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Towards the prediction of cardiovascular effects in human Nelleke - - PowerPoint PPT Presentation

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PAGE 2013; Glasgow Towards the prediction of cardiovascular effects in human Nelleke Snelder , Bart Ploeger, Olivier Luttringer, Dean Rigel, Fumin Fu, Michael Beil, Donald Stanski and Meindert Danhof n.snelder@lapp.nl 1 fingolimod

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SLIDE 1

1

Towards the prediction of cardiovascular effects in human

PAGE 2013; Glasgow

Nelleke Snelder, Bart Ploeger, Olivier Luttringer, Dean Rigel, Fumin Fu, Michael Beil, Donald Stanski and Meindert Danhof

n.snelder@lapp.nl

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SLIDE 2

Introduction 2

fingolimod

  • Fingolimod is effective in the treatment of multiple sclerosis
  • In 2010 fingolimod was approved at a dose of 0.5 mg
  • A dose of 0.5 mg resulted in:
  • A small increase in blood pressure
  • 1-2 mm Hg after 2 months
  • A transient bradycardia
  • 8 bpm at 5 hours after the 1st dose

(attenuation after 6 hours)

  • Are cardiovascular effects of relevance for fingolimod?
  • Is the effect reversible?
  • What are the long term effects?
  • Can early selection of follow-up compounds be improved?

Event fingolimod 0.5 mg (N=425) placebo (N=418)

Hypertension 26 (6.1 %) 16 (3.8 %) Bradycardia 9 (2.1 %) 3 (0.7 %)

Freedoms trial: patients with MS

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SLIDE 3

Introduction 3

Effect of fingolimod on the CVS

  • Sphingosine-1-phosphate (S1P)

is a major regulator of vascular and immune systems

  • Fingolimod is a S1P agonist
  • Subtypes S1P1, S1P3,

S1P4 and S1P5

  • The mechanism of action needs further investigation

Vascular Endothelium Atrial myocytes Bronchial smooth muscle Vascular smooth muscle Heart-rate AV Conduction Airway resistance Vascular tone

S1P3 (S1P1 in humans?) S1P3 (S1P1, S1P2?) S1P3 / S1P1? S1P3 (S1P1, S1P2?)

Angiogenesis

S1P1 S1P1/ S1P3

Barrier function

S1P

Vasocontriction/dilation

S1P

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SLIDE 4

Introduction 4

  • Physiological principles of BP regulation
  • Preclinical research may contribute to a quantitative understanding
  • f the cardiovascular system (CVS)

Hypothesis: a better understanding of the mechanism of action of compounds can result from a quantitative understanding of the system

Mean Arterial Pressure (MAP) Cardiac Output (CO) Stroke Volume (SV) Heart Rate (HR) Total Peripheral Resistance (TPR) Cardiac Output (CO)

= x = x

  • Several feedback mechanism:
  • Baroreflex system
  • Renin-Angiotensin-Aldosterone System
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SLIDE 5

Objectives 5

Objectives

1) Development of a systems pharmacology model characterizing the effects of drugs on the interrelationship between BP, TPR, CO, HR and SV

⇒ Drug-independent CVS model

2) Characterization of the effect of fingolimod on the CVS using the developed systems pharmacology model

⇒ A better understanding of mechanisms leading to

cardiovascular effects following administration of fingolimod

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SLIDE 6

6

CVS model

PAGE 2013 Glasgow

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SLIDE 7

CVS model 7

Collect preclinical data from different drugs acting on CVS to identify system specific parameters

  • Compounds:

2-3 rats per compound

  • Study design:

Effect on HR Effect on TPR Effect on SV

atropine (M2 receptor antagonist) amlodipine (calcium channel blocker) amiloride (diuretic) propanolol (non-selectiveβ blocker) enalapril (ACE-inhibitor) enalapril (ACE-inhibitor) fasudil (rho-kinase inhibitor) HCTZ (diuretic) prazosin (selective α1 blocker)

