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Christian Schnell
Associate Director Oncology NIBR
Novartis in Basel
Programmable Pumps for
Compound Delivery in
Oncology Research
An expert shares describes the
validation studies performed in his
pharmacology unit in rats and mice.
Programmable Pumps for
Compound Delivery in
Oncology Research
Christian Schnell
Associate Director Oncology NIBR
Novartis in Basel
Programmable Pumps for
Compound Delivery in
Oncology Research
Copyright 2021 C. Schnell and InsideScientific. All Rights Reserved.
4 iPRECIO webinar, June 16th 2021 | Business Use Only
Programmable pumps for compounds delivery in oncology research:
implication for refinement and reduction of animal use
➢ one of the primary objectives of an oncology drug
discovery program is to understand the target
coverage required for desired anti-tumor therapeutic
efficacy
5 iPRECIO webinar, June 16th 2021 | Business Use Only
Programmable pumps for compounds delivery in oncology research:
implication for refinement and reduction of animal use
➢ PK/PD modeling is based on the assumption of a causal
relationship between compound exposure, target
inhibition and its anti-tumor therapeutic activity
6 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
PD
response
(%
of
control)
Study design is based on the assumption of a causal relationship between exposure,
target inhibition and its therapeutic activity following oral treatment
➢ Study design:
- single dose, one dose level
- select the most relevant matrix
- monitoring a single PD biomarker
- select a relevant, sensitive and
reproducible PD read-out
- analyze effect of time on PD
7 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
➢ Samples for PK and PD:
- important to include a vehicle treated
group (ref. for PD modulation assessment)
- PK and PD should be analyzed
concomitantly from the same animal
- dynamic range of plasma exposure should
cover absence and maximum PD effect
- multiple dose levels and time points post
treatment to obtain reliable relationship
Tumor concentration (nmol/g)
0
.
0
0
2
0
.
0
0
4
0
.
0
0
6
0
.
0
2
0
.
0
4
0
.
0
6
0
.
2
0
.
4
0
.
6
2
4
6
2
0
4
0
6
0
0
.
0
0
1
0
.
0
1
0
.
1
1
1
0
1
0
0
Tumor
p-Akt
Inhibition
(%,
RPPA)
0
20
40
60
80
100
120
Plasma level (µmol/L)
PD
response
(%
inhibition)
IC80
IC50
Study design is based on the assumption of a causal relationship between exposure,
target inhibition and its therapeutic activity following oral treatment
8 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
Time post treatment (hours)
0 2 4 6 8 10 12 14 16 18 20 22 24
Plasma
concentration
(µmol/L,
mean
±
SEM)
BYL719 50 mg/kg p.o.
IC80 (
Fraction of time PD inhibition > 80% : 0.60
IC80
Plasma
level
(µmol/L)
Tumor concentration (nmol/g)
0
.
0
0
2
0
.
0
0
4
0
.
0
0
6
0
.
0
2
0
.
0
4
0
.
0
6
0
.
2
0
.
4
0
.
6
2
4
6
2
0
4
0
6
0
0
.
0
0
1
0
.
0
1
0
.
1
1
1
0
1
0
0
Tumor
p-Akt
Inhibition
(%,
RPPA)
0
20
40
60
80
100
120
Plasma level (µmol/L)
PD
response
(%
inhibition)
IC80
IC50
Study design is based on the assumption of a causal relationship between exposure,
target inhibition and its therapeutic activity following oral treatment
9 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
Time post treatment (hours)
0 2 4 6 8 10 12 14 16 18 20 22 24
Plasma
concentration
(µmol/L,
mean
±
SEM)
BYL719 50 mg/kg p.o.
IC80 (4 µmol)
Fraction of time PD inhibition > 80% : 0.60
IC80
Plasma
level
(µmol/L)
T/C:
1.0
0.2
Reg:
0.4
Study design is based on the assumption of a causal relationship between exposure,
target inhibition and its therapeutic activity following oral treatment
10 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
Time post treatment (hours)
0 2 4 6 8 10 12 14 16 18 20 22 24
Plasma
concentration
(µmol/L,
mean
±
SEM)
BYL719 50 mg/kg p.o.
IC80 (4 µmol)
Fraction of time PD inhibition > 80% : 0.60
IC80
Plasma
level
(µmol/L)
0 10 20 30 40 50 60 70 80 90 100
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
% Time > IC80
Tumor
growth
inhibition
(ratio)
Regression
Stasis
50% regression
Study design is based on the assumption of a causal relationship between exposure,
target inhibition and its therapeutic activity following oral treatment
11 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
➢ PK/PD modeling help the team to:
- understand the mechanism of action of a
drug
- select the optimal compound
- shorten the development time
- estimate the therapeutic index
- better predict the dose range in early clinical
testing
PD
response
(%
of
control)
Study design is based on the assumption of a causal relationship between exposure,
target inhibition and its therapeutic activity following oral treatment
12 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
(adapted from Tuntland et al., Frontiers in Pharmacology Vol.5, Article 174, 2014)
➢ Caveats:
- variability associated with PK (≠ absorption
profile per animal) and PD (≠ expression of the
target in tumor) within each study is a possible
concern
- temporal delays in effects (Hysteresis)
- use of pooled data from different studies needed
to define a mean relationship between
exposure and effect
- high numbers of animals needed to achieve
statistically significant results (3R’s)
Study design is based on the assumption of a causal relationship between exposure,
target inhibition and its therapeutic activity following oral treatment
13 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
How can we improve the robustness and translatability of our modeling activities?
