The action pharmacological profiles
This presentation is the property of its rightful owner.
Sponsored Links
1 / 30

The action – pharmacological profiles PowerPoint PPT Presentation


  • 59 Views
  • Uploaded on
  • Presentation posted in: General

The action – pharmacological profiles. Tim Heise. Germany. Basal insulins: GIR profiles in patients with T1DM. Subject no: 222. Subject no: 224. Subject no: 228. 7. 7. 7. 6. 6. 6. NPH (0.4 U/kg). 5. 5. 5. 4. 4. 4. GIR (mg/kg/min). 3. 3. 3. 2. 2. 2. 1. 1. 1. 0. 0. 0.

Download Presentation

The action – pharmacological profiles

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


The action pharmacological profiles

The action – pharmacological profiles

Tim Heise

Germany


Basal insulins gir profiles in patients with t1dm

Basal insulins: GIR profiles in patients with T1DM

Subject no: 222

Subject no: 224

Subject no: 228

7

7

7

6

6

6

NPH (0.4 U/kg)

5

5

5

4

4

4

GIR (mg/kg/min)

3

3

3

2

2

2

1

1

1

0

0

0

0

4

8

12

16

20

24

0

4

8

12

16

20

24

0

4

8

12

16

20

24

Subject no: 211

Subject no: 213

Subject no: 217

7

7

7

6

6

6

5

5

5

IGlar (0.4 U/kg)

4

4

4

GIR (mg/kg/min)

3

3

3

2

2

2

1

1

1

0

0

0

0

4

8

12

16

20

24

0

4

8

12

16

20

24

0

4

8

12

16

20

24

Subject no: 210

Subject no: 215

Subject no: 218

7

7

7

6

6

6

IDet (0.4 U/kg)

5

5

5

4

4

4

GIR (mg/kg/min)

3

3

3

2

2

2

1

1

1

0

0

0

0

4

8

12

16

20

24

0

4

8

12

16

20

24

0

4

8

12

16

20

24

Elapsed time (hours)

Elapsed time (hours)

Elapsed time (hours)

GIR, glucose infusion rate; IDet, insulin detemir; IGlar, insulnglargine

Heise et al. Diabetes 2004;53:1614–20


Basal insulins gir profiles in patients with t2dm

Basal insulins: GIR profiles in patients with T2DM

8

NPH

IDet

IGlar

Glucose infusion rate (µmol/kg/min)

6

4

2

0

0

4

8

12

16

20

24

28

32

Time (hours post-dosing)

Lucidi et al. Diabetes Care 2011;34:1312–14


Ideg formation of multi hexamers

IDeg: Formation of multi-hexamers

[Zn2+ ]

Subcutaneous depot

IDeg

multi-hexamers

Zinc diffuses slowly causing individual hexamers to disassemble, releasing

monomers

Monomers are absorbed from the depot into the circulation


Objectives of developing insulin degludec

Objectives of developing insulin degludec

  • Ultra-long duration of action:

    • Control fasting blood glucose with one injection in all individuals

  • Flat time–action profile:

    • Lower risk of hypoglycaemia

  • Low day-to-day variability:

    • Less hypoglycaemia and hyperglycaemia


Mathematical model 24h insulin

Mathematical model: 24h insulin


Mathematical model 72h insulin

Mathematical model: 72h insulin


Ultra long action peakless insulin

Ultra-long action = Peakless insulin


Ideg reaching steady state

IDeg: Reaching steady state

10,000

9000

8000

7000

ITC IDeg (pmol/L)

6000

5000

4000

3000

2000

1000

0

192

0

24

72

48

96

120

144

168

Time (hours)

ITC, insulin trough concentration

Heise et al. ADA 2011; 37-P LB;

Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P) (NN1250-1993)


Ideg pk profile at steady state in t1dm

IDeg PK profile at steady state in T1DM

10000

IDeg (pmol/L)

1000

100

0

4

8

12

16

20

24

Time since last injection (hours)

Jonassen et al. Diabetes 2010;59(Suppl. 1):0039-OR


Ideg pd profile at steady state in t1dm

IDeg PD profile at steady state in T1DM

6

5

GIR (mg/kg/min)

4

3

2

1

0

0

2

4

6

8

10

12

14

16

18

20

22

24

Time (hours)

IDeg = 0.4 U/kg

Heise et al. ADA 2011; 37-P LB;

Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P) (NN1250-1993)


Ideg bg control over 42 hours in t1dm

IDeg: BG control over 42 hours in T1DM

11.1

Blood glucose level (mmol/L)

8.3

5.6

2.8

0.0

42

0

6

12

18

24

30

36

Time since injection (hours)

IDeg = 0.6 U/kg

Kurtzhals et al. ADA 2011; 32-LB;

Kurtzhals et al. Diabetologia 2011;54(Suppl. 1):S426 (1049-P) (MoP + NN1250-1993)


Ideg pd profiles in t2dm at steady state

IDeg PD profiles in T2DM at steady state

0.8 U/kg

0.6 U/kg

0.4 U/kg

Nosek et al. ADA 2011; 49-P LB;

Nosek et al. Diabetologia 2011;54(Suppl. 1):S429 (1055-P) (NN1250-1987)


Ideg in t2dm at steady state

IDeg in T2DM at steady state

AUCGIR,0–12h

AUCGIR,12–24h

AUC, area under the curve

Nosek et al. ADA 2011; 49-P LB;

Nosek et al. Diabetologia 2011;54(Suppl. 1):S429 (1055-P) (NN1250-1987)


