Over the past decade, there is increasing interest in establishing a robust mechanistic understanding of the pharmacokinetics–pharmacodynamics (PK–PD) relationship of a given compound and its connection to the anti-tumor efficacy profile. In this webinar, Christian describes the validation studies performed in his pharmacology unit in rats and mice. Accurate PK-PD assessment and corresponding antitumor activity were assessed among several drug discovery programs. He provides evidence that the investigation of such compound specific relationships are a pre-requisite for the planning of meaningful efficacy studies in preclinical models and the subsequent translation into patient’s clinical trials. Taking into account best practices and the 3Rs of animal research (Reduction, Refinement and Replacement), implantable pumps are one of the most effective ways to deliver drugs without interfering with normal animal activity, especially in a group-housed environment. Long term, chronic dosing regimens and quantitative pharmacology for PK-PD may be scheduled and executed with minimal human intervention and animal stress, and in doing so reducing the impact of these important confounding factors. Therefore, data variability will be lower leading to reduction of animal use. Moreover, it should be emphasized that the simultaneous use of complementary novel technologies within the same animal (like radio-telemetry and programmable pumps as described here) will enable advances in the understanding of complex physiological regulation mechanism following pharmacological intervention, possibly leading to improved therapies in the clinic.

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
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