➢ parenteral drug-delivering technologies:
- less variability associated with PK (similar
absorption profile per animal following i.v. route)
foreseen
- no temporal delays in effects (Hysteresis)
- lower numbers of animals needed to achieve
statistically significant results (3R’s)
- ability to explore varying degrees of sustained
target engagement having an important role in
facilitating validation of novel targets (3R’s)
➢ Caveats:
- variability associated with PK (≠ absorption
profile per animal) and PD (≠ expression of the
target in tumor) within each study is a possible
concern
- temporal delays in effects (Hysteresis)
- use of pooled data from different studies needed
to define a mean relationship between
exposure and effect
- high numbers of animals needed to achieve
statistically significant results (3R’s)
14 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
iPRECIO technical notes: SMP-200 for rat implantation
Implantable, programmable, refillable
➢ microprocessor controlled peristalsis mechanism for accurate controlled flow
(+/-5%)
➢ Infusion rate: 0 µl/hour to 30.0 µl/hour in 0.1μl/hour steps
Refillable (reservoir 900 µl)
percutaneously via refill port
re-sealable septum
ex-vivo
15 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
iPRECIO technical notes: SMP-200 for rat implantation
➢ Jugular vein infusion
➢ Weight: 7.9g
➢ Size: 38.7(L) x 19.2(W) x 9.7mm(H)
⌀ = +-1cm
Distance of inserted
catheter = 1.5cm
Preligatures are linked to
each other for more stability
16 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
iPRECIO technical notes: SMP-310R
➢ microprocessor controlled peristalsis mechanism for accurate controlled flow
(+/-5%)
➢ Infusion rate: 0 µl/hour to 10.0 µl/hour in 0.1μl/hour steps
Refillable (reservoir 130 µl)
percutaneously via refill port
re-sealable septum
Implantable, programmable, refillable
in-vivo
17 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
iPRECIO technical notes: SMP-310R for mice implantation
➢ Jugular vein infusion
➢ Weight: 3.4g
➢ Size: 24.8(L) x 15.0(W) x 7.4mm(H)
Implantable
➢ 177 performed Iprecio surgeries
➢ 2 mice and 6 rats were able to reach and section the
catheter in the neck area → ~ 4%
➢ Daily check-up are important
18 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
SMP-310R: Assessment of infusion accuracy at 4 µl/h infusion in nude mice (n=3-4)
➢ Jugular vein infusion
➢ Weight: 3.4g
➢ Size: 24.8(L) x 15.0(W) x 7.4mm(H)
Implantable
0 1 2 3 4 5 6 7 8 9 10
0
1
2
3
4
5
6
7
8
9
10
Time (days)
Measured
infusion
rate
(Ll/h,
mean

SEM)
19 iPRECIO webinar, June 16th 2021 | Business Use Only
Programmable pumps for compounds delivery in oncology research:
implication for refinement and reduction of animal use
➢ Confirmation of i.v. clearance:
- clearance for compound A was previously calculated from
PK data obtained from IV single dose bolus in the
respective species (n=3)
- the standard equation using IV clearance (CL) and
achievable dose concentration was used to predict the
infusion rate required for Css (rate = Css x CL)
- compound A was tested at 3 different infusion rate (n=2 to
8 per group)
- predicted versus observed blood levels at steady state
were plotted and compared
PK analysis
Compound A i.v. infusion
(100–300 µl/h) in 20% HPbCD
Validation study in freely moving single housed BN rats via an automated blood sampling
system (ABS) using compound A infusion (i.v. via jugular vein)
20 iPRECIO webinar, June 16th 2021 | Business Use Only
Programmable pumps for compounds delivery in oncology research:
implication for refinement and reduction of animal use
Validation study in freely moving single housed BN rats via an automated blood sampling
system (ABS) using compound A infusion (i.v. via jugular vein)
PK analysis
Compound A i.v. infusion
(100–300 µl/h) in 20% HPbCD
0.15 0.20 0.25 0.30 0.35 0.40 0.45
2
3
4
5
6
Blood collected via ABS in conscious rats
Total dose of compound A infused i.v.
(mg/h)
Plasma
concentration
at
Day
3
(mol/L,
mean
±
SEM)
Observed
Predicted (CL= 11.5 ml/min/kg)
(2)
(8)
(2)
(n)
Prediction based on
Css = infusion rate / CL
21 iPRECIO webinar, June 16th 2021 | Business Use Only
Programmable pumps for compounds delivery in oncology research:
implication for refinement and reduction of animal use
Validation study in freely moving grouped housed nude rats via an programmable iPRECIO
pump using tool compound A infusion (i.v. via jugular vein)
0 1 2 3 4 5 6
0
1
2
3
4
5
6
7
Tail vein blood collection in conscious rats
Predicted blood levels at SS
(µmol/L)
Observed
blood
levels
at
SS
(µmol/L)
Compound A (r2
=0.96, p<0.003)
Dose
(mg/ml)
Infusion rate
(µl/h)
15 20
10 20
5 20
5 16
2 20
22 iPRECIO webinar, June 16th 2021 | Business Use Only
Programmable pumps for compounds delivery in oncology research:
implication for refinement and reduction of animal use
Validation study in freely moving grouped housed nude rats via an programmable iPRECIO
pump using tool compound B infusion (i.v. via jugular vein)
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
Tail vein blood collection in conscious rats
Predicted blood levels at SS
(µmol/L)
Observed
blood
levels
at
SS
(µmol/L)
Compound B (r2
=0.94, p<0.0001, n=12)
Dose
(mg/ml)
Infusion rate
(µl/h)
1 4
1.5 4
2 4
2.5 4
3.5 4
4 4
8 4
1.4 10
23 iPRECIO webinar, June 16th 2021 | Business Use Only
Programmable pumps for compounds delivery in oncology research:
implication for refinement and reduction of animal use
Validation study in freely moving grouped housed nude rats via an programmable iPRECIO
pump using tool compound B infusion (i.v. via jugular vein)
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
Tail vein blood collection in conscious rats
Predicted blood levels at SS
(µmol/L)
Observed
blood
levels
at
SS
(µmol/L)
Compound B (r2
=0.94, p<0.0001, n=12)
ALZET®
osmotic pump
Dose
(mg/ml)
Infusion rate
(µl/h)
1 4
1.5 4
2 4
2.5 4
3.5 4
4 4
8 4
1.4 10
Dose
(mg/ml)
Infusion rate
(µl/h)
10 0.25
1002
24 iPRECIO webinar, June 16th 2021 | Business Use Only
Programmable pumps for compounds delivery in oncology research:
implication for refinement and reduction of animal use
Validation study in freely moving grouped housed nude mice via an programmable iPRECIO
pump using tool compound A infusion (i.v. via jugular vein)
Dose
(mg/ml)
Infusion rate
(µl/h)
3 2.2
6 2.2
6 4.5
SMP-310/R
Compound A
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Tail vein blood collection in conscious mice
Predicted blood levels at SS
(µmol/L)
Observed
blood
levels
at
SS
(µmol/L)
Compound A (r2
=1, p<0.02, n=3)
25 iPRECIO webinar, June 16th 2021 | Business Use Only
