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

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Christian Schnell
Associate Director Oncology NIBR
Novartis in Basel
Programmable Pumps for
Compound Delivery in
Oncology ...

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An expert shares describes the
validation studies performed in his
pharmacology unit in rats and mice.
Programmable Pumps ...

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Christian Schnell
Associate Director Oncology NIBR
Novartis in Basel
Programmable Pumps for
Compound Delivery in
Oncology ...

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

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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.


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.

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

  1. 1. Christian Schnell Associate Director Oncology NIBR Novartis in Basel Programmable Pumps for Compound Delivery in Oncology Research
  2. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 46. 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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