Baseline measurements Day 1 A different dose each day Day 2-5 Washout Days 6-7

BP, CO and TPR measured

Baseline measurements Day 1 A different dose each day Day 2-5 Washout Days 6-7

BP, CO and TPR measured

Baseline measurements Day 1 A different dose each day Day 2-5 Washout Days 6-7

BP, CO and TPR measured

BP, CO and HR are measured

Ascending aortic flow probe arterial radiotransmitter Electical swivel

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SLIDE 8

CVS model 8

System-specific Model

  • Linked turnover model with

differential equations for HR, SV and TPR linked by negative feedback through MAP

  • Direct inverse relationship

between HR and SV

  • Circadian rhythm: two cosine

functions, one influencing HR and one influencing TPR

  • Handling effect: exponentially decreasing functions influencing Kin_HR and Kin_TPR
  • Differences between hypertensive and normotensive rats:
  • Different baseline
  • The feedback was found to be dependent on the baseline blood pressure

Kin_TPR

  • FB

Kin_SV

SVT T TP PR R M MA AP P

kout_SV kout_TPR Kin_HR

HR

kout_HR

  • FB
  • FB

TPR CO MAP SV HR CO HR)) LN(HR/BSL_ * HR_SV

  • (1

* SV SV

T

⋅ = ⋅ = =

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SLIDE 9

9

120 140 M AP m m HG 150 250 HR beats/m in 40 50 60 70 CO m L/m in

Negative effect on HR

4 0.22 0.26 0.30 SV m L/beat 2.3 2.5 2.7 TPR m m HG /(m L/m in) 12 24 36 T im e (h )

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SLIDE 10

10

320 360 400 HR beats/m in 70 80 90 CO m L/m in 0.22 0.24 SV m L/beat 1.2 1.8 TPR m m HG /(m L/m in) 12 24 36 T im e (h )

Negative effect on TPR

100 130 M AP m m HG

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SLIDE 11

CVS model 11

  • PKPD modelling approach (NONMEM):

PK models from literature

  • Drug effects on HR, SV or TPR
  • Best drug effect models:
  • The effect of ACE inhibitors is delayed. This was described by an effect compartment model

Kin_TPR

  • FB

Kin_SV

C SVT T TP PR R M MA AP P

kout_SV kout_TPR Kin_HR

C HR

kout_HR

  • FB
  • FB

TPR CO MAP SV HR CO HR)) LN(HR/BSL_ * HR_SV

  • (1

* SV SV

T

⋅ = ⋅ = =

Drug-specific Model

EFF_TPR EFF_HR EFF_SV

Compound Effect site Drug effect model

amiloride SV Emax with Emax fixed to 1 amlodipine TPR Emax with Emax fixed to 1 atropine HR Linear enalapril TPR and SV Emax with Emax fixed to 1 fasudil TPR Emax with Emax fixed to 1 HCTZ SV Emax with Emax fixed to 1 prazosin TPR Power propranolol HR No effect

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SLIDE 12

CVS model 12 Derived Measured

Adequate description of the effect of amlodipine

hypertensive rats

Individual prediction Population prediction (n=38) Observations (colored per rat)

  • 100

140 180 M AP m m HG Veh icle 0.3 m g/kg 1 m g/kg 3 m g/kg 10 m g/kg 250 400 HR beats/m in 50 70 90 CO m L/m in 0.20 0.30 SV m L/beat 1.0 2.0 3.0 TPR m m HG /(m L/m in) 12 24 36 48 60 72 84 96 108 132 156 T im e (h )

Effect on all five endpoints can be described by a single drug effect on TPR

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SLIDE 13

CVS model 13

Adequate description of the effect of amlodipine

normotensive rats

Individual prediction Population prediction (n=38) Observations (colored per rat)

  • 80

100 M AP m m HG Veh icle 0.3 m g/kg 1 m g/kg 3 m g/kg 10 m g/kg 250 400 HR beats/m in 120 160 CO m L/m in 0.35 0.45 SV m L/beat 0.4 0.7 1.0 TPR m m HG /(m L/m in) 12 24 36 48 60 72 84 96 108 132 156 T im e (h )