Programmable pumps for compounds delivery in oncology research:
implication for refinement and reduction of animal use
Validation study in freely moving grouped housed nude mice via an programmable iPRECIO
pump using tool compound B infusion (i.v. via jugular vein)
SMP-310/R
0.0 0.1 0.2 0.3 0.4 0.5 0.6
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Tail vein blood collection in conscious mice
Predicted blood levels at SS
(µmol/L)
Observed
blood
levels
at
SS
(µmol/L)
Compound B (r2
=1, p<0.001, n=4)
Dose
(mg/ml)
Infusion rate
(µl/h)
0.2 4
0.3 4
0.6 4
1.2 4
Compound B
26 iPRECIO webinar, June 16th 2021 | Business Use Only
Programmable pumps for compounds delivery in oncology research:
implication for refinement and reduction of animal use
Validation study in freely moving grouped housed nude mice via an programmable iPRECIO
pump using tool compound C infusion (i.v. via jugular vein)
SMP-310/R
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Tail vein blood collection in conscious mice
Predicted blood levels at SS
(µmol/L)
Observed
blood
levels
at
SS
(µmol/L)
Compound C (r2
=0.99, p<0.0002, n=4)
Dose
(mg/ml)
Infusion rate
(µl/h)
2 4
3 4
5 4
10 4
Compound C
27 iPRECIO webinar, June 16th 2021 | Business Use Only
Programmable pumps for compounds delivery in oncology research:
implication for refinement and reduction of animal use
Validation study in freely moving grouped housed nude mice and rats via an programmable
iPRECIO pump using all tested doses and compound (i.v. via jugular vein)
0.01 0.1 1 10
0.01
0.1
1
10
100
Predicted blood levels at SS
(µmol/L)
Observed
blood
levels
at
SS
(µmol/L)
r2
= 0.94, p<0.0001, n=28
➢ 2 species (mice and rats)
➢ 2 pumps (SMP-200 and SMP-310R)
➢ 3 tool compounds
➢ 24 doses
➢ 7 infusion rates (2.2 to 20 µl/h)
 r2 = 0.94, p<0.0001, n=28
28 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
Study design is based on the assumption of a causal relationship between exposure,
target inhibition and its anti-tumor activity
➢ Rat1myrp110α tumors
ulin i.v. infusion
O
➢ Rat1myrp110alpha tumors
➢ Iprecio pumps
(SMP-200)
T/C:
1.0
0.2
Reg:
0.4
29 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
Study design is based on the assumption of a causal relationship between exposure,
target inhibition and its anti-tumor activity
➢ Rat1myrp110α tumors
ulin i.v. infusion
O
➢ Rat1myrp110alpha tumors
➢ Iprecio pumps
(SMP-200)
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
0.0
0.5
1.0
2.0
2.5
3.0
3.5
Tumor growth inhibition (ratio)
Compound
plasma
levels
(mol/L
at
Css)
Regression
1.5
0.7
Stasis
50% regression
30 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
Study design is based on the assumption of a causal relationship between exposure,
target inhibition and its anti-tumor activity
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
0.0
0.5
1.0
2.0
2.5
3.0
3.5
Tumor growth inhibition (ratio)
Compound
plasma
levels
(mol/L
at
Css)
Regression
1.5
0.7
0.1 1 10 100
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Compound plasma concentration
(mol/L)
Tumor
PD
(
%
average
vehicle
control
)
r2
=0.75, n=19
1
.
5
0
.
7
Stasis
50% regression
Stasis
50% regression
31 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
Study design is based on the assumption of a causal relationship between exposure,
target inhibition and its anti-tumor activity
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Tumor growth inhibition (ratio)
Compound
plasma
levels
(mol/L
at
Css)
Regression
0.1 1 10 100
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Compound plasma concentration
(mol/L)
Tumor
PD
(
%
average
vehicle
control
)
r2
=0.75, n=19
1
.
5
0
.
7
Using this PK/PD modeling approach, we could demonstrate that the anti-tumor activity is
Cthrough (time over threshold) driven and not Cmax dependent
32 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
Study design is based on the assumption of a causal relationship between exposure,
target inhibition and its anti-tumor activity
➢ Tumor
➢ iPRECIO pump infusion
iPRECIO pumps (SMP-310R)
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Tumor growth inhibition (ratio)
Compound
plasma
levels
(mol/L
at
Css)
Regression
in nude rats
in nude mice
PDX tumor
Stasis
50% regression
33 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
Study design is based on the assumption of a causal relationship between exposure,
target inhibition and its anti-tumor activity
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Tumor growth inhibition (ratio)
Compound
plasma
levels
(mol/L
at
Css)
Regression
in nude rats
in nude mice
0.1 1 10 100
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Compound plasma concentration
(mol/L)
Tumor
PD
(
%
average
vehicle
control
)
r2
=0.76, n=26
1
.
5
0
.
7
in nude rats
in nude mice
Stasis
50% regression
34 iPRECIO webinar, June 16th 2021 | Business Use Only
Programmable pumps for compounds delivery in oncology research:
implication for refinement and reduction of animal use
➢ Anticancer agents often have a narrow therapeutic index
(TI), requiring precise dosing to ensure sufficient
exposure for clinical activity while minimizing toxicity
35 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
How can we improve the assessment of therapeutic index (TI) ?
Conventional (Oral / IV)
• Multiple injection/dose
• Low TI, large dose,
• Side effects (drug, dose,
administration)
• Poor Compliance
Ze
•
•
•
Oral treatment (per os)
➢ Multiple dose
➢ Large dose
➢ Side effects
36 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
How can we improve the assessment of therapeutic index (TI) ?
Conventional (Oral / IV)
• Multiple injection/dose
• Low TI, large dose,
• Side effects (drug, dose,
administration)
• Poor Compliance
Zero Order Kinetics
• Improved therapeutic efficacy
• Reduced drug dose,
• Reduced Side effects Better
compliance
Conventional (Oral / IV)
• Multiple injection/dose
• Low TI, large dose,
• Side effects (drug, dose,
administration)
• Poor Compliance
Zero Order Kinetics
• Improved therapeutic efficacy
• Reduced drug dose,
• Reduced Side effects Better
compliance
Oral treatment (per os) Pump delivery
➢ Multiple dose
➢ Large dose
➢ Side effects
➢ Sustained exposure
➢ Reduced drug dose
➢ Reduced side effects
37 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
How can we improve the assessment of therapeutic index (TI) ?
0 2 4 6 8 10 12
0
100
200
300
400
500
600
Time post treatment (days)
Blood
Levels
(nmol/L
total,
mean

SEM)
Start Infusion i.v.
0 2 4 6 8 10
-20
-15
-10
-5
0
5
10
15
20
Time post treatment (days)
Change
in
body
weight
(%
vs
day
0,
mean

SEM)
Start Infusion i.v.
0.2 mg/ml at 4 l/h inf.
