Treatment options for     Aspergillus         Tim Felton   MRC Clinical Research Fellow
Introduction1. What are the treatment options?2. What is TDM and why do we need it?3. Is resistance a really a problem?4. ...
What are the treatment      options?
Option 1 – Polyenes• Bind ergosterol in fungal cell membrane• Transmembrane pores  cell depolarization• Fungal cell death...
Lipid Amphotericin B Formulations      Abelcet ® ABLC         Amphotec ® ABCD             Ambisome ® L-AMBRibbon-like part...
Amphotericin BPros                 Cons•   Broad spectrum   • Infusional toxicity•   Fungicidal         (less with lipid• ...
Option 2 - Triazoles• Bind cytochrome P450-enzyme lanosterol  14- demethylase• Inhibits the conversion of lanosterol to  e...
Itraconazole and PosaconazolePros                 Cons• Safe               • Fungistatic• Effective          • Cross resis...
VoriconazolePros                  Cons• Effective           • Hepatitis• Excellent tissue    • Photosensitive rash  penetr...
Option 3 - Echinocandins• Non-reversible inhibitor of glucan synthase• Production of 1,3 β-D glucan (cell wall)• Caspofung...
EchinocandinsPros                      Cons• Fungicidal against      • ? Aspergillus  Candida                 • Phlebitis•...
What is TDM and why do we          need it?
Back to basics•   Pharmacokinetics•   Exposure•   Pharmacodynamics•   Exposure-response relationship•   Therapeutic window
Pharmacokinetics• The effect the body has on a drug• Most commonly blood drug concentration1.   Absorption2.   Distributio...
Exposure                                     1. 20                                                            Peak Concent...
Pharmacodynamics• Effect the drug has on its target1. Clinical endpoint  – Survival  – Resolution of syndrome (“cure”)2. B...
Exposure-response relationship              1.0              0.9              0.8                        Emergence of resi...
Therapeutic drug monitoring• Aims to adjust the dosage of a drug based  on blood level (and knowledge of the PK-  PD relat...
Indications for TDM1. Variable pharmacokinetics
Pharmacokinetic variability                                                  20    V or i conazol C oncent r at i ons ( (m...
Pharmacokinetic variability                     Hope WW. AAC. 2012. In press
Pharmacokinetic variability                    Howard S. TDM. 2012. 34:72-76
Pharmacogenomics                                               9                                                          ...
Saturation of metabolism                                               9                                               8  ...
Absorption –                                             Posaconazole 200mg                                   600Posaconaz...
Pharmacokinetic variability• Absorption                        • Metabolism   – Vomiting                         – Hepatic...
Indications for TDM1. Variable pharmacokinetics2. Clinically relevant exposure–response relationships
Clinical IPA                                        Effect                     1.00                     0.90              ...
Indications for TDM1. Variable pharmacokinetics2. Clinically relevant exposure–response relationships3. Clinically relevan...
Concentration-toxicity                   Lestner J M. CID. 2009. 49:928-930
Clinical IPA                                                Effect                                Toxicity                ...
Indications for TDM1.   Variable pharmacokinetics2.   Clinically relevant exposure–response relationships3.   Clinically r...
Clinical IPA                                                Effect                                     Toxicity           ...
Indications for TDM1.   Variable pharmacokinetics2.   Clinically relevant exposure–response relationships3.   Clinically r...
Itraconazole• Tips to improve low levels – Usually poor absorption 1.Capsule with food or acid drink? 2.Stop PPI or H2-ant...
Itraconazole• Tips to reduce high levels +/- toxicity – Usually saturated clearance 1. Stop drug for 1-2 weeks 2. Re-start...
Voriconazole• Tips on use – Loading dose – Switch IV to oral• Tips to improve low levels – Dosage escalation carefully by ...
Posaconazole• Tips to improve low levels – Fatty foods, milk or fatty food supplements – Stop enzyme inducers – Stop PPIs ...
Is resistance a really a        problem?
Resistance• Target site mutations• Amphotericin B  – Aspergillus terreus  – Otherwise rare• Eichinocandin  – Rarely report...
Reports of Acquired Azole       Resistance    Frequency 2-3% cases                 Howard MM 2011;49(Supp1):S90-5
100                                                                                                        20%            ...
20                        15                                     Manchester                        10Percentage resistance...
Summary
3 classes of drugs• Amphotericin B• Triazole• Eichinocandins
1.0              0.9              0.8                        Emergence of resistance                                      ...
TDM• Required for itraconazole and voriconazole• Probably for posaconazole, amphotericin B  or eichocandins• TDM should – ...
Resistance• Is a real problem!• Is increased by drug use  – Especially if levels are low
Upcoming SlideShare
Loading in …5
×

Dr Tim Felton - Aspergillosis Study Day May 1st 2012

1,661 views

Published on

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

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
1,661
On SlideShare
0
From Embeds
0
Number of Embeds
12
Actions
Shares
0
Downloads
0
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide
  • 20 patients given IV voriconazole 4mg/kg
  • FIGURE 1 . A Monte Carlo simulation from the population pharmacokinetic model of AbuTarif 17 showing the median along with the 5th and 95th percentiles for concentration-time profiles of 5000 simulated patients throughout the first week of therapy for patients receiving posaconazole 200 mg every 8 hours. A 2-compartment model with the following parameters was used: Ka 0.0396 h-1, elimination rate constant 0.0198 h-1 (between-subject variability 0.221), and V/F 3290 L (between-subject variability 0.156). The simulations were performed using the pharmacokinetic program ADAPT 5.
  • CYP2C19 status makes a big difference to voriconazole levels, but only accounts for a small portion of observed variance
  • And, the PK are nonlinear
  • Genetic variabilty P-glycoproteinConcomitant medications - PPI
  • 181 measurements with high-pressure liquid chromatography were performed during 2388treatment days in 52 patients. A
  • Rabbit Neonatal HCME with anidulafungin
  • 181 measurements with high-pressure liquid chromatography were performed during 2388treatment days in 52 patients. A
  • 181 measurements with high-pressure liquid chromatography were performed during 2388treatment days in 52 patients. A
  • PD of hyper/hypotension
  • (enzyme inducers - rifampicin, phenytoin, carbamazepine)
  • Serum level changes are unpredictableRifampacin, carbamazepine, phenytonin etc
  • (especially in more severe disease with less therapeutic options
  • Dr Tim Felton - Aspergillosis Study Day May 1st 2012

