This day was held for all professional allied to medicine and was intended to educate and raise awareness throughout all professional that may come across aspergillosis

1. Treatment options for
Aspergillus
Tim Felton
MRC Clinical Research Fellow

2. Introduction
1. What are the treatment options?
2. What is TDM and why do we need it?
3. Is resistance a really a problem?
4. Summary

3. What are the treatment
options?

4. Option 1 – Polyenes
• Bind ergosterol in fungal cell membrane
• Transmembrane pores  cell depolarization
• Fungal cell death
1. Amphotericin B-deoxycholate
2. Lipid formulations of amphotericin B

5. Lipid Amphotericin B Formulations
Abelcet ® ABLC Amphotec ® ABCD Ambisome ® L-AMB
Ribbon-like particles Disk-like particles Unilaminar liposome
Particle size (µm): 1.6- Particle size (µm): 0.12- Particle size (µm) : 0.08
11 0.14

6. Amphotericin B
Pros Cons
• Broad spectrum • Infusional toxicity
• Fungicidal (less with lipid
• Effective preparations)
• No drug • Nephrotoxicity
interactions (less with lipid
preparations)
• Hypokalaemia
• Cost

7. Option 2 - Triazoles
• Bind cytochrome P450-enzyme lanosterol
14- demethylase
• Inhibits the conversion of lanosterol to
ergosterol (membrane)
• Itraconazole
• Voriconazole
• Posaconazole
• (Isavuconazole)

8. Itraconazole and Posaconazole
Pros Cons
• Safe • Fungistatic
• Effective • Cross resistance
• Excellent tissue • Hepatotoxic
penetration • GI intolerances
• Fluid retention (itra)
• LV dysfunction (itra)
• Inhibition of CYP 3A4
• Oral bioavailability
depends on preparations
• TDM ideally required

9. Voriconazole
Pros Cons
• Effective • Hepatitis
• Excellent tissue • Photosensitive rash
penetration • Altered vision
• Confusion +/- hallucinations
• CYP3A4 and 2C19
• Non-linear pharmacokinetics
• Inter-individual variability
• Very rapid metabolism in
children
• TDM ideally required
• IV formulations (cyclodextran)

10. Option 3 - Echinocandins
• Non-reversible inhibitor of glucan synthase
• Production of 1,3 β-D glucan (cell wall)
• Caspofungin
• Micafungin
• Anidulafungin Caspofungin
Micafungin Anidulafungin

11. Echinocandins
Pros Cons
• Fungicidal against • ? Aspergillus
Candida • Phlebitis
• Safe in renal and • Nausea
hepatic impairment • Deranged LFT
(rarely)
• Few drug interactions
• Histamine-like
reactions (Anidula)
• Diarrhoea (Anidula)
• Expensive

12. What is TDM and why do we
need it?

13. Back to basics
• Pharmacokinetics
• Exposure
• Pharmacodynamics
• Exposure-response relationship
• Therapeutic window

14. Pharmacokinetics
• The effect the body has on a drug
• Most commonly blood drug concentration
1. Absorption
2. Distribution
3. Metabolism
4. Excretion

15. Exposure
1. 20
Peak Concentration
D r ug C oncent r at i on ( mg/ L)
0. 80
AUC
0. 40 MIC
Time>threshold
0. 00
0 1 2 3 4 5 6 7 8 9 10 11 12
Ti e ( hour s)
m

16. Pharmacodynamics
• Effect the drug has on its target
1. Clinical endpoint
– Survival
– Resolution of syndrome (“cure”)
2. Biomarkers
– Bacterial/fungal amount
– Inflammatory markers

17. Exposure-response relationship
1.0
0.9
0.8
Emergence of resistance
Therapeutic window
0.7
Probability
0.6
Response
0.5
Toxicity
0.4
0.3
0.2
0.1
0.0
2 3 4 5 6 7 8
Drug exposure

18. Therapeutic drug monitoring
• Aims to adjust the dosage of a drug based
on blood level (and knowledge of the PK-
PD relationship)
• Examples
– Warfarin
– Digoxin
– Gentamicin/Vancomycin
– Triazole

19. Indications for TDM
1. Variable pharmacokinetics

20. Pharmacokinetic variability
20
V or i conazol C oncent r at i ons ( (mg/L)
18
VoriconazoleeConcentrationmg/ L)
16
14
12
10
8
Toxic
6
4
2
0 Sub-
0 24 48 72 96 120 144 168 therapeutic
Time (hours)
Ti e ( hour s)
m

21. Pharmacokinetic variability
Hope WW. AAC. 2012. In press

22. Pharmacokinetic variability
Howard S. TDM. 2012. 34:72-76

23. Pharmacogenomics
9
E ensi e Met abol er
xt v s
i
8
V or i conazol e C oncent r at i on ( mg/ L)
Poor Met abol er
s
i
7
6
5
4
3
2
1
0
0 96 192 288 384 480
Ti e ( hour s)
m

24. Saturation of metabolism
9
8 Dosage escalation from
V or i conazol e C oncent r at i on ( mg/ L)
200 mg bd to 300 mg bd
7
6
5
4
3
2
1
0
0 29 58 87 116 145 174 203 232 261 290 319 348
Ti e ( hour s)
m

25. Absorption –
Posaconazole 200mg
600
Posaconazole plasma conc (ng/mL)
500 Suspension (fasted)
Suspension (non-fat meal)
Suspension (high-fat meal)
400
300
200
100
0
0 12 24 36 48 60 72
Time (hours)
Courtney R . Br J Clin Pharmacol 2004:218–222.