Summary from steady state trials

Summary from steady-state trials

In these trials, the glucose-lowering effect of IDeg

  • is flat and stable

  • is evenly distributed over a 24-hour period

  • lasts beyond 24 hours in all individuals studied


Pk pd data and half life for ideg and iglar

PK/PD data and half-life for IDeg and IGlar

Second treatment period

8 days

First treatment period

8 days

7–21 days

washout period

Follow-up

7–21 days

Screening

2–21 days

IDeg

0.4, 0.6 or 0.8 U/kg

IDeg

0.4, 0.6 or 0.8 U/kg

n=66

IGlar

0.4, 0.6 or 0.8 U/kg

IGlar

0.4, 0.6 or 0.8 U/kg

  • Inclusion criteria

  • T1DM 12 months

  • HbA1c 6.7–10.0%

  • BMI 18–28 kg/m2

  • Age 18–65 years

42-hour euglycaemic clamp at steady state

Clinical trial.gov identifier: NCT01114542

Heise et al. ADA 2011; 37-P LB;

Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P) (NN1250-1993)


Serum concentration and half life of ideg and iglar

Serum concentration and half-life of IDeg and IGlar

IDeg 0.8 U/kg

IGlar 0.8 U/kg

Heise et al. ADA 2011; 37-P LB;

Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P) (NN1250-1993)


Distribution of glucose lowering effect over 24 hours at steady state

Distribution of glucose-lowering effect over 24 hours at steady state

AUCGIR,t, total area under the glucose-infusion rate curve over 24 hours (in steady state)

Heise et al. ADA 2011; 37-P LB;

Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P) (NN1250-1993)


Summary of half life study

Summary of half-life study

Insulin degludec

  • Half-life of more than 25 hours(twice as long as that for IGlar)

  • More consistent and evenly distributed metabolic effect across a 24-hour dosing interval than IGlar

Heise et al. ADA 2011; 37-P LB;

Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P) (NN1250-1993)


Objectives of developing ideg

Objectives of developing IDeg

  • Duration of action:

    • Control fasting blood glucose with one injection in all individuals

  • Flat time–action profile:

    • Lower risk of hypoglycaemia

  • Day-to-day variability:

    • Less hypoglycaemia and hyperglycaemia


Targeting fasting plasma glucose

Targeting fasting plasma glucose

FPG(mmol/L)

FPG(mg/dL)

Average FPG

12.0

216

11.0

198

10.0

180

9.0

162

8.0

144

7.0

126

6.0

108

5.0

90

Target zone

4.0

72

3.0

54

2.0

36

Hypoglycaemia zone

1.0

18

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

Day


Targeting fasting plasma glucose1

Targeting fasting plasma glucose

FPG(mmol/L)

FPG(mg/dL)

Average FPG

12.0

216

11.0

198

10.0

180

9.0

162

8.0

144

7.0

126

6.0

108

5.0

90

Target zone

4.0

72

3.0

54

2.0

36

Hypoglycaemia zone

1.0

18

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

Day


Targeting fasting plasma glucose2

Targeting fasting plasma glucose

FPG(mmol/L)

FPG(mg/dL)

Average FPG

12.0

216

11.0

198

10.0

180

9.0

162

8.0

144

7.0

126

6.0

108

5.0

90

Target zone

4.0

72

3.0

54

2.0

36

Hypoglycaemia zone

1.0

18

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

Day


Targeting fasting plasma glucose3

Targeting fasting plasma glucose

FPG(mmol/L)

FPG(mg/dL)

Average FPG

12.0

216

11.0

198

10.0

180

9.0

162

8.0

144

7.0

126

6.0

108

5.0

90

Target zone

4.0

72

3.0

54

2.0

36

Hypoglycaemia zone

1.0

18

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

Day


Within subject variability of ideg and iglar in t1dm

Within-subject variability of IDeg and IGlar in T1DM

Screening

2–21 days

Follow-up

7–21 days

IDeg OD (n=27)

IGlar OD (n=27)

0

12 days

9

6

  • Inclusion criteria

  • T1DM ≥12 months

  • HbA1c10.0%

  • BMI 18–28 kg/m2

  • Age 18–65 years

24-hour euglycaemic clamp

Clinical trial.gov identifier: NCT00961324

Heiseet al. Diabetes 2011;60(Suppl. 1):A263 (Abstract 960-P)


Variability with ideg and iglar

Variability with IDeg and IGlar

CV, coefficient of variation

Heise et al. Diabetes 2011;60(Suppl. 1):A263;

Heise et al. Diabetologia 2010;53(Suppl. 1):S387


Within subject variability over time

Within-subject variability over time

IDeg

Heise et al. Diabetes 2011;60(Suppl. 1):A263


Within subject variability over time1

Within-subject variability over time

IDeg

IGlar

Heise et al. Diabetes 2011;60(Suppl. 1):A263


Summary of variability study

Summary of variability study

Day-to-day variability of IDeg

  • Considerably (up to four times) lower than IGlar

  • Consistently low over the entire 24 hours(substantial increase in the variability of IGlar after 6–8 hours)

Heise et al. Diabetes 2011;60(Suppl. 1):A263


Overall conclusions

Overall conclusions

Insulin degludec

  • flat and stable glucose-lowering effect, equally distributed over 24 hours

    • Half-life twice as long as that of IGlar

    • Variability considerably lower than that of IGlar

  • may facilitate titration to lower FPG targets

  • has the potential to lower the risk of both hypoglycaemia and hyperglycaemia


  • Login