    1. 1. Treatment options for Aspergillus Tim Felton MRC Clinical Research Fellow
    2. 2. Introduction1. 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. 3. What are the treatment options?
    4. 4. Option 1 – Polyenes• Bind ergosterol in fungal cell membrane• Transmembrane pores  cell depolarization• Fungal cell death1. Amphotericin B-deoxycholate2. Lipid formulations of amphotericin B
    5. 5. Lipid Amphotericin B Formulations Abelcet ® ABLC Amphotec ® ABCD Ambisome ® L-AMBRibbon-like particles Disk-like particles Unilaminar liposomeParticle size (µm): 1.6- Particle size (µm): 0.12- Particle size (µm) : 0.0811 0.14
    6. 6. Amphotericin BPros Cons• Broad spectrum • Infusional toxicity• Fungicidal (less with lipid• Effective preparations)• No drug • Nephrotoxicity interactions (less with lipid preparations) • Hypokalaemia • Cost
    7. 7. Option 2 - Triazoles• Bind cytochrome P450-enzyme lanosterol 14- demethylase• Inhibits the conversion of lanosterol to ergosterol (membrane)• Itraconazole• Voriconazole• Posaconazole• (Isavuconazole)
    8. 8. Itraconazole and PosaconazolePros 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. 9. VoriconazolePros 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. 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. 11. EchinocandinsPros 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. 12. What is TDM and why do we need it?
    13. 13. Back to basics• Pharmacokinetics• Exposure• Pharmacodynamics• Exposure-response relationship• Therapeutic window
    14. 14. Pharmacokinetics• The effect the body has on a drug• Most commonly blood drug concentration1. Absorption2. Distribution3. Metabolism4. Excretion
    15. 15. Exposure 1. 20 Peak ConcentrationD 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. 16. Pharmacodynamics• Effect the drug has on its target1. Clinical endpoint – Survival – Resolution of syndrome (“cure”)2. Biomarkers – Bacterial/fungal amount – Inflammatory markers
    17. 17. Exposure-response relationship 1.0 0.9 0.8 Emergence of resistance Therapeutic window 0.7Probability 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. 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. 19. Indications for TDM1. Variable pharmacokinetics
    20. 20. Pharmacokinetic variability 20 V or i conazol C oncent r at i ons ( (mg/L) 18VoriconazoleeConcentrationmg/ 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. 21. Pharmacokinetic variability Hope WW. AAC. 2012. In press
    22. 22. Pharmacokinetic variability Howard S. TDM. 2012. 34:72-76
    23. 23. Pharmacogenomics 9 E ensi e Met abol er xt v s i 8V 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. 24. Saturation of metabolism 9 8 Dosage escalation fromV 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. 25. Absorption – Posaconazole 200mg 600Posaconazole 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. 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. 27. Indications for TDM1. Variable pharmacokinetics2. Clinically relevant exposure–response relationships
    28. 28. Clinical IPA Effect 1.00 0.90 0.80 0.70Probability 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. 29. Indications for TDM1. Variable pharmacokinetics2. Clinically relevant exposure–response relationships3. Clinically relevant exposure–toxicity relationships
    30. 30. Concentration-toxicity Lestner J M. CID. 2009. 49:928-930
    31. 31. Clinical IPA Effect Toxicity 1.00 0.90 0.80Probability 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. 32. Indications for TDM1. Variable pharmacokinetics2. Clinically relevant exposure–response relationships3. Clinically relevant exposure–toxicity relationships4. Narrow therapeutic window
    33. 33. Clinical IPA Effect Toxicity 1.00 Therapeutic window 0.90 0.80Probability 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. 34. Indications for TDM1. Variable pharmacokinetics2. Clinically relevant exposure–response relationships3. Clinically relevant exposure–toxicity relationships4. Narrow therapeutic window5. Unable to rapidly assess response6. Serious/poor prognostic disease7. Drug–drug interactions8. Compliance9. Dosage adjustment
    35. 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. 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. 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. 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. 39. Is resistance a really a problem?
    40. 40. Resistance• Target site mutations• Amphotericin B – Aspergillus terreus – Otherwise rare• Eichinocandin – Rarely reported• Little cross-resistance
    41. 41. Reports of Acquired Azole Resistance Frequency 2-3% cases Howard MM 2011;49(Supp1):S90-5
    42. 42. 100 20% Multi-azole resistant Itraconazole & posaconazole resistant 90 Voriconazole resistant 80 Itraconazole resistant Fully susceptibleNumber 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. 43. 20 15 Manchester 10Percentage 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. 44. Summary
    45. 45. 3 classes of drugs• Amphotericin B• Triazole• Eichinocandins
    46. 46. 1.0 0.9 0.8 Emergence of resistance Therapeutic window 0.7Probability 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. 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. 48. Resistance• Is a real problem!• Is increased by drug use – Especially if levels are low

    ×