26. Pharmacokinetic variability
• Absorption • Metabolism
– Vomiting – Hepatic dysfunction
– Diet – Genetic differences in drug-
– Genetic differences in drug- metabolism
transport/gut-metabolism – Concomitant medications
– Concomitant medications
• Distribution • Excretion
– Amount of body fat – Hepatic dysfunction
– Presence of extravascular – Renal insufficiency
fluid collections – Genetic differences in drug-
– Hypoalbuminaemia elimination pathways

27. Indications for TDM
1. Variable pharmacokinetics
2. Clinically relevant exposure–response relationships

28. Clinical IPA
Effect
1.00
0.90
0.80
0.70
Probability effect
0.60
0.50
0.40
0.30
0.20
0.10
0.00
0 1 2 3 4 5 6 7 8 9 10
Voriconazole trough concentrations (mg/L)
Pascual et al. CID. 2008. 46:201-11

29. Indications for TDM
1. Variable pharmacokinetics
2. Clinically relevant exposure–response relationships
3. Clinically relevant exposure–toxicity relationships

30. Concentration-toxicity
Lestner J M. CID. 2009. 49:928-930

31. Clinical IPA
Effect Toxicity
1.00
0.90
0.80
Probability effect or toxicity
0.70
0.60
0.50
0.40
0.30
0.20
0.10
0.00
0 1 2 3 4 5 6 7 8 9 10
Voriconazole trough concentrations (mg/L)
Pascual et al. CID. 2008. 46:201-11

32. Indications for TDM
1. Variable pharmacokinetics
2. Clinically relevant exposure–response relationships
3. Clinically relevant exposure–toxicity relationships
4. Narrow therapeutic window

33. Clinical IPA
Effect Toxicity
1.00
Therapeutic window
0.90
0.80
Probability effect or toxicity
0.70
0.60
0.50
0.40
0.30
0.20
0.10
0.00
0 1 2 3 4 5 6 7 8 9 10
Voriconazole trough concentrations (mg/L)
Pascual et al. CID. 2008. 46:201-11

34. Indications for TDM
1. Variable pharmacokinetics
2. Clinically relevant exposure–response relationships
3. Clinically relevant exposure–toxicity relationships
4. Narrow therapeutic window
5. Unable to rapidly assess response
6. Serious/poor prognostic disease
7. Drug–drug interactions
8. Compliance
9. Dosage adjustment

35. Itraconazole
• Tips to improve low levels
– Usually poor absorption
1.Capsule with food or acid drink?
2.Stop PPI or H2-antagonist (if possible)
3. Compliance
4. Consistently prescribe the same preparation
5. Check for drug interactions
6. Increase to capsule 300mg twice daily or change to
suspension 200mg twice daily
7. Check serum levels again!

36. Itraconazole
• Tips to reduce high levels +/- toxicity
– Usually saturated clearance
1. Stop drug for 1-2 weeks
2. Re-start at a lower dose
3. Check serum levels again!

37. Voriconazole
• Tips on use
– Loading dose
– Switch IV to oral
• Tips to improve low levels
– Dosage escalation carefully by 50mg daily
– Check levels every 1-2/52
• Tips to reduce high levels +/- toxicity
– Stop for 1 week or by TDM then reduce dosage
– Stop omeprazole
– Check levels

38. Posaconazole
• Tips to improve low levels
– Fatty foods, milk or fatty food supplements
– Stop enzyme inducers
– Stop PPIs
– Can try fractionating the regimen
– Dosage escalation unhelpful above 800mg/day

39. Is resistance a really a
problem?

40. Resistance
• Target site mutations
• Amphotericin B
– Aspergillus terreus
– Otherwise rare
• Eichinocandin
– Rarely reported
• Little cross-resistance

41. Reports of Acquired Azole
Resistance
Frequency 2-3% cases
Howard MM 2011;49(Supp1):S90-5

42. 100 20%
Multi-azole resistant
Itraconazole & posaconazole resistant
90
Voriconazole resistant
80 Itraconazole resistant
Fully susceptible
Number of patient cases
70 14%
5%
60 17%
50 7%
5%
3%
40 0%
30 0%
5%
20 7%
0% 0%
10
0
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Year
Bueid JAC 2010; 65:2116-8

43. 20
15
Manchester
10
Percentage resistance
5
0
-5
Nijmegen
-10
-15
-20
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
Year
Denning AAC 1997;41:1364-8 Verweij DRU 2009;12:141-7

44. Summary

45. 3 classes of drugs
• Amphotericin B
• Triazole
• Eichinocandins

46. 1.0
0.9
0.8
Emergence of resistance
Therapeutic window
0.7
Probability
0.6
Response
0.5
Toxicity
0.4
0.3
0.2
0.1
0.0
2 3 4 5 6 7 8
Drug exposure

47. TDM
• Required for itraconazole and voriconazole
• Probably for posaconazole, amphotericin B
or eichocandins
• TDM should
– Improve outcomes
– Reduce emergence of resistance
– BUT there is an associated cost

48. Resistance
• Is a real problem!
• Is increased by drug use
– Especially if levels are low