1. Vehicles – The Infusion Confusion Dean R Hatt

2. Introduction Chaotic Exam Question Chaotic Exam Question Q. Slow intravenous administration of solvents are tolerated better than a quick bolus injection. Discuss. Q. Slow intravenous administration of solvents are tolerated better than a quick bolus injection. Discuss.

3. Agenda Default iv Vehicles Default iv Vehicles Other Vehicles (Guidance) Other Vehicles (Guidance) Default and Other Vehicles - Guidance Default and Other Vehicles - Guidance Combination Vehicles Combination Vehicles The Infusion Confusion The Infusion Confusion Conlusions Conlusions

4. Default iv Vehicles For intravenous use: For intravenous use: 0.9% (w/v) aq. Sodium chloride 0.9% (w/v) aq. Sodium chloride 3-5% (w/v) aq. Dextrose 3-5% (w/v) aq. Dextrose Above vehicles pH adjusted to 4-10 Above vehicles pH adjusted to 4-10 PBS (pH 7.4) PBS (pH 7.4) Same Vehicle as previous used for structurally similar drug Same Vehicle as previous used for structurally similar drug

5. Other Vehicles - Guidance For Parenteral use (max levels assuming 5 mL/kg by bolus): For Parenteral use (max levels assuming 5 mL/kg by bolus): Captisol – 20% w/v [Note. Cydex agreement] Captisol – 20% w/v [Note. Cydex agreement] 2HP Beta cyclodextrin – 10% w/v [Note. Also Alpha/Gamma 2HPCD] 2HP Beta cyclodextrin – 10% w/v [Note. Also Alpha/Gamma 2HPCD] PEG 400 – 30% v/v [Note. 100% at lower volumes] PEG 400 – 30% v/v [Note. 100% at lower volumes] PEG 300 – [Note. not well tolerated] PEG 300 – [Note. not well tolerated] DMSO – 10% v/v DMSO – 10% v/v Ethanol – 5% v/v Ethanol – 5% v/v Glycofurol - 5% v/v [Note. No in house data] Glycofurol - 5% v/v [Note. No in house data] PVP – 12.5% v/v [Note. No in house data] PVP – 12.5% v/v [Note. No in house data] Cremophor – 10% [Lower for Dogs/Cyno, use RH40 not EL in dogs] Cremophor – 10% [Lower for Dogs/Cyno, use RH40 not EL in dogs] Propylene glycol – 20% v/v [Note. 100% at low volumes] Propylene glycol – 20% v/v [Note. 100% at low volumes]

6. Other Vehicles - Guidance For Parenteral use (cont’d – again assumes 5 mL/kg) For Parenteral use (cont’d – again assumes 5 mL/kg) Labrasol/Labrafil – not at all [Note < 1% probably OK] Labrasol/Labrafil – not at all [Note < 1% probably OK] Solutal – 10% v/v [Note. Not in Dog/Cyno] Solutal – 10% v/v [Note. Not in Dog/Cyno] Tween 80 – 1% v/v [Note. Not in Dog] Tween 80 – 1% v/v [Note. Not in Dog] Propylene Carbonate – 5% v/v Propylene Carbonate – 5% v/v Buffer Systems [Case by Case] [Note. Issues with Citrate ] Buffer Systems [Case by Case] [Note. Issues with Citrate ] Oils [Note. only for sc/ip use] Oils [Note. only for sc/ip use] Oil/Solvent complexes [Note. Only for sc/ip use] Oil/Solvent complexes [Note. Only for sc/ip use] Others e.g Tetraglycol/Sorbitol /sucrose/amino acids[Case by Case]] Others e.g Tetraglycol/Sorbitol /sucrose/amino acids[Case by Case]]

