
structure
PKPD ACEI London 05 - 12
The renin-angiotensin system
Angiotensinogen (a-globulin) from the liver
Renin (released by kidney
(juxtaglomerular cells)
Angiotensin I
ACE or Angiotensin
Converting Enzyme (Kininase II)
Angiotensin II
Aminopeptidases
Angiotensin III
PKPD ACEI London 05 - 13
ACEI
Angiotensin I
Bradykinin
ACE inhibitor
Angiotensin II
AT1-blocker
Inactive metabolites
Vasodilation
Natriuresis
Extracellular matrix degradation
Cough
Angioedema
AT1Receptor
AT2Receptor
Hypertension
Aldosterone
Transforming growth factor 
Plasminogen activator
Vasodilatation
Natriuresis
Antiproliferative effects
PKPD ACEI London 05 - 14
The non-conventional PK of
ACR inhibitors
PKPD ACEI London 05 - 15
The non-conventional PK of
ACE-inhibitors
– A long or very long terminal half-life is
calculated predicting an accumulation of ACE
inhibitors during multiple dosing
thus
however
t1/2 = 20 h
Time (days)
Accumulation
(predicted)
No accumulation
PKPD ACEI London 05 - 16
(observed)
The unconventional PK/PD relationship for
ACE-inhibitors
• It has been claimed that there is no relation between
plasma ACE inhibitor concentration and effect !
• Usefulness of PK and PK/PD information has been
questioned
• This is a misconception due to the :
– complexities of ACE inhibitors disposition (PK)
– non-linear nature of the concentration/effect relationship
(PK/PD)
PKPD ACEI London 05 - 17
ACEI: PK and PK/PD issues
–
–
–
–
–
–
oral administration: requirement for prodrugs
bioconversion: prodrug  drug
interpretation of disposition curve
PK/PD relationship
dosage regimen (selection)
dosage regimen adjustment
• renal and hepatic failure
PKPD ACEI London 05 - 18
Administration / Absorption of
ACE inhibitors
PKPD ACEI London 05 - 19
ACEI administration
• Long term therapy (months, years)
 Only the oral route is convenient
 Only drugs having an appropriate
bioavailability are usable
PKPD ACEI London 05 - 20
Prodrug vs. drug for ACEI
administration
• Benazeprilat, enalaprilat, imidaprilat and
ramiprilat are diacid ACE inhibitors with very
poor intestinal absorption
• Prodrugs were developed to circumvent this
poor absorption:
– Benazepril, Enalapril, Ramipril, imidapril
• Ester derivatives : more lipophilic, but no activity
PKPD ACEI London 05 - 21
Imidapril / imidaprilat
Imidapril
COOH
COOC2H5
CH3
(s)
N
N
(s)
H3C
O
O
N
H
(s)
Imidaprilat
(active metabolite)
• Higher lipophilicity
(passive absorption)
• Transported by peptide
transporters (active
absorption)
COOH
COOH
CH3
(s)
N
N
(s)
(s)
H3C
O
O
N
H
PKPD ACEI London 05 - 22
ACE inhibitor absorption
ACEI are lipophilic carboxyalkyl di- or tri-peptides
lipophilic
Passive
PEPT (I & II)
Peptide carrier-mediated
transporter
Physical carrier for peptides
and other drugs (betalactams)
Active
The relative contribution of the 2 routes of absorption is unknown
PKPD ACEI London 05 - 23
The question of ACE-inhibitors
Bioavailability
PKPD ACEI London 05 - 24
Bioavailability : Benazepril vs Benazeprilat
• From radioactivity excreted in urine
– Benazepril : 38%
– Benazeprilat : 4 %
Waldmeier and Schmid, Drug Res. 1989, 39, 62
PKPD ACEI London 05 - 25
How to estimate bioavailability
Classical approach
x 100
concentration
F% =
AUCoral
AUCIV
IV
oral
PKPD ACEI London 05 - 26
Time
How to calculate an absolute
bioavailability
F% =
AUCoral
AUCIV
x 100
Eq.1
Assumption for Eq.1
Clearance,oral = Clearance,IV i.e. :
F% =
AUCoral
AUCIV
x
Cloral
ClIV
x 100
PKPD ACEI London 05 - 27
How to calculate an absolute
bioavailability