Compound B: (n=2)
0.6 mg/ml at 4 l/h inf.
0.3 mg/ml at 4 l/h inf.
1.2 mg/ml at 4 l/h inf.
0 2 4 6 8 10 12
-20
-15
-10
-5
0
5
10
15
20
Time post treatment (days)
Change
in
body
weight
(%
vs
day
0,
mean

SEM)
Start Infusion i.v.
0.2 mg/ml at 4 l/h inf.
Compound B: (n=2)
0.6 mg/ml at 4 l/h inf.
0.3 mg/ml at 4 l/h inf.
1.2 mg/ml at 4 l/h inf.
(n=2)
➢ Experimental design
38 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
How can we improve the assessment of therapeutic index (TI) ?
0 2 4 6 8 10 12
0
100
200
300
400
500
600
Time post treatment (days)
Blood
Levels
(nmol/L
total,
mean

SEM)
Start Infusion i.v.
0 2 4 6 8 10
-20
-15
-10
-5
0
Time post treatment (days)
Change
in
b
(%
vs
day
0,
m
0.2 mg/ml at 4 l/h inf.
Compound B: (n=2)
0.6 mg/ml at 4 l/h inf.
0.3 mg/ml at 4 l/h inf.
1.2 mg/ml at 4 l/h inf.
0 2 4 6 8 10 12
-20
-15
-10
-5
0
5
10
15
20
Time post treatment (days)
Change
in
body
weight
(%
vs
day
0,
mean

SEM)
Start Infusion i.v.
0.2 mg/ml at 4 l/h inf.
Compound B: (n=2)
0.6 mg/ml at 4 l/h inf.
0.3 mg/ml at 4 l/h inf.
1.2 mg/ml at 4 l/h inf.
(n=2)
➢ Blood glucose measurement
➢ Experimental design
39 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
0 2 4 6 8 10 12
0
100
200
300
400
500
600
Time post treatment (days)
Blood
Levels
(nmol/L
total,
mean

SEM)
Start Infusion i.v.
0 2 4 6 8 10
-20
-15
-10
-5
0
Time post treatment (days)
Change
in
b
(%
vs
day
0,
m
0.2 mg/ml at 4 l/h inf.
Compound B: (n=2)
0.6 mg/ml at 4 l/h inf.
0.3 mg/ml at 4 l/h inf.
1.2 mg/ml at 4 l/h inf.
0 2 4 6 8 10 12
-20
-15
-10
-5
0
5
10
15
20
Time post treatment (days)
Change
in
body
weight
(%
vs
day
0,
mean

SEM)
Start Infusion i.v.
0.2 mg/ml at 4 l/h inf.
Compound B: (n=2)
0.6 mg/ml at 4 l/h inf.
0.3 mg/ml at 4 l/h inf.
1.2 mg/ml at 4 l/h inf.
0 2 4 6 8 10 12
0
5
10
15
20
25
Time post treatment (days)
Blood
Glucose
Levels
(mmol/l,
mean

SEM)
Start Infusion i.v. 0.2 mg/ml at 4 l/h inf.
DZA621: (n=2)
0.6 mg/ml at 4 l/h inf.
0.3 mg/ml at 4 l/h inf.
1.2 mg/ml at 4 l/h inf.
0 2 4 6 8 10 12
0
5
10
15
Time post treatment (days)
Plasma
Insulin
Levels
(ng/ml,
mean

SEM)
Start Infusion i.v. 0.2 mg/ml at 4 l/h inf.
DZA621: (n=2)
0.6 mg/ml at 4 l/h inf.
0.3 mg/ml at 4 l/h inf.
1.2 mg/ml at 4 l/h inf.
(n=2)
How can we improve the assessment of therapeutic index (TI) ?
➢ Experimental design
40 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
0.0
0.5
1.0
2.0
2.5
3.0
3.5
Tumor growth inhibition (ratio)
Compound
plasma
levels
(mol/L
at
Css)
Regression
1.5
0.01 0.1 1 10 100
0
5
10
15
20
25
30
Compound plasma levels
(mol/L)
Blood
Glucose
levels
(mmol/L)
G2
G3
G1
5
How can we improve the assessment of therapeutic index (TI) for compound A?
➢ TI in conscious rats = 5 µmol/L (glucose ≥11 mmol/L) / 1.5 µmol/L (50% tumor regression) → 3.3
Stasis
50% regression
41 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
How can we improve the robustness and translatability of our modeling activities?
Tumor xenograft model
Radio-telemetry
Glucose sensor
 intra-arterial
Compound A →
 Around-the-clock remote monitoring
42 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
How can we improve the robustness and translatability of our modeling activities?
SMP-310R
 Around-the-clock remote monitoring combined with in-vivo programmable pumps
43 iPRECIO webinar, June 16th 2021 | Business Use Only
PK/PD modeling to integrate quantitative information about the
pharmacologic properties of a compound with its pharmacokinetics:
How can we improve the robustness and translatability of our modeling activities?
(adapted from Tuntland et al., Frontiers in Pharmacology Vol.5, Article 174, 2014)
➢ parenteral drug-delivering technologies:
- less variability associated with PK (similar
absorption profile per animal following i.v. route)
foreseen
- no temporal delays in effects (Hysteresis)
- lower numbers of animals needed to achieve
statistically significant results
- ability to explore varying degrees of sustained
target engagement having an important role in
facilitating validation of novel targets
➢ Caveats of i.v. drug delivery systems:
- target steady-state concentration (Css)
should be achieved rapidly
- good solubility and stability at 37°C in a
compatible vehicle volume
- requested infusion rate that is acceptable
for the preclinical species
- duration of the infusion depending on the
preclinical species
- battery life limitation
44 iPRECIO webinar, June 16th 2021 | Business Use Only
Programmable pumps for compounds delivery in oncology research:
implication for refinement and reduction of animal use
Summary and conclusions (1)
➢ Validation of the iPRECIO pumps (SMP-200 and SMP310/R) in terms of accuracy
and reliability were successfully achieved across several tool compounds
➢ Parenteral delivery via implantable pumps allows:
➢ unprecedented PK-PD correlations and corresponding antitumor activity to better
understand mechanism of action and dose response across different species and tumor
models
➢ drug delivery without interfering with normal activity in group-housed animals, reducing
stress and data variability (refinement) leading to lower numbers of animals needed to
achieve statistical power (reduction)
45 iPRECIO webinar, June 16th 2021 | Business Use Only
Programmable pumps for compounds delivery in oncology research:
implication for refinement and reduction of animal use
Summary and conclusions (2)
➢ In addition, simultaneous use of complementary novel technologies within the
same animal (like radio-telemetry and programmable pumps) will enable
advances in the understanding of complex physiological regulation mechanism
following pharmacological intervention, possibly leading to improved therapies
in the clinic by enhancing translatability of pre-clinical data
Thank you for participating!