7. Combination Vehicles It is more difficult to assess Combinations It is more difficult to assess Combinations 25% PEG400 in 20% Captisol has similar effects to either 25% PEG 400 alone or 20% Captisol alone 25% PEG400 in 20% Captisol has similar effects to either 25% PEG 400 alone or 20% Captisol alone 10:10:25:55 (v/v/v/v) DMSO:Solutol:PEG-400:12.5% (w/v) aqueous Captisol, lethal yet individually all components are free of effects 10:10:25:55 (v/v/v/v) DMSO:Solutol:PEG-400:12.5% (w/v) aqueous Captisol, lethal yet individually all components are free of effects Combinations therefore need to be assessed very carefully Combinations therefore need to be assessed very carefully Assess similar acting/target effects Assess similar acting/target effects Assume worse case scenario Assume worse case scenario GSK assess vehicle in control ahead of test animals GSK assess vehicle in control ahead of test animals

8. The Infusion Confusion CASE STUDY 1. 5:20:75 (v/v/v) Ethanol:Propylene Glycol:10% (w/v) Aq. 2-Hydroxypropyl β- Cyclodextrin CASE STUDY 1. 5:20:75 (v/v/v) Ethanol:Propylene Glycol:10% (w/v) Aq. 2-Hydroxypropyl β- Cyclodextrin 5 mL/kg/hr in 3 hr infusion to rats 5 mL/kg/hr in 3 hr infusion to rats Resulted in very necrotic tails Resulted in very necrotic tails Not considered acceptable to continue dosing Not considered acceptable to continue dosing

9. The Infusion Confusion (cont’d) CASE STUDY 1. CASE STUDY 1. By bolus injection - ethanol By bolus injection - ethanol Given at 7.5% at 10 mL/kg with no effects Given at 7.5% at 10 mL/kg with no effects By bolus injection – propylene glycol By bolus injection – propylene glycol Given at 20% at 10 mL/kg with no effects Given at 20% at 10 mL/kg with no effects By bolus injection – 2H beta Cyclodextrin By bolus injection – 2H beta Cyclodextrin Given at 16% at 5 mL/kg with no effects Given at 16% at 5 mL/kg with no effects By infusion – 2H beta Cyclodextrin By infusion – 2H beta Cyclodextrin Given at 12% at 10 mL/kg for 4 hours infusion with no effects Given at 12% at 10 mL/kg for 4 hours infusion with no effects

10. The Infusion Confusion (cont’d) CASE STUDY 1. CASE STUDY 1. By bolus injection - ethanol By bolus injection - ethanol Given at 7.5% at 10 mL/kg with no effects Given at 7.5% at 10 mL/kg with no effects By bolus injection – propylene glycol By bolus injection – propylene glycol Given at 20% at 10 mL/kg with no effects Given at 20% at 10 mL/kg with no effects By bolus injection – 2H beta Cyclodextrin By bolus injection – 2H beta Cyclodextrin Given at 16% at 5 mL/kg with no effects Given at 16% at 5 mL/kg with no effects By infusion – 2H beta Cyclodextrin By infusion – 2H beta Cyclodextrin Given at 12% at 10 mL/kg for 4 hours infusion with no effects Given at 12% at 10 mL/kg for 4 hours infusion with no effects Reminder: 5:20:75 Ethanol: Propylene Glycol:10% Cyclodextrin at 5 mL/kg over 3 hours

11. The Infusion Confusion (cont’d) CASE STUDY 1. CASE STUDY 1. By bolus injection - ethanol By bolus injection - ethanol Given at 7.5% at 10 mL/kg with no effects Given at 7.5% at 10 mL/kg with no effects By bolus injection – propylene glycol By bolus injection – propylene glycol Given at 20% at 10 mL/kg with no effects Given at 20% at 10 mL/kg with no effects By bolus injection – 2H beta Cyclodextrin By bolus injection – 2H beta Cyclodextrin Given at 16% at 5 mL/kg with no effects Given at 16% at 5 mL/kg with no effects By infusion – 2H beta Cyclodextrin By infusion – 2H beta Cyclodextrin Given at 12% at 10 mL/kg for 4 hours infusion with no effects Given at 12% at 10 mL/kg for 4 hours infusion with no effects = 0.75 mL/kg Ethanol = 3 mL/kg Propylene Glycol = 1.125 g/kg Cyclodextrin