• In the case of ACE inhibitors :
Clearance,IV  Clearance,oral
Consequently equation :
F% =
AUCoral
AUCIV
x 100
is not applicable
PKPD ACEI London 05 - 28
How to evaluate the absolute
bioavailability for ACE inhibitors
F% =
AUCoral, free concentration
AUCIV, free concentration
x 100
The equation is applicable because :
Cl oral, free concentration = Cl IV, free concentration
PKPD ACEI London 05 - 29
How to evaluate the absolute
bioavailability for ACE inhibitors
• AUC free concentration can be
determined either
– by direct measurement
– by modelisation of ACEI disposition
• e.g.: Benazeprilat
PKPD ACEI London 05 - 30
Bioavailability of ACEI
• Benazeprilat
– single dose, dog: 2.57 ± 1.23 %
– multiple dose, dog : 3.95 ± 0.83 %
– Single dose : cat = 2.5%
• Ramiprilat : dog = 6.7%
PKPD ACEI London 05 - 31
Conversion of the ACE prodrug
to its active moiety
PKPD ACEI London 05 - 32
Imidapril / Imidaprilat
Concentrations (ng/mL)
25
imidapril
20
15
10
Imidaprilat
5
0
0
3
6
9
12
15
18
21
24
Time (h)
PKPD ACEI London 05 - 33
Where does hydrolysis occur ?
• Hydrolysis of the active diacid occurs
mainly in the liver although it may occur
in plasma and other tissues
 Liver : first pass effect
 Other tissues : Relevance for the active
moiety distribution
PKPD ACEI London 05 - 34
The first-pass effect
PKPD ACEI London 05 - 35
Bioconversion of Enalapril to Enalaprilat
Blood tissue
barrier
Blood tissue
barrier
Kidney
Enalapril
Low
lipophilicity
Enalapril
Enalaprilat
Enalaprilat
Liver bioactivation
Aorta
(no
conversion)
slow uptake
of Enalaprilat
(First pass effect)
non specific
carboxyl esterase
Enalapril
Administration
Portal system, carrier system
Digestive tract
Enalapril
Enalaprilat
Elimination
(faeces)
PKPD ACEI London 05 - 36
Bioconversion of Fosinipril to Fosiniprilat
Blood tissue
barrier
Blood tissue
barrier
Kidney
Fosinipril
Fosinipril
Fosiniprilat
High
lipophilicity
Fosiniprilat
Fosinipril
Liver
Fosinipril
Administration
Aorta
(no
conversion)
Fosiniprilat
slow uptake
of Fosiniprilat
(First pass effect)
Portal system, carrier system
Digestive tract
Fosinipril
Fosiniprilat
Elimination
(faeces)
PKPD ACEI London 05 - 37
Prodrug and drug elimination
• Prodrug:
– metabolic transformation
• Drug
– Mainly kidney
• Dosage regimen adapted in case of renal failure
• Enalaprilat : kidney (95%)
• Benazeprilat : kidney = liver = 50%
PKPD ACEI London 05 - 38
ACE inhibitors
Pharmacokinetics modelling
See Toutain PL. & Lefebvre H.P, JVPT 2004, 27: 515-525
PKPD ACEI London 05 - 39
The non-conventional PK of
ACE-inhibitors
– A long or very long terminal half-life is
calculated predicting an accumulation of ACE
inhibitors during multiple dosing
thus
however
t1/2 = 20 h
Time (days)
Accumulation
(predicted)
No accumulation
PKPD ACEI London 05 - 40
(observed)
The non conventional disposition
profile of ACEI
• Ramiprilat : 0.25 mg/kg/day
B
A
70
10000
Concentrations (mg/L)
Concentrations (mg/L)
60
1000
100
10
Day 1 = day 8 :
no accumulation
50
40
30
20
10
1
0
0
24
48
Time (h)
72
0
6
12
18
24
Time (h)
PKPD ACEI London 05 - 41
The binding of ACE inhibitors
• Non specific
• Specific to the ACE
PKPD ACEI London 05 - 42
The non-specific binding of
ACE inhibitors
• To albumin
– Benazepril
– Benazeprilat
– Enalapril
– Enalaprilat
94%
93%
< 60%
19%
PKPD ACEI London 05 - 43
The non-specific binding of
ACE inhibitors
• Therapeutic meaning
– almost none
– displacement (drug interaction) or decreased
protein concentration (nephrotic syndrome) are
unlikely to be relevant