Effect of amlodipine described adequately in normotensive rats Derived Measured

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SLIDE 14

CVS model 14

Conclusions and Future perspective CVS model

  • A systems pharmacology model was developed to describe

the interrelationship between MAP, CO, HR, SV and TPR

  • The developed systems pharmacology model can be used

to quantify cardiovascular drug effects of novel compounds

  • Can the CVS model be used to elucidate the mechanism
  • f action of novel compounds?
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SLIDE 15

15

Application of the developed drug- independent CVS model to fingolimod

PAGE 2013 Glasgow

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SLIDE 16

Effect of fingolimod on the CVS 16

400 800 1200 Time (h) 280 300 320 340 360 beats/min 400 800 1200 Time (h) 120 130 140 150 160 mmHg

MAP

400 800 1200 Time (h) 1.0 1.2 1.4 1.6 1.8 mmHG/(mL/min)

TPR TPR

400 800 1200 Time (h) 80 90 100 110 120 mL/min 400 800 1200 Time (h) 0.25 0.30 0.35 0.40 0.45 0.50 mL/beat

CO SV SV HR

Prediction of the effect of fingolimod on the CVS

Example of a typical hyeprtensive rat (10 mg/kg)

Experimental design:

  • Dose: 0, 0.1, 0.3, 1, 3 and 10 mg/kg
  • MD administration (4 weeks)
  • Hypertensive and normotensive rats
  • 32 rats
  • Measured: MAP, HR and CO
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SLIDE 17

Effect of fingolimod on the CVS 17

Prediction of the effect of fingolimod on the CVS

  • The CVS model was used to

predict the effect of fingolimod

  • System-specific parameters were fixed

Kin_TPR

  • FB

Kin_SV

C SVT T TP PR R M MA AP P

kout_SV kout_TPR Kin_HR

C HR

kout_HR

  • FB
  • FB

TPR CO MAP SV HR CO HR)) LN(HR/BSL_ * HR_SV

  • (1

* SV SV

T

⋅ = ⋅ = =

400 800 1200 Time (h) 280 300 320 340 360 beats/min 400 800 1200 Time (h) 120 130 140 150 160 mmHg

MAP

400 800 1200 Time (h) 1.0 1.2 1.4 1.6 1.8 mmHG/(mL/min)

TPR TPR

400 800 1200 Time (h) 80 90 100 110 120 mL/min 400 800 1200 Time (h) 0.25 0.30 0.35 0.40 0.45 0.50 mL/beat

CO SV SV HR

Hypothesis 1: effect is on HR

The CVS model indicates that it is not likely that the primary effect of fingolimod is on HR

EFF_HR

400 800 1200 Time (h) 300 350 400 450 beats/min 400 800 1200 Time (h) 120 130 140 150 160 mmHg

MAP

400 800 1200 Time (h) 0.9 1.2 1.5 1.8 mmHG/(mL/min)

TPR TPR

400 800 1200 Time (h) 80 95 110 125 140 mL/min 400 800 1200 Time (h) 0.25 0.30 0.35 0.40 0.45 0.50 mL/beat

CO SV SV HR

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SLIDE 18

Effect of fingolimod on the CVS 18

400 800 1200 Time (h) 300 350 400 450 beats/min 400 800 1200 Time (h) 120 130 140 150 160 mmHg

MAP

400 800 1200 Time (h) 0.9 1.2 1.5 1.8 mmHG/(mL/min)

TPR TPR

400 800 1200 Time (h) 80 95 110 125 140 mL/min 400 800 1200 Time (h) 0.25 0.30 0.35 0.40 0.45 0.50 mL/beat

CO SV SV HR

400 800 1200 Time (h) 250 270 290 310 330 350 beats/min 400 800 1200 Time (h) 120 130 140 150 160 mmHg

MAP

400 800 1200 Time (h) 0.9 1.2 1.5 1.8 mmHG/(mL/min)

TPR TPR

400 800 1200 Time (h) 80 95 110 125 140 mL/min 400 800 1200 Time (h) 0.25 0.30 0.35 0.40 0.45 0.50 mL/beat