12. The Infusion Confusion (cont’d) CASE STUDY 1. CASE STUDY 1. By bolus injection - ethanol By bolus injection - ethanol Given at 7.5% at 10 mL/kg with no effects Given at 7.5% at 10 mL/kg with no effects By bolus injection – propylene glycol By bolus injection – propylene glycol Given at 20% at 10 mL/kg with no effects Given at 20% at 10 mL/kg with no effects By bolus injection – 2H beta Cyclodextrin By bolus injection – 2H beta Cyclodextrin Given at 16% at 5 mL/kg with no effects Given at 16% at 5 mL/kg with no effects By infusion – 2H beta Cyclodextrin By infusion – 2H beta Cyclodextrin Given at 12% at 10 mL/kg for 4 hours infusion with no effects Given at 12% at 10 mL/kg for 4 hours infusion with no effects = 0.75 mL/kg Ethanol = 3 mL/kg Propylene Glycol = 1.125 g/kg Cyclodextrin = 0.75 mL/kg

13. The Infusion Confusion (cont’d) CASE STUDY 1. CASE STUDY 1. By bolus injection - ethanol By bolus injection - ethanol Given at 7.5% at 10 mL/kg with no effects Given at 7.5% at 10 mL/kg with no effects By bolus injection – propylene glycol By bolus injection – propylene glycol Given at 20% at 10 mL/kg with no effects Given at 20% at 10 mL/kg with no effects By bolus injection – 2H beta Cyclodextrin By bolus injection – 2H beta Cyclodextrin Given at 16% at 5 mL/kg with no effects Given at 16% at 5 mL/kg with no effects By infusion – 2H beta Cyclodextrin By infusion – 2H beta Cyclodextrin Given at 12% at 10 mL/kg for 4 hours infusion with no effects Given at 12% at 10 mL/kg for 4 hours infusion with no effects = 0.75 mL/kg Ethanol = 3 mL/kg Propylene Glycol = 1.125 g/kg Cyclodextrin = 0.75 mL/kg = 2 mL/kg

14. The Infusion Confusion (cont’d) CASE STUDY 1. CASE STUDY 1. By bolus injection - ethanol By bolus injection - ethanol Given at 7.5% at 10 mL/kg with no effects Given at 7.5% at 10 mL/kg with no effects By bolus injection – propylene glycol By bolus injection – propylene glycol Given at 20% at 10 mL/kg with no effects Given at 20% at 10 mL/kg with no effects By bolus injection – 2H beta Cyclodextrin By bolus injection – 2H beta Cyclodextrin Given at 16% at 5 mL/kg with no effects Given at 16% at 5 mL/kg with no effects By infusion – 2H beta Cyclodextrin By infusion – 2H beta Cyclodextrin Given at 12% at 10 mL/kg for 4 hours infusion with no effects Given at 12% at 10 mL/kg for 4 hours infusion with no effects = 0.75 mL/kg Ethanol = 3 mL/kg Propylene Glycol = 1.125 g/kg Cyclodextrin = 0.75 mL/kg = 2 mL/kg

15. The Infusion Confusion (cont’d) CASE STUDY 1. CASE STUDY 1. By bolus injection - ethanol By bolus injection - ethanol Given at 7.5% at 10 mL/kg with no effects Given at 7.5% at 10 mL/kg with no effects By bolus injection – propylene glycol By bolus injection – propylene glycol Given at 20% at 10 mL/kg with no effects Given at 20% at 10 mL/kg with no effects By bolus injection – 2H beta Cyclodextrin By bolus injection – 2H beta Cyclodextrin Given at 16% at 5 mL/kg with no effects Given at 16% at 5 mL/kg with no effects By infusion – 2H beta Cyclodextrin By infusion – 2H beta Cyclodextrin Given at 12% at 10 mL/kg for 4 hours infusion with no effects Given at 12% at 10 mL/kg for 4 hours infusion with no effects = 0.75 mL/kg Ethanol = 3 mL/kg Propylene Glycol = 1.125 g/kg Cyclodextrin = 0.75 mL/kg = 2 mL/kg = 0.8 g/kg