Christian Schnell
Associate Director Oncology NIBR
Novartis in Basel
CLICK HERE to learn more and
watch the webinar

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Compound Delivery, PK-PD, & Validation Studies in Oncology Research

  • 1. Christian Schnell Associate Director Oncology NIBR Novartis in Basel Programmable Pumps for Compound Delivery in Oncology Research
  • 2. An expert shares describes the validation studies performed in his pharmacology unit in rats and mice. Programmable Pumps for Compound Delivery in Oncology Research
  • 3. Christian Schnell Associate Director Oncology NIBR Novartis in Basel Programmable Pumps for Compound Delivery in Oncology Research Copyright 2021 C. Schnell and InsideScientific. All Rights Reserved.
  • 4. 4 iPRECIO webinar, June 16th 2021 | Business Use Only Programmable pumps for compounds delivery in oncology research: implication for refinement and reduction of animal use ➢ one of the primary objectives of an oncology drug discovery program is to understand the target coverage required for desired anti-tumor therapeutic efficacy
  • 5. 5 iPRECIO webinar, June 16th 2021 | Business Use Only Programmable pumps for compounds delivery in oncology research: implication for refinement and reduction of animal use ➢ PK/PD modeling is based on the assumption of a causal relationship between compound exposure, target inhibition and its anti-tumor therapeutic activity
  • 6. 6 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: PD response (% of control) Study design is based on the assumption of a causal relationship between exposure, target inhibition and its therapeutic activity following oral treatment ➢ Study design: - single dose, one dose level - select the most relevant matrix - monitoring a single PD biomarker - select a relevant, sensitive and reproducible PD read-out - analyze effect of time on PD
  • 7. 7 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: ➢ Samples for PK and PD: - important to include a vehicle treated group (ref. for PD modulation assessment) - PK and PD should be analyzed concomitantly from the same animal - dynamic range of plasma exposure should cover absence and maximum PD effect - multiple dose levels and time points post treatment to obtain reliable relationship Tumor concentration (nmol/g) 0 . 0 0 2 0 . 0 0 4 0 . 0 0 6 0 . 0 2 0 . 0 4 0 . 0 6 0 . 2 0 . 4 0 . 6 2 4 6 2 0 4 0 6 0 0 . 0 0 1 0 . 0 1 0 . 1 1 1 0 1 0 0 Tumor p-Akt Inhibition (%, RPPA) 0 20 40 60 80 100 120 Plasma level (µmol/L) PD response (% inhibition) IC80 IC50 Study design is based on the assumption of a causal relationship between exposure, target inhibition and its therapeutic activity following oral treatment
  • 8. 8 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Time post treatment (hours) 0 2 4 6 8 10 12 14 16 18 20 22 24 Plasma concentration (µmol/L, mean ± SEM) BYL719 50 mg/kg p.o. IC80 ( Fraction of time PD inhibition > 80% : 0.60 IC80 Plasma level (µmol/L) Tumor concentration (nmol/g) 0 . 0 0 2 0 . 0 0 4 0 . 0 0 6 0 . 0 2 0 . 0 4 0 . 0 6 0 . 2 0 . 4 0 . 6 2 4 6 2 0 4 0 6 0 0 . 0 0 1 0 . 0 1 0 . 1 1 1 0 1 0 0 Tumor p-Akt Inhibition (%, RPPA) 0 20 40 60 80 100 120 Plasma level (µmol/L) PD response (% inhibition) IC80 IC50 Study design is based on the assumption of a causal relationship between exposure, target inhibition and its therapeutic activity following oral treatment
  • 9. 9 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Time post treatment (hours) 0 2 4 6 8 10 12 14 16 18 20 22 24 Plasma concentration (µmol/L, mean ± SEM) BYL719 50 mg/kg p.o. IC80 (4 µmol) Fraction of time PD inhibition > 80% : 0.60 IC80 Plasma level (µmol/L) T/C: 1.0 0.2 Reg: 0.4 Study design is based on the assumption of a causal relationship between exposure, target inhibition and its therapeutic activity following oral treatment
  • 10. 10 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Time post treatment (hours) 0 2 4 6 8 10 12 14 16 18 20 22 24 Plasma concentration (µmol/L, mean ± SEM) BYL719 50 mg/kg p.o. IC80 (4 µmol) Fraction of time PD inhibition > 80% : 0.60 IC80 Plasma level (µmol/L) 0 10 20 30 40 50 60 70 80 90 100 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 % Time > IC80 Tumor growth inhibition (ratio) Regression Stasis 50% regression Study design is based on the assumption of a causal relationship between exposure, target inhibition and its therapeutic activity following oral treatment
  • 11. 11 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: ➢ PK/PD modeling help the team to: - understand the mechanism of action of a drug - select the optimal compound - shorten the development time - estimate the therapeutic index - better predict the dose range in early clinical testing PD response (% of control) Study design is based on the assumption of a causal relationship between exposure, target inhibition and its therapeutic activity following oral treatment
  • 12. 12 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: (adapted from Tuntland et al., Frontiers in Pharmacology Vol.5, Article 174, 2014) ➢ Caveats: - variability associated with PK (≠ absorption profile per animal) and PD (≠ expression of the target in tumor) within each study is a possible concern - temporal delays in effects (Hysteresis) - use of pooled data from different studies needed to define a mean relationship between exposure and effect - high numbers of animals needed to achieve statistically significant results (3R’s) Study design is based on the assumption of a causal relationship between exposure, target inhibition and its therapeutic activity following oral treatment
  • 13. 13 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: How can we improve the robustness and translatability of our modeling activities? ➢ parenteral drug-delivering technologies: - less variability associated with PK (similar absorption profile per animal following i.v. route) foreseen - no temporal delays in effects (Hysteresis) - lower numbers of animals needed to achieve statistically significant results (3R’s) - ability to explore varying degrees of sustained target engagement having an important role in facilitating validation of novel targets (3R’s) ➢ Caveats: - variability associated with PK (≠ absorption profile per animal) and PD (≠ expression of the target in tumor) within each study is a possible concern - temporal delays in effects (Hysteresis) - use of pooled data from different studies needed to define a mean relationship between exposure and effect - high numbers of animals needed to achieve statistically significant results (3R’s)