• For the ACE PK modelling
– fraction non specifically bound to albumin will
be considered as "free" i.e. "free from any
specific ACE binding"
PKPD ACEI London 05 - 44
The specific binding to
ACE inhibitors
PKPD ACEI London 05 - 45
The Angiotensin Converting
Enzyme (ACE)
PKPD ACEI London 05 - 46
Protein structure of ACE
zinc binding sites
(catalytic centers)
Cell membrane
Vascular
endothelium
"N-domain"
"C-domain"
C-terminal hydrophobic tail
(transmembrane domain)
extracellular
"ectopeptidase"
intracellular
PKPD ACEI London 05 - 47
Localisation of ACE
• Tissues
–Everywhere but mainly:
• Lung
• Kidney (brush border)
• Endothelium surface
• Plasma (circulating)
PKPD ACEI London 05 - 48
ACE localisation and distribution
Same binding parameters
BLOOD
ACEI
ACEI
Not measurable
Circulating (soluble) ACE
by analytical
Measurable by
technique
analytical technique
Tissue bound ACE
Vascular endothelium
PKPD ACEI London 05 - 49
Plasma vs tissular ACE
• Consequence for a physiologically
oriented kinetic model
Blood
Extracellular fluid
Circulating ACE
I
Slow exchange
I
slow
exchange
very rapid
exchange
Bound
ACE
I
Instantaneous
exchange
II
I
Albumin
Tissue
PKPD ACEI London 05 - 50
The modeling of ACE inhibitors
PKPD ACEI London 05 - 51
The classical compartmental modelling
approach applied to ACE inhibitors
Ka
distribution
K12
thus
elimination
Vc
K21
K10
-Kat + Y e-1t + Y e-2t
C(t)
=
-(Y
+
Y
)e
1
2
1
2
absorption / bioconversion
PKPD ACEI London 05 - 52
Problems encountered with the
classical compartmental modeling
approach applied to ACE inhibitors
– A long or very long terminal half-life is
calculated predicting an accumulation of ACE
inhibitors during multiple dosing
thus
however
t1/2 = 20 h
Time (days)
Accumulation
No accumulation
PKPD ACEI London 05 - 53
Development of a
physiologically based model
for ACE inhibitors
PKPD ACEI London 05 - 54
Rationale for the development
of a physiologically oriented
kinetic model for ACE
Bound to Circulating ACE
Bound to tissular ACE
ACE
I
Alb
ACEI
free
ACEI
Bound to alb.
1 compartment model
(simplification by merging events
linked by rapid exchange)
PKPD ACEI London 05 - 55
ACEI: The model
Bound (tissular) ACE
Kd, Bmax
(1-fcirc)
Alb
Peripheral
compartment
Free
fcirc
circulating ACE
Kd, Bmax
Volume : Vc
K10
Parameters: Cl, Vc, Bmax, Kd, fcirc
measurable
concentration
PKPD ACEI London 05 - 56
ACEI disposition
Classical compartmental model
Physiologically based model
Absorption/bioconversion
absorption
distribution
Elimination
(clearance, VD)
Elimination (kidney,
hepatic failure)
Binding phase
(Bmax, Kd, K10)
PKPD ACEI London 05 - 57
Concentration
The two phases of ACEI disposition
• Phase influenced by renal / hepatic
elimination processes
• control drug accumulation and time to
reach equilibrium
• explains possible overexposure
• Phase not influenced by renal
and hepatic elimination
• Influenced by Bmax, Kd and K10
• control effect on ACE
Time
PKPD ACEI London 05 - 58
Consequence of drug ACE binding
on its pharmacodynamics
• The long t1/2 reflects the high affinity of the
drug for the enzyme
t1 2
0.693 B max


K10
Kd
• The terminal phase is relevant to the PD
properties
PKPD ACEI London 05 - 59
Concentration (nmol/L)
The Benazeprilat disposition :
IV route
•
•
•
•
•
•
10000
1000
100
Vcfree = 0.2 L/kg (extracellular water)
Clfree = 3.4 mL/kg/min
t1/2 free = 39 min no possible accumulation
Bmax = 119 nmol/L (concentration of ACE in dog)
fcirc = 10.5 % (most ACE bound to tissue)
Kd = 4.5 nmol/L (drug affinity)
10
1
0