16. The Infusion Confusion (cont’d) CASE STUDY 1. CASE STUDY 1. By bolus injection - ethanol By bolus injection - ethanol Given at 7.5% at 10 mL/kg with no effects Given at 7.5% at 10 mL/kg with no effects By bolus injection – propylene glycol By bolus injection – propylene glycol Given at 20% at 10 mL/kg with no effects Given at 20% at 10 mL/kg with no effects By bolus injection – 2H beta Cyclodextrin By bolus injection – 2H beta Cyclodextrin Given at 16% at 5 mL/kg with no effects Given at 16% at 5 mL/kg with no effects By infusion – 2H beta Cyclodextrin By infusion – 2H beta Cyclodextrin Given at 12% at 10 mL/kg for 4 hours infusion with no effects Given at 12% at 10 mL/kg for 4 hours infusion with no effects = 0.75 mL/kg Ethanol = 3 mL/kg Propylene Glycol = 1.125 g/kg Cyclodextrin = 0.75 mL/kg = 2 mL/kg = 0.8 g/kg = 1.2 g/kg

17. The Infusion Confusion (cont’d) CASE STUDY 2. 10:10:80 (v/v/v) Solutal:DMSO:5% (w/v) Aq. Dextrose CASE STUDY 2. 10:10:80 (v/v/v) Solutal:DMSO:5% (w/v) Aq. Dextrose 5 mL/kg/hr in 3 hr infusion to rats 5 mL/kg/hr in 3 hr infusion to rats No findings at all ! No findings at all !

18. The Infusion Confusion (cont’d) CASE STUDY 2. 10:10:80 (v/v/v) Solutal:DMSO:5% (w/v) Aq. Dextrose CASE STUDY 2. 10:10:80 (v/v/v) Solutal:DMSO:5% (w/v) Aq. Dextrose Same Vehicle Same Vehicle 5 mL/kg by bolus injection 5 mL/kg by bolus injection Ataxia, effects on breathing rate, mild shakes Ataxia, effects on breathing rate, mild shakes

19. The Infusion Confusion (cont’d) CASE STUDY 1. showed that vehicles/excipients infused rather than by bolus injection may not be tolerated as well (in terms of total load) CASE STUDY 1. showed that vehicles/excipients infused rather than by bolus injection may not be tolerated as well (in terms of total load) CASE STUDY 2. showed that vehicles/excipients infused rather than by bolus injection may be tolerated much better(in terms of total load) CASE STUDY 2. showed that vehicles/excipients infused rather than by bolus injection may be tolerated much better(in terms of total load)

20. The Infusion Conclusion Assess the potential effects of combinations of vehicles Assess the potential effects of combinations of vehicles

21. The Infusion Conclusion Assess the potential effects of combinations of vehicles Assess the potential effects of combinations of vehicles Don’t assume that a slower administration leads to better tolerability Don’t assume that a slower administration leads to better tolerability Even similar total loads may be less tolerated by infusion Even similar total loads may be less tolerated by infusion However, slow infusion may allow higher concentrations to be given However, slow infusion may allow higher concentrations to be given

22. The Infusion Conclusion Assess the potential effects of combinations of vehicles Assess the potential effects of combinations of vehicles Don’t assume that a slower administration leads to better tolerability Don’t assume that a slower administration leads to better tolerability Even similar total loads may be less tolerated by infusion Even similar total loads may be less tolerated by infusion However, slow infusion may allow higher concentrations to be given However, slow infusion may allow higher concentrations to be given Procede with Caution Procede with Caution

23. Questions ?