Transcript Slide 1

PK and PD as predictors of clinical effect
PKPD workshop at AGAH/Club Phase I
•drug action
– the interaction of the drug molecule at the binding site
e.g. receptor, carrier, channel
•drug effect
– a measurable consequence of drug binding or drug action
e.g. EEC change, QT prolongation
•drug response
– a desirable or undesirable clinical outcome
e.g. reduced frequency of seizures, reduction in blood
pressure
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PKPD workshop at AGAH/Club Phase I
How do we find and test new drugs?
clinical
preclinical
○ screening (empirical)
○ dose ranging (empirical)
○ molecular modeling
○ PKPD modeling
○ molecular design
○ optimal study design
screening
learning
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design
PKPD workshop at AGAH/Club Phase I
…modeling may be understood as mechanized intuition
applying the rules of
– biology
– logic
– mathematics
– statistics
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PKPD workshop at AGAH/Club Phase I
to learn from experience
to develop models based on data………what data do we need?
Preclinical:
◦ affinities of active drug molecules for the binding site (in vitro,
in situ, in vivo)
◦ mechanism between binding and measurable effect including
auto-regulation (feedback, synthesis)
◦ in vivo: dose(time) – concentration(time) – measurable
effect(time)
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PKPD workshop at AGAH/Club Phase I
to learn from experience
to develop models based on data………what data do we need?
Clinical:
◦ ideally everything measured in the preclinical program (in
vivo affinities will be difficult to obtain), but at least the
following:
dose(time)
concentration(time)
effect(time)
◦ in addition, drug response data as a function of time
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PKPD workshop at AGAH/Club Phase I
How can this strategy be incorporated into R&D planning?
◦ Every preclinical experiment and every clinical study is
designed to add data to the PKPD knowledge base.
◦ The modeling and simulation (M&S) scientist participates in
the project teams.
◦ For the M&S scientist there exists no boundary between
preclinical and clinical development.
The design route will prove to be faster than the “shortcut”.
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PKPD workshop at AGAH/Club Phase I
…from the work of EMF-Consulting: Example1
Selection of optimal doses for a new anti-epileptic drug
to be tested in patients.
M. Marchand1, O. Petricoul1, E. Fuseau1, D. Bentley2, D. Critchley2
1 EMF consulting, BP 2, 13545 Aix en Provence, France
2 EISAI Global Clinical Development, 3 Shortlands, London W6 8EE, UK
○
Rufinamide modulates the activity of sodium channels thus suppressing seizures
induced by electroshock (maximal electroshock, MES) or by injection of
pentylenetrazole (PTZ) in mice (PD). In clinical studies, rufinamide significantly
reduced seizure frequency (PD).
○
Drug X is a new chemical entity with a novel mechanism of action. It shows
anticonvulsant effects in rodents. The dose(time)-concentration(time) relationship (PK)
was studied in epileptic patients.
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PKPD workshop: Example 1
○ PKPD modeling in mice:
− Population PKPD modeling used NONMEM.
− A one-compartment model with first order
elimination was chosen for both rufinamide and
Drug X.
− For PKPD modelling, drug concentrations were
predicted in male mice according to weight, the
administered dose in mg/kg, population PK
parameters (previously estimated), and time of test.
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PKPD workshop: Example 1
PKPD modeling in mice – where are the problems?
+ mice are cheap
+ mice are genetically well defined
+ small interindividual variability
− mice are small
− difficult to dose accurately
− difficult to obtain more than one blood sample
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PKPD workshop: Example 1
PKPD modeling in mice – Population approach:
Population PK model based on toxicokinetic data
-free choice oral dosing (continuous
input during dark hours)
-oral dosing by gavage (controlled
time of drug input)
-blood sampling at steady state
-blood sampling after single or
multiple doses
-destructive, only one sample per
mouse
-destructive, only one sample per
mouse
DR
Cl/F =
D·ka
C(t)=
Css
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V/F·(ka – k)
· (e
-k·t
−e
-ka·t
)
PKPD workshop: Example 1
PKPD modeling in mice – Population approach:
Population PD model using predicted individual
concentrations at the time of the effect measurement
Individual concentrations are predicted based on:
-the dose given at the PD experiment
-the gender and weight of the mouse
-the time of the effect measurement after the dose
-the population PK model
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PKPD workshop: Example 1
CONC  Emax
DV 