12
24
36
Time (h)
PKPD ACEI London 05 - 60
The model parameters: K10
CE
Tissue
• K10 : (time-1)
CE
Plasma
– rate constant of elimination
F
of the free fraction
– half-life of elimination = 0.693/K10
K10
K10
PKPD ACEI London 05 - 61
The model parameters: clearance
• Clfree = parameters
– Clfree = K10 x Vc =
Dose
AUCfree

Dose
AUCtot
– computation of bioavailability allowed with
Cfree
• Cltot = variable
– Cltot = Dose / AUCtot
– computation of bioavailability not allowed
with Cltot
PKPD ACEI London 05 - 62
The ACEI model parameters: Bmax
• Bmax : maximal capacity (nmol/L)
– assumption : 1 molecule of ACE inhibitor
binds to 1 molecule of ACE
– thus : Bmax is not a property of the drug but
of the animal
Bmax is the same for all ACE inhibitors
Bmax is a measure of ACE pool
PKPD ACEI London 05 - 63
The model parameters: Bmax
Bmax
About 100-200 nmol/L
(f)
Circulating enzyme
 10%
(1-f)
Tissular enzyme
 90%
expressed as % of circulating enzyme
PKPD ACEI London 05 - 64
The ACEI model parameters: Kd
• Kd (nmol/L)
– concentration of the free fraction required to
saturate half Bmax
– measures the affinity of the drug for ACE (Kd
= 1/Ka)
– is related to drug potency
– is a property of the drug
• Benazeprilat: 4.5 nmol/L
• Enalaprilat: 7.1
• Imidaprilat: 5.0
• Ramiprilat: 0.51
PKPD ACEI London 05 - 65
PK consequence of the non-linear
ACE inhibitor disposition
• No dose proportionality
• No possible accumulation but possible
over-exposure if plasma clearance (free)
is decreased
• Impossible to calculate properly the
bioavailability using non-compartmental
approach
PKPD ACEI London 05 - 66
AUC / Effect relationship
Benazeprilat (mg/kg)
Concentration
4.0
Therapeutically
relevant phase
(non-linear
binding to ACE)
0.5
Dose (mgl/kg)
Effect (AUIC)
0.5
18653
1.0
17525
2.0
16747
4.0
16007
Time
PKPD ACEI London 05 - 67
Consequence of drug ACE binding
on its pharmacodynamics
• The long terminal t1/2 reflects the high
affinity of the drug for the enzyme
• The terminal phase is relevant to the
dynamics
PKPD ACEI London 05 - 68
PK / PD relationships for
the ACE inhibitors
PKPD ACEI London 05 - 69
Objectives of the PK/PD
relationship
Effect (%)
Emax : efficacy
100
50
Slope (n) (sensitivity)
concentrations
EC50 (potency)
PKPD ACEI London 05 - 70
Endpoints to investigate for ACE inhibitors
• Blood pressure
• Angiotensin II
• Ex-vivo plasma ACE activity on synthetic
substrates
Nussberger et al. Am. Heart.J. 1989, 117, 717
PKPD ACEI London 05 - 71
The ex-vivo endpoint : principle
• ACE inhibitors competitively inhibit the
action of the ACE (conversion of the
inactive AI into active AII)
• This inhibitory property can be quantified
ex-vivo from circulating ACE using an
artificial substrate
PKPD ACEI London 05 - 72
The ex-vivo end-point
Synthetic substrate
ACE
Hippuryl-glycyl-glycine
Hippuric acid
End product
ACE binding site
(a 1:1 enzyme interaction)
ACE inhibitors
PKPD ACEI London 05 - 73
Imidaprilat: PK/PD relationship
20
24
ACE inhibition
40
60
8
80
0
100
0
6
12
24
18
0
32
24
ACE inhibition
20
40
16
60
8
80
0
168
174
180 186
192
198
204 210
Effect (% inhibition)
8th administration
Concentrations (ng/mL)
16
Effect (% inhibition)
First administration
0
32
100
216
PKPD ACEI London 05 - 74
Time (h)
Dose / exposition / effect
relationship for ACEI
PKPD ACEI London 05 - 75
AUC / Effect relationship
• Conventional drug
3
Effect
Concentration
4
4
3
2
2
1
1
Dose
Time
PKPD ACEI London 05 - 76
Measured AUC of ACE
inhibitor an index of drug
exposure and drug efficacy ?