  • 14. 14 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: iPRECIO technical notes: SMP-200 for rat implantation Implantable, programmable, refillable ➢ microprocessor controlled peristalsis mechanism for accurate controlled flow (+/-5%) ➢ Infusion rate: 0 µl/hour to 30.0 µl/hour in 0.1μl/hour steps Refillable (reservoir 900 µl) percutaneously via refill port re-sealable septum ex-vivo
  • 15. 15 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: iPRECIO technical notes: SMP-200 for rat implantation ➢ Jugular vein infusion ➢ Weight: 7.9g ➢ Size: 38.7(L) x 19.2(W) x 9.7mm(H) ⌀ = +-1cm Distance of inserted catheter = 1.5cm Preligatures are linked to each other for more stability
  • 16. 16 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: iPRECIO technical notes: SMP-310R ➢ microprocessor controlled peristalsis mechanism for accurate controlled flow (+/-5%) ➢ Infusion rate: 0 µl/hour to 10.0 µl/hour in 0.1μl/hour steps Refillable (reservoir 130 µl) percutaneously via refill port re-sealable septum Implantable, programmable, refillable in-vivo
  • 17. 17 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: iPRECIO technical notes: SMP-310R for mice implantation ➢ Jugular vein infusion ➢ Weight: 3.4g ➢ Size: 24.8(L) x 15.0(W) x 7.4mm(H) Implantable ➢ 177 performed Iprecio surgeries ➢ 2 mice and 6 rats were able to reach and section the catheter in the neck area → ~ 4% ➢ Daily check-up are important
  • 18. 18 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: SMP-310R: Assessment of infusion accuracy at 4 µl/h infusion in nude mice (n=3-4) ➢ Jugular vein infusion ➢ Weight: 3.4g ➢ Size: 24.8(L) x 15.0(W) x 7.4mm(H) Implantable 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Time (days) Measured infusion rate (Ll/h, mean  SEM)
  • 19. 19 iPRECIO webinar, June 16th 2021 | Business Use Only Programmable pumps for compounds delivery in oncology research: implication for refinement and reduction of animal use ➢ Confirmation of i.v. clearance: - clearance for compound A was previously calculated from PK data obtained from IV single dose bolus in the respective species (n=3) - the standard equation using IV clearance (CL) and achievable dose concentration was used to predict the infusion rate required for Css (rate = Css x CL) - compound A was tested at 3 different infusion rate (n=2 to 8 per group) - predicted versus observed blood levels at steady state were plotted and compared PK analysis Compound A i.v. infusion (100–300 µl/h) in 20% HPbCD Validation study in freely moving single housed BN rats via an automated blood sampling system (ABS) using compound A infusion (i.v. via jugular vein)
  • 20. 20 iPRECIO webinar, June 16th 2021 | Business Use Only Programmable pumps for compounds delivery in oncology research: implication for refinement and reduction of animal use Validation study in freely moving single housed BN rats via an automated blood sampling system (ABS) using compound A infusion (i.v. via jugular vein) PK analysis Compound A i.v. infusion (100–300 µl/h) in 20% HPbCD 0.15 0.20 0.25 0.30 0.35 0.40 0.45 2 3 4 5 6 Blood collected via ABS in conscious rats Total dose of compound A infused i.v. (mg/h) Plasma concentration at Day 3 (mol/L, mean ± SEM) Observed Predicted (CL= 11.5 ml/min/kg) (2) (8) (2) (n) Prediction based on Css = infusion rate / CL
  • 21. 21 iPRECIO webinar, June 16th 2021 | Business Use Only Programmable pumps for compounds delivery in oncology research: implication for refinement and reduction of animal use Validation study in freely moving grouped housed nude rats via an programmable iPRECIO pump using tool compound A infusion (i.v. via jugular vein) 0 1 2 3 4 5 6 0 1 2 3 4 5 6 7 Tail vein blood collection in conscious rats Predicted blood levels at SS (µmol/L) Observed blood levels at SS (µmol/L) Compound A (r2 =0.96, p<0.003) Dose (mg/ml) Infusion rate (µl/h) 15 20 10 20 5 20 5 16 2 20
  • 22. 22 iPRECIO webinar, June 16th 2021 | Business Use Only Programmable pumps for compounds delivery in oncology research: implication for refinement and reduction of animal use Validation study in freely moving grouped housed nude rats via an programmable iPRECIO pump using tool compound B infusion (i.v. via jugular vein) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Tail vein blood collection in conscious rats Predicted blood levels at SS (µmol/L) Observed blood levels at SS (µmol/L) Compound B (r2 =0.94, p<0.0001, n=12) Dose (mg/ml) Infusion rate (µl/h) 1 4 1.5 4 2 4 2.5 4 3.5 4 4 4 8 4 1.4 10
  • 23. 23 iPRECIO webinar, June 16th 2021 | Business Use Only Programmable pumps for compounds delivery in oncology research: implication for refinement and reduction of animal use Validation study in freely moving grouped housed nude rats via an programmable iPRECIO pump using tool compound B infusion (i.v. via jugular vein) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Tail vein blood collection in conscious rats Predicted blood levels at SS (µmol/L) Observed blood levels at SS (µmol/L) Compound B (r2 =0.94, p<0.0001, n=12) ALZET® osmotic pump Dose (mg/ml) Infusion rate (µl/h) 1 4 1.5 4 2 4 2.5 4 3.5 4 4 4 8 4 1.4 10 Dose (mg/ml) Infusion rate (µl/h) 10 0.25 1002
  • 24. 24 iPRECIO webinar, June 16th 2021 | Business Use Only Programmable pumps for compounds delivery in oncology research: implication for refinement and reduction of animal use Validation study in freely moving grouped housed nude mice via an programmable iPRECIO pump using tool compound A infusion (i.v. via jugular vein) Dose (mg/ml) Infusion rate (µl/h) 3 2.2 6 2.2 6 4.5 SMP-310/R Compound A 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Tail vein blood collection in conscious mice Predicted blood levels at SS (µmol/L) Observed blood levels at SS (µmol/L) Compound A (r2 =1, p<0.02, n=3)