CONC  C50
Emax = 100% (FIXED)
C50 = 1.35 mg/mL
 = 5.98
% of mice protected from tonic hind limb seizure
Rufinamide data: Observed and predicted % of protected mice from MES Test
100
80
60
40
20
Observations
Predictions
0
0.0
0.5
1.0
1.5
2.0
Rufinamide concentrations (mg/mL)
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2.5
3.0
PKPD workshop: Example 1
Rufinamide data: observed and predicted % of protected mice from PTZ Test
CONC  Emax
CONC  C50
Emax = 76.4%
C50 = 1.64 mg/mL
% of mice protected from clonic seizure
DV 
100
80
60
40
20
Observations
Predictions
0
2
0
4
6
8
10
12
14
Rufinamide concentrations (mg/mL)
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PKPD workshop: Example 1
CONC  Emax
DV 

CONC  C50
Emax = 100% (FIXED)
C50 = 141.6 ng/mL

= 4.56
% of mice protected from tonic hind limb seizure
Drug X data: observed and predicted % of protected mice from MES Test
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Observations
Predictions
80
60
40
20
0
0
50
100
150
Drug X concentrations (ng/mL)
15
200
250
PKPD workshop: Example 1
Drug X data: observed and predicted % of protected mice from PTZ Test
Emax = 100%
(FIXED)
C50 = 88.1 ng/mL
% of mice protected from clonic seizure
CONC  Emax
DV 
CONC  C50
100
Observations
Predictions
80
60
40
20
0
0
50
100
150
200
Drug X concentrations (ng/mL)
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250
300
PKPD workshop: Example 1
PKPD modeling in patients:
Rufinamide: PD model based on clinical data
Predicted total seizure frequency per 28 days
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10
8
6
4
2
0
0
20
40
60
80
Cavss rufinamide concentrations (mg/mL)
Loge (total seizure frequency)  0.893 0.0187 Cavss
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PKPD workshop: Example 1
Link from mice to humans:
assumes that the effective concentrations in mice are
also effective in humans
A generic mathematical link function (Weibull) was
used to relate rufinamide preclinical effects to its
clinical response (Loge of total seizure frequency
over a period of 28 days).
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PKPD workshop: Example 1
Predicted Loge (total seizure frequency per 28 days)
Rufinamide preclinical effect (MES test): the link function shows that effective
concentrations in the preclinical MES test are not effective clinically.
Is the approach wrong? Not necessarily, but MES is definitely not a suitable
preclinical test.
-0.8
-1.0
-1.2
an ideal relationship:
-1.4
50% protected mice
are related to half the
maximal reduction in
seizure frequency in
patients.
-1.6
-1.8
-2.0
-2.2
-2.4
-2.6
-2.8
0
20
40
60
80
Predicted % of protected mice from tonic hind limb seizure
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100
PKPD workshop: Example 1
Predicted Loge (total seizure frequency per 28 days)
Rufinamide preclinical effect (PTZ test): the link function shows that
concentrations which protect more than 50% of mice also reduce total seizure
frequency per 28 days in patients. The relationship is not ideal but sensitive enough
to be used for the following extrapolation (next slide).
-0.8
Weibull Function
-1.0
-1.2
-1.4
-1.6
-1.8
-2.0
-2.2
-2.4
-2.6
-2.8
0
20
40
60
80
Predicted % of protected mice from clonic seizure
20
100
PKPD workshop: Example 1
○ Extrapolation from known to unknown:
− assuming that the link between the preclinical and
the clinical test is generally valid and independent of
the pharmacologic agent used to cause the response,
− the PTZ preclinical effect measurements of Drug X
are used to predict total seizure frequency per 28
days (clinical response).
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PKPD workshop: Example 1
Predicted Loge(total seizure frequency per 28 days)
The link function is now applied to drug X: whatever drug X concentration is
related to 70% of mice protected from seizures (PTZ test) is expected to be related
to a clinical response of 28·e-1.3 =7.6 seizures in 28 days, a minimal response.
0
-1
-2
-3
-4
Answer: ~200ng/ml
-5
-6
0
20
40
60
80
Predicted % mice protected from clonic seizure
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PKPD workshop: Example 1
○ Extrapolation from response to concentration:
− the preclinical PD model for PTZ test of Drug X is
used to predict the concentration in humans
necessary to achieve a certain clinical response.
− knowing… that for rufinamide the link function
relates effective concentrations in mice to effective
concentrations in humans.
− assuming… that the link function has general
applicability and is thus also valid for drug X.
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PKPD workshop: Example 1
Drug X: Finding the necessary concentrations to achieve a certain total seizure
frequency per 28 days (response)
Predicted total seizure frequency per 28 days
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10
8
6
4
2
0
0
50
100
150
200
250
Drug X concentrations (ng/mL)
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300