PKPD ACEI London 05 - 77
Dose (mg/kg)
0.1
0.25
0.5
1.0
2.0
150
n = 10
0.1
Effect
Concentration (nmol/L)
Benazeprilat
Dose effect relationship (simulation)
0.25
0.5
1.0
2.0
120
90
60
30
0
1
2
3 0
1
Time (day)
2
3
Time
PKPD ACEI London 05 - 78
AUC / Effect relationship
Benazeprilat, control dog
doses
4.0
0.5
Therapeutically
relevant phase
(non-linear
binding to ACE)
Dose (mgl/kg)
Effect (AUIC)
0.5
18653
1.0
17525
2.0
16747
4.0
16007
Time
PKPD ACEI London 05 - 79
How to characterize properly
the exposure-effect relationship
for ACE inibitors
 By PK/PD modelling
PKPD ACEI London 05 - 80
Effect, Concentration
The ex-vivo endoint
concentration
Effect
(inhibition)
effect
Emax
Time
IC50
Cfree
! • free plasma concentration, not the measured
plasma concentration
• thus : modelling is required to determine Cfree
PKPD ACEI London 05 - 81
Concentration effect modelling for
ACEI
The inhibitory Emax model
Effect =
with
E0 
E max  C nfree
IC50n  C nfree


C nfree

 E0 1  n
 IC  C 
50
free 

– Emax, the maximum ACE inhibition
– Cfree , the free plasma concentration
– IC50,free , the free plasma concentration corresponding to 50%
inhibition of the maximum activities
– n : a slope factor (steepness of the concentration effect curve)
PKPD ACEI London 05 - 82
Imidaprilat in dog:
pharmacodynamic parameters
Effect
100
Emax / efficacy=100%
75
Slope : 0.67
50
25
0
0.1
1
10
100
Concentrations (ng/mL)
IC50
2.78 nmol/L (1 ng/mL)
PKPD ACEI London 05 - 83
(potency)
What is the relationship between the
IC50 (ex-vivo) and Kd (in-vivo) ?
with
• IC50 : a measure of drug efficacy
(functional experiment)
• Kd : a measure of drug affinity
(binding experiment)
PKPD ACEI London 05 - 84
The use of the PK/PD model for
the establishment of a dosage
regimen of ACE inhibitors
PKPD ACEI London 05 - 85
Dose (mg/kg)
0.1
0.25
0.5
1.0
2.0
150
120
90
60
Effect
Concentration (nmol/L)
Benazeprilat (10 control dogs)
Dose effect relationship (simulation)
30
0
1
2
3 0
1
Time (day)
2
3
Time
PKPD ACEI London 05 - 86
Benazeprilat: dose-effect
relationship in cat
60.0
ACE activity (units/mL)
50.0
40.0
30.0
0.0315
20.0
10.0
0.0625
0.125
0.25
0.0
0.5
-10.0
-12
24
60
96
132
168
204
240 276
312
348
384
420
Time (h)
PKPD ACEI London 05 - 87
Benazeprilat: dose-effect relationship
8
6
4
2
0
0
4
2
6
10
8
6
4
2
0
0
200
Time (h)
Time (day)
10
5
0
0
2
4
Time (day)
6
8
6
4
2
0
0
100
200
20
Effects
Effects
15
10
Time (h)
20
20
Effects
100
0.0313mg/kg/12h x 12
Concentrations (nmol/L)
10
0.0625 mg/kg/12h x 12
Concentrations (nmol/L)
Concentrations (nmol/L)
0.125 mg/kg/24h x 6
15
10
15
10
5
5
0
0
0
100
Time (h)
200
0
100
200
Time (h)
PKPD ACEI London 05 - 88
CONCLUSIONS
• ACEI PK is required to understand the drug
• ACEI PK/PD helps to determine optimal
dosage regimen
• ACEI PK/PD allows to adjust dosage regimen
(renal or hepatic failure)
PKPD ACEI London 05 - 89