  • 25. 25 iPRECIO webinar, June 16th 2021 | Business Use Only Programmable pumps for compounds delivery in oncology research: implication for refinement and reduction of animal use Validation study in freely moving grouped housed nude mice via an programmable iPRECIO pump using tool compound B infusion (i.v. via jugular vein) SMP-310/R 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 Tail vein blood collection in conscious mice Predicted blood levels at SS (µmol/L) Observed blood levels at SS (µmol/L) Compound B (r2 =1, p<0.001, n=4) Dose (mg/ml) Infusion rate (µl/h) 0.2 4 0.3 4 0.6 4 1.2 4 Compound B
  • 26. 26 iPRECIO webinar, June 16th 2021 | Business Use Only Programmable pumps for compounds delivery in oncology research: implication for refinement and reduction of animal use Validation study in freely moving grouped housed nude mice via an programmable iPRECIO pump using tool compound C infusion (i.v. via jugular vein) SMP-310/R 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 Tail vein blood collection in conscious mice Predicted blood levels at SS (µmol/L) Observed blood levels at SS (µmol/L) Compound C (r2 =0.99, p<0.0002, n=4) Dose (mg/ml) Infusion rate (µl/h) 2 4 3 4 5 4 10 4 Compound C
  • 27. 27 iPRECIO webinar, June 16th 2021 | Business Use Only Programmable pumps for compounds delivery in oncology research: implication for refinement and reduction of animal use Validation study in freely moving grouped housed nude mice and rats via an programmable iPRECIO pump using all tested doses and compound (i.v. via jugular vein) 0.01 0.1 1 10 0.01 0.1 1 10 100 Predicted blood levels at SS (µmol/L) Observed blood levels at SS (µmol/L) r2 = 0.94, p<0.0001, n=28 ➢ 2 species (mice and rats) ➢ 2 pumps (SMP-200 and SMP-310R) ➢ 3 tool compounds ➢ 24 doses ➢ 7 infusion rates (2.2 to 20 µl/h)  r2 = 0.94, p<0.0001, n=28
  • 28. 28 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: Study design is based on the assumption of a causal relationship between exposure, target inhibition and its anti-tumor activity ➢ Rat1myrp110α tumors ulin i.v. infusion O ➢ Rat1myrp110alpha tumors ➢ Iprecio pumps (SMP-200) T/C: 1.0 0.2 Reg: 0.4
  • 29. 29 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: Study design is based on the assumption of a causal relationship between exposure, target inhibition and its anti-tumor activity ➢ Rat1myrp110α tumors ulin i.v. infusion O ➢ Rat1myrp110alpha tumors ➢ Iprecio pumps (SMP-200) 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 0.0 0.5 1.0 2.0 2.5 3.0 3.5 Tumor growth inhibition (ratio) Compound plasma levels (mol/L at Css) Regression 1.5 0.7 Stasis 50% regression
  • 30. 30 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: Study design is based on the assumption of a causal relationship between exposure, target inhibition and its anti-tumor activity 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 0.0 0.5 1.0 2.0 2.5 3.0 3.5 Tumor growth inhibition (ratio) Compound plasma levels (mol/L at Css) Regression 1.5 0.7 0.1 1 10 100 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Compound plasma concentration (mol/L) Tumor PD ( % average vehicle control ) r2 =0.75, n=19 1 . 5 0 . 7 Stasis 50% regression
  • 31. Stasis 50% regression 31 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: Study design is based on the assumption of a causal relationship between exposure, target inhibition and its anti-tumor activity 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Tumor growth inhibition (ratio) Compound plasma levels (mol/L at Css) Regression 0.1 1 10 100 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Compound plasma concentration (mol/L) Tumor PD ( % average vehicle control ) r2 =0.75, n=19 1 . 5 0 . 7 Using this PK/PD modeling approach, we could demonstrate that the anti-tumor activity is Cthrough (time over threshold) driven and not Cmax dependent
  • 32. 32 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: Study design is based on the assumption of a causal relationship between exposure, target inhibition and its anti-tumor activity ➢ Tumor ➢ iPRECIO pump infusion iPRECIO pumps (SMP-310R) 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Tumor growth inhibition (ratio) Compound plasma levels (mol/L at Css) Regression in nude rats in nude mice PDX tumor Stasis 50% regression
  • 33. 33 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: Study design is based on the assumption of a causal relationship between exposure, target inhibition and its anti-tumor activity 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Tumor growth inhibition (ratio) Compound plasma levels (mol/L at Css) Regression in nude rats in nude mice 0.1 1 10 100 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Compound plasma concentration (mol/L) Tumor PD ( % average vehicle control ) r2 =0.76, n=26 1 . 5 0 . 7 in nude rats in nude mice Stasis 50% regression
  • 34. 34 iPRECIO webinar, June 16th 2021 | Business Use Only Programmable pumps for compounds delivery in oncology research: implication for refinement and reduction of animal use ➢ Anticancer agents often have a narrow therapeutic index (TI), requiring precise dosing to ensure sufficient exposure for clinical activity while minimizing toxicity
  • 35. 35 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: How can we improve the assessment of therapeutic index (TI) ? Conventional (Oral / IV) • Multiple injection/dose • Low TI, large dose, • Side effects (drug, dose, administration) • Poor Compliance Ze • • • Oral treatment (per os) ➢ Multiple dose ➢ Large dose ➢ Side effects
  • 36. 36 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: How can we improve the assessment of therapeutic index (TI) ? Conventional (Oral / IV) • Multiple injection/dose • Low TI, large dose, • Side effects (drug, dose, administration) • Poor Compliance Zero Order Kinetics • Improved therapeutic efficacy • Reduced drug dose, • Reduced Side effects Better compliance Conventional (Oral / IV) • Multiple injection/dose • Low TI, large dose, • Side effects (drug, dose, administration) • Poor Compliance Zero Order Kinetics • Improved therapeutic efficacy • Reduced drug dose, • Reduced Side effects Better compliance Oral treatment (per os) Pump delivery ➢ Multiple dose ➢ Large dose ➢ Side effects ➢ Sustained exposure ➢ Reduced drug dose ➢ Reduced side effects