350
PKPD workshop: Example 1
○ Extrapolation from concentration to dose:
− a PK model for Drug X established in epileptic
patients in a phase IIa pilot study is used to predict
the dosing regimen to produce the necessary
concentrations.
− this PK model takes the drug interaction with
CYP3A4 inducers into account. The recommended
dosage is stratified accordingly:
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PKPD workshop: Example 1
In order to achieve similar decrease (2.8 per 28 days) of total seizure frequency as
with a typical Cavss (15 μg/ml) of rufinamide, the following daily doses for Drug X
are likely to produce a Cavss of 215 ng/mL:
○ Sub-population 1, without co-administration of CYP3A4
inducers:
1.8 units
○ Sub-population 1, with co-administration of CYP3A4
inducers:
7.7 units
○ Sub-population 2, without co-administration of CYP3A4
inducers:
4 units
○ Sub-population 2, with co-administration of CYP3A4
inducers:
15 units
Note: a Cavss of 215 ng/mL was observed in healthy subjects following repeated
daily doses of 4 units which were well tolerated.
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PKPD workshop: Example 1
workshop…english
atelier……..français
Werkstatt…deutsch
This is not a place to shop for work but a place to work.
Before I go on to my second example I would like to
solicit contributions, comments, anecdotes… from the
attendees.
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PKPD workshop at AGAH/Club Phase I
…from the work of EMF-Consulting: Example 2
Selection of an optimal biomarker for neutral
endopeptidase (NEP) inhibitors in humans.
A.C. Heatherington, S. Sultana, R. Hidi, M. Boucher, E. Fuseau, M. Marchand, P. Ellis, S.W. Martin
Pfizer Ltd, Sandwich, UK; EMF Consulting, Aix-en-Provence, France
Objectives:
○ to select a reliable soluble biomarker for NEP inhibitors
○ to compare clinical PD models to in vitro PD models
○ to build a suitable PKPD model to optimally design future
clinical studies
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PKPD workshop: Example 2
Background:
Neutral endopeptidase (NEP) is a metallopeptidase enzyme involved in the
degradation of a number of endogenous peptides, including
○ vasoactive intestinal peptide (VIP)
○ substance P
○ endothelins (hydrolysis of big endothelin, Big ET-1, to endothelin)
○ atrial natriuretic peptide (ANP).
It is hypothesized that NEP inhibitors would increase VIP leading to enhanced
vasodilatation in genital tissues. Two molecules, UK-447,841 (in vitro IC50 10
nM) and UK-505,749 (in vitro IC50 1.1nM), have undergone pharmacological
evaluation to assess their effect on plasma Big ET-1 and ANP levels.
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PKPD workshop: Example 2
Studies: Double-blind, randomized, placebo-controlled phase 1 studies
in healthy volunteers
Design
Dosing
PK data
PD data
(big ET-1 and ANP)
UK-447,841
Cross-over
Parallel group
Single escalating oral
Multiple daily oral
doses,
doses, 100, 400
3 to 800 mg
and 800 mg
14 samples up to 48 h
13 + 15 up to 48h
3 samples
7 samples
up to 8h
up to 12h
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UK-505,749
Cross-over
Single escalating oral
doses,
0.1 to 540 mg
14 samples up to 48h
7 samples
up to 12h
PKPD workshop: Example 2
UK-447,841 median concentration (mg/L)
median PK data, Phase I, healthy volunteers
UK-447,841
100
3 mg
10 mg
30 mg
100 mg
200 mg
400 mg
800 mg
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1
0.1
0.01
0.001
0.0001
0
10
20
30
Time (h)
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PKPD workshop at AGAH/Club Phase I
UK-505,749 median concentration (mg/L)
median PK data, Phase I, healthy volunteers
UK-505,749
100
0.1 mg
0.3 mg
1 mg
3 mg
10 mg
30 mg
90 mg
270 mg
540 mg
10
1
0.1
0.01
0.001
0
10
20
30
Time (h)
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40
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PKPD workshop: Example 2
Combined PKPD population model (NONMEM) for
two drugs (PK) and two biomarkers (PD indirect response
model for Big ET-1 and ANP)
• the NEP inhibitors slow down the degradation (kout1,2) of Big ET-1 and ANP
• Big ET-1 stimulates production rate (kin2) of ANP
• ANP stimulates production rate (kin1) of Big ET-1
• age enhances production rate (kin2) of ANP
• Emax , the maximum decrease in kout , is the same for both drugs but different
for ANP (41%) and for Big ET-1 (66%)
• age increases Emax for ANP
• IC50, the drug concentration at half-maximal effect, if different for Big ET-1
and ANP and different for UK-505,749 and UK-447,841
• also in vivo UK-505,749 is 10 times more potent than UK-447,841
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PKPD workshop: Example 2
PD indirect response model for Big ET-1 and ANP
Pop PK model
Cpred (447)
Cpred (505)
Pop PD model
IC50
η (IIV)
IC50
η (IIV)
Emax
kin1
η (IIV)
kout1
BigET1
η (IIV)
IC50
η (IOV)
Emax 2
η (IIV)
+
kin2
ANP
IC50
Age effect (+)
kout2
η (IIV)
Age effect (+)
+