CO SV SV HR

Prediction of the effect of fingolimod on the CVS

  • The CVS model was used to

predict the effect of fingolimod

  • System-specific parameters were fixed

Kin_TPR

  • FB

Kin_SV

C SVT T TP PR R M MA AP P

kout_SV kout_TPR Kin_HR

C HR

kout_HR

  • FB
  • FB

TPR CO MAP SV HR CO HR)) LN(HR/BSL_ * HR_SV

  • (1

* SV SV

T

⋅ = ⋅ = =

The CVS model indicates that the primary effect of fingolimod is on TPR

There may be a secondary effect on HR

Hypothesis 2: effect is on TPR

EFF_TPR

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SLIDE 19

Effect of fingolimod on the CVS 19

Kin_TPR

  • FB

Kin_SV

C SVT T TP PR R M MA AP P

kout_SV kout_TPR Kin_HR

C HR

kout_HR

  • FB
  • FB

TPR CO MAP SV HR CO HR)) LN(HR/BSL_ * HR_SV

  • (1

* SV SV

T

⋅ = ⋅ = =

Model to describe the effect of fingolimod

  • PKPD modelling approach:
  • PK of the pro-drug fingolimod and its

active metabolite were described simultaneously by a compartmental model

  • The effect of fingolimod on the CVS was

described by a combination of 3 effects:

  • Fast positive effect on TPR: log-linear model
  • Slow positive effect on TPR: linear model
  • Slow structural effect only in hypertensive rat at high doses
  • Transient negative effect on HR: power model
  • Tolerance was described by feedback model - type 1

Kin

R

Kout·M

M

Ktol·R Ktol·M

Fast positive EFF_TPR Transient negative EFF_HR Slow positive disease altering EFF_TPR Slow positive EFF_TPR

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SLIDE 20

Effect of fingolimod on the CVS 20

Adequate description of the effect of fingolimod on the CVS in hypertensive rat

Individual prediction Observations (colored per rat)

  • Example: Dose 10 mg/kg

600 1200 1800 2400 Time (h) 250 270 290 310 330 350 beats/min 600 1200 1800 2400 Time (h) 120 140 160 180 200 mmHg

MAP

600 1200 1800 2400 Time (h) 1.00 1.75 2.50 3.25 4.00 mmHG/(mL/min) 600 1200 1800 2400 Time (h) 40 60 80 100 120 mL/min

CO

600 1200 1800 2400 Time (h) 0.1 0.2 0.3 0.4 0.5 mL/beat

TPR SV SV HR

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SLIDE 21

Effect of fingolimod on the CVS 21

Adequate description of the effect of fingolimod on the CVS in normotensive rat

Example: Dose 10 mg/kg Individual prediction Observations (colored per rat)

  • 600

1200 1800 2400 Time (h) 250 270 290 310 330 350 beats/min 600 1200 1800 2400 Time (h) 80 95 110 125 140 mmHg

MAP

600 1200 1800 2400 Time (h) 0.5 1.0 1.5 2.0 mmHG/(mL/min)

TPR

600 1200 1800 2400 Time (h) 60 80 100 120 140 mL/min

CO

600 1200 1800 2400 Time (h) 0.1 0.2 0.3 0.4 0.5 mL/beat

SV HR

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SLIDE 22

Effect of fingolimod on the CVS 22

Conclusions Effect of fingolimod on the CVS

  • The effect of fingolimod on MAP, CO, HR, SV and TPR was

characterized adequately using the developed CVS model

  • The CVS model was used to elucidate the mechanism of action of the

effect of fingolimod on the CVS

  • The long term effect of fingolimod on BP resulted from an effect on TPR
  • The primary effect was reversible
  • The secondary effect, which is relevant in hypertensive rat for extreme high doses,

was structural

  • A transient effect on HR was quantified
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SLIDE 23

Conclusions 23

General Conclusions and Future Perspectives

  • A systems pharmacology model was developed to describe the

interrelationship between MAP, CO, HR, SV and TPR in rat

  • The CVS model can be used to elucidate the mechanism of action
  • f novel compounds
  • Future research: prediction of the clinical response based on

preclinical data for fingolimod and other (follow-up) compounds

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SLIDE 24

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Acknowledgements

Novartis-Leiden collaboration

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SLIDE 25

25

Further reading