  • 37. 37 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: How can we improve the assessment of therapeutic index (TI) ? 0 2 4 6 8 10 12 0 100 200 300 400 500 600 Time post treatment (days) Blood Levels (nmol/L total, mean  SEM) Start Infusion i.v. 0 2 4 6 8 10 -20 -15 -10 -5 0 5 10 15 20 Time post treatment (days) Change in body weight (% vs day 0, mean  SEM) Start Infusion i.v. 0.2 mg/ml at 4 l/h inf. Compound B: (n=2) 0.6 mg/ml at 4 l/h inf. 0.3 mg/ml at 4 l/h inf. 1.2 mg/ml at 4 l/h inf. 0 2 4 6 8 10 12 -20 -15 -10 -5 0 5 10 15 20 Time post treatment (days) Change in body weight (% vs day 0, mean  SEM) Start Infusion i.v. 0.2 mg/ml at 4 l/h inf. Compound B: (n=2) 0.6 mg/ml at 4 l/h inf. 0.3 mg/ml at 4 l/h inf. 1.2 mg/ml at 4 l/h inf. (n=2) ➢ Experimental design
  • 38. 38 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: How can we improve the assessment of therapeutic index (TI) ? 0 2 4 6 8 10 12 0 100 200 300 400 500 600 Time post treatment (days) Blood Levels (nmol/L total, mean  SEM) Start Infusion i.v. 0 2 4 6 8 10 -20 -15 -10 -5 0 Time post treatment (days) Change in b (% vs day 0, m 0.2 mg/ml at 4 l/h inf. Compound B: (n=2) 0.6 mg/ml at 4 l/h inf. 0.3 mg/ml at 4 l/h inf. 1.2 mg/ml at 4 l/h inf. 0 2 4 6 8 10 12 -20 -15 -10 -5 0 5 10 15 20 Time post treatment (days) Change in body weight (% vs day 0, mean  SEM) Start Infusion i.v. 0.2 mg/ml at 4 l/h inf. Compound B: (n=2) 0.6 mg/ml at 4 l/h inf. 0.3 mg/ml at 4 l/h inf. 1.2 mg/ml at 4 l/h inf. (n=2) ➢ Blood glucose measurement ➢ Experimental design
  • 39. 39 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: 0 2 4 6 8 10 12 0 100 200 300 400 500 600 Time post treatment (days) Blood Levels (nmol/L total, mean  SEM) Start Infusion i.v. 0 2 4 6 8 10 -20 -15 -10 -5 0 Time post treatment (days) Change in b (% vs day 0, m 0.2 mg/ml at 4 l/h inf. Compound B: (n=2) 0.6 mg/ml at 4 l/h inf. 0.3 mg/ml at 4 l/h inf. 1.2 mg/ml at 4 l/h inf. 0 2 4 6 8 10 12 -20 -15 -10 -5 0 5 10 15 20 Time post treatment (days) Change in body weight (% vs day 0, mean  SEM) Start Infusion i.v. 0.2 mg/ml at 4 l/h inf. Compound B: (n=2) 0.6 mg/ml at 4 l/h inf. 0.3 mg/ml at 4 l/h inf. 1.2 mg/ml at 4 l/h inf. 0 2 4 6 8 10 12 0 5 10 15 20 25 Time post treatment (days) Blood Glucose Levels (mmol/l, mean  SEM) Start Infusion i.v. 0.2 mg/ml at 4 l/h inf. DZA621: (n=2) 0.6 mg/ml at 4 l/h inf. 0.3 mg/ml at 4 l/h inf. 1.2 mg/ml at 4 l/h inf. 0 2 4 6 8 10 12 0 5 10 15 Time post treatment (days) Plasma Insulin Levels (ng/ml, mean  SEM) Start Infusion i.v. 0.2 mg/ml at 4 l/h inf. DZA621: (n=2) 0.6 mg/ml at 4 l/h inf. 0.3 mg/ml at 4 l/h inf. 1.2 mg/ml at 4 l/h inf. (n=2) How can we improve the assessment of therapeutic index (TI) ? ➢ Experimental design
  • 40. 40 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 0.0 0.5 1.0 2.0 2.5 3.0 3.5 Tumor growth inhibition (ratio) Compound plasma levels (mol/L at Css) Regression 1.5 0.01 0.1 1 10 100 0 5 10 15 20 25 30 Compound plasma levels (mol/L) Blood Glucose levels (mmol/L) G2 G3 G1 5 How can we improve the assessment of therapeutic index (TI) for compound A? ➢ TI in conscious rats = 5 µmol/L (glucose ≥11 mmol/L) / 1.5 µmol/L (50% tumor regression) → 3.3 Stasis 50% regression
  • 41. 41 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: How can we improve the robustness and translatability of our modeling activities? Tumor xenograft model Radio-telemetry Glucose sensor  intra-arterial Compound A →  Around-the-clock remote monitoring
  • 42. 42 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: How can we improve the robustness and translatability of our modeling activities? SMP-310R  Around-the-clock remote monitoring combined with in-vivo programmable pumps
  • 43. 43 iPRECIO webinar, June 16th 2021 | Business Use Only PK/PD modeling to integrate quantitative information about the pharmacologic properties of a compound with its pharmacokinetics: How can we improve the robustness and translatability of our modeling activities? (adapted from Tuntland et al., Frontiers in Pharmacology Vol.5, Article 174, 2014) ➢ parenteral drug-delivering technologies: - less variability associated with PK (similar absorption profile per animal following i.v. route) foreseen - no temporal delays in effects (Hysteresis) - lower numbers of animals needed to achieve statistically significant results - ability to explore varying degrees of sustained target engagement having an important role in facilitating validation of novel targets ➢ Caveats of i.v. drug delivery systems: - target steady-state concentration (Css) should be achieved rapidly - good solubility and stability at 37°C in a compatible vehicle volume - requested infusion rate that is acceptable for the preclinical species - duration of the infusion depending on the preclinical species - battery life limitation
  • 44. 44 iPRECIO webinar, June 16th 2021 | Business Use Only Programmable pumps for compounds delivery in oncology research: implication for refinement and reduction of animal use Summary and conclusions (1) ➢ Validation of the iPRECIO pumps (SMP-200 and SMP310/R) in terms of accuracy and reliability were successfully achieved across several tool compounds ➢ Parenteral delivery via implantable pumps allows: ➢ unprecedented PK-PD correlations and corresponding antitumor activity to better understand mechanism of action and dose response across different species and tumor models ➢ drug delivery without interfering with normal activity in group-housed animals, reducing stress and data variability (refinement) leading to lower numbers of animals needed to achieve statistical power (reduction)
  • 45. 45 iPRECIO webinar, June 16th 2021 | Business Use Only Programmable pumps for compounds delivery in oncology research: implication for refinement and reduction of animal use Summary and conclusions (2) ➢ In addition, simultaneous use of complementary novel technologies within the same animal (like radio-telemetry and programmable pumps) will enable advances in the understanding of complex physiological regulation mechanism following pharmacological intervention, possibly leading to improved therapies in the clinic by enhancing translatability of pre-clinical data
  • 46. Thank you for participating! Christian Schnell Associate Director Oncology NIBR Novartis in Basel CLICK HERE to learn more and watch the webinar