 (Emax  C( 447 ) pred )
(Emax  C( 505 ) pred )
k in  k out  1  

 IC

IC50 ( 505 )  C( 505 ) pred
 50 ( 447 )  C( 447 ) pred

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
  R


Response compartment
PKPD workshop: Example 2
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Doses 3 to 800 mg of UK-447,841
Doses 0.1 to 540 mg of UK-505,749
Median Big ET-1 (pg/mL)
8
6
4
2
0
0
2
4
6
Time (h)
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8
10
12
PKPD workshop: Example 2
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Doses 3 to 400 mg of UK-447,841
Doses 0.1 to 540 mg of UK-505,749
Median ANP (pg/mL)
120
100
80
60
40
20
0
2
4
6
Time (h)
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8
10
12
PKPD workshop: Example 2
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Big Endothelin (pg/mL)
10
8
6
4
observed Big ET1
Population prediction of Big ET1
Individual prediction of Big ET1
2
0
0
2
4
6
8
10
12
UK-505,749 predicted concentration in effect compartment (mg/L)
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PKPD workshop: Example 2
(3 to 800 mg)
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after UK447,841 treatment
BigE concentrations (pg/mL)
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P5, P50 and P95 Sim
P5, P50 and P95 Obs
10
8
6
4
2
0
0
5
10
15
Time (h)
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PKPD workshop: Example 2
(0.1 to 540 mg)
14
after UK505,749 treatment
BigE concentrations (pg/mL)
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P5, P50 and 95 Sim
P5, P50 and P95 Obs
10
8
6
4
2
0
0
2
4
6
Time (h)
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8
10
12
PKPD workshop: Example 2
(3 to 400 mg)
ANP concentrations (pg/mL)
250
after UK447,841 treatment
200
P5, P50 and P95 Sim
P5, P50 and P95 Obs
150
100
50
0
0
2
4
6
Time (h)
40
8
10
12
PKPD workshop: Example 2
250
(0.1 to 540 mg)
ANP concentrations (pg/mL)
after UK505,749 treatment
P5, P50 and P95 Sim
P5, P50 and P95 Obs
200
150
100
50
0
0
2
4
6
Time (h)
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8
10
12
PKPD workshop: Example 2
Conclusion
○ Big ET-1 plasma concentration and, to a lesser extent, ANP plasma concentration
can be used as a pharmacological biomarker for the inhibitory drug effect on
enzyme (NEP) activity in healthy volunteers.
○ Big ET-1 has ideal characteristics of a soluble biomarker: it demonstrates doseconcentration-effect, time-linearity, reproducibility of effect with similar Emax for
two NEP inhibitors.
○ The ratio of the in vivo IC50 of the 2 compounds is similar to the in vitro ratio. This
allows extrapolation between species and between different drugs.
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PKPD workshop at AGAH/Club Phase I
I hope to meet many of you again at the PAGE meeting in
June 2007 in Copenhagen!
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