Transcript Slide 1

Anti-fungal therapeutic drug
monitoring and azole dose
modification
Tim Felton
Advances Against Aspergillosis
Istanbul, 2012
Contents
• Triazoles – an overview
• Therapeutic drug monitoring (TDM)
• Specific drugs
Advances Against Aspergillosis
Istanbul, 2012
Triazoles
• Bind cytochrome P450-enzyme lanosterol 14-
demethylase
• Inhibits the conversion of lanosterol to ergosterol
• Fluconazole
• Itraconazole
• Voriconazole
• Posaconazole
• (Isavuconazole)
Advances Against Aspergillosis
Istanbul, 2012
1.0
0.9
Probability
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
2
Therapeutic window
Emergence of resistance
0.8
3
4
5
Drug exposure
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Response
Toxicity
6
7
8
Exposure
1. 20
Dr ug Concent r at ion ( mg/ L)
Peak Concentration
0. 80
AUC
0. 40
MIC
Time>threshold
0. 00
0
1
2
3
4
5
6
7
Tim e ( hour s)
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8
9
10
11
12
Indications for TDM
1. Variable pharmacokinetics
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PK-PD: the black arts
DOSE
BIOMARKER
•Quantifiable
•Linked to pathogenesis
•Linked to an outcome
of clinical interest
7
5
Ef f ect ( 1lo0CFU/
g)
g
•Survival
•Resolution of
clinical
syndrome
6
Conc
OUTCOME OF CLINICAL
INTEREST/IMPORTANCE
4
3
2
1
0
0. 01
0. 1
1
10
100
1000
Tot al dose 5FC ( m g/ kg)
Dose
PHARMACOKINETICS
PHARMACODYNAMICS
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Pharmacokinetic variability
Vor ic onazoleConcentration
Concent r at ions (mg/L)
( mg/ L)
Voriconazole
20
18
16
14
12
10
8
Toxic
6
4
2
0
0
24
48
72
96
Time
Tim e(hours)
( hour s)
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120
144
Sub168 therapeutic
Pharmacokinetic variability
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Hope WW. AAC. 2012. In press
Pharmacokinetic variability
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Howard S. TDM. 2012. 34:72-76
Pharmacokinetic variability
• Absorption
• Metabolism
– Vomiting
– Diet
– Genetic differences in drugtransport/gut-metabolism
– Concomitant medications
• Distribution
– Amount of body fat
– Presence of extravascular
fluid collections
– Hypoalbuminaemia
– Hepatic dysfunction
– Genetic differences in drugmetabolism
– Concomitant medications
• Excretion
– Hepatic dysfunction
– Renal insufficiency
– Genetic differences in drugelimination pathways
Advances Against Aspergillosis
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Pharmacogenomics
Vor ic onazole Concent r at ion ( mg/ L)
9
Ext ensiv e M et abolis er
8
Poor M et abolis er
7
6
5
4
3
2
1
0
0
96
192
288
Tim e ( hour s)
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384
480
Absorption
Suspension (fasted)
Suspension (non-fat meal)
Suspension (high-fat meal)
Time (hours)
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Courtney R . Br J Clin Pharmacol 2004:218–222.
Saturation of metabolism
Vor ic onazole Concent r at ion ( mg/ L)
9
Dosage escalation from
200 mg bd to 300 mg bd
8
7
6
5
4
3
2
1
0
0
29
58
87
116
145
174
203
Tim e ( hour s)
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232
261
290
319
348
Indications for TDM
1. Variable pharmacokinetics
2. Clinically relevant exposure–response relationships
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Indications for TDM
1. Variable pharmacokinetics
2. Clinically relevant exposure–response relationships
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Experimental IPA in rabbits
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Berenguar et al, AAC 1994;38:1303-8
Exposure-trough conc.
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Hope WW AAC. 2012. 56:526-31.
Clinical IPA
Effect
1.00
0.90
Probability effect
0.80
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)
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Pascual et al. CID. 2008. 46:201-11
Indications for TDM
1. Variable pharmacokinetics
2. Clinically relevant exposure–response relationships
3. Clinically relevant exposure–toxicity relationships
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Concentration-toxicity
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Lestner J M. CID. 2009. 49:928-930
Clinical IPA
Effect
Toxicity
1.00
Probability effect or toxicity
0.90
0.80
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)
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Pascual et al. CID. 2008. 46:201-11
Indications for TDM
1.
2.
3.
4.
Variable pharmacokinetics
Clinically relevant exposure–response relationships
Clinically relevant exposure–toxicity relationships
Narrow therapeutic window
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Clinical IPA
Effect
Toxicity
Therapeutic window
1.00
Probability effect or toxicity
0.90
0.80
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)
Advances Against Aspergillosis
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Pascual et al. CID. 2008. 46:201-11
Indications for TDM
1.
2.
3.
4.
5.
6.
7.
8.
9.
Variable pharmacokinetics
Clinically relevant exposure–response relationships
Clinically relevant exposure–toxicity relationships
Narrow therapeutic window
Unable to rapidly assess response
Serious/poor prognostic disease
Drug–drug interactions
Compliance
Dosage adjustment
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Specific dugs
•
•
•
•
Fluconazole
Itraconazole
Voriconazole
Posaconazole
•
•
•
•
•
Indication
Pharmacology/pharmacokinetics
Exposure–response relationship
Exposure–toxicity relationship
TDM target
Advances Against Aspergillosis
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Fluconazole
• Indication
– Prophylaxis
– Empirical therapy
– Treatment of superficial and invasive candidiasis
• Pharmacology/pharmacokinetics
– Linear PK
– High bioavailability
• Exposure–response relationship
– Well defined
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Rodríguez-Tudela J L. AAC. 2007. 51:3599-3604
Fluconazole
• Exposure–toxicity relationship
– High LFTs, nausea, vomiting, seizures at high dosages
• TDM target
–
–
–
–
Wide therapeutic index
Treatment of isolates with reduced susceptibility
Poor absorption
Paediatric patients
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Itraconazole
• Indication
–
–
–
–
Prophylaxis of IFI
Treatment of IPA
Treatment of CPA
Treatment of ABPA
Advances Against Aspergillosis
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Itraconazole
• Pharmacology/pharmacokinetics
–
–
–
–
–
–
–
–
–
Highly lipophilic and protein bound
 capsule solubility in acidic environment
Different manufactures' capsules behave differently
 absorption with PPI and H2-antagonists
Suspension (cyclodextrin) 20-50% higher bioavailability
Non-linear (probably)
Extensive variability
Active metabolite (OH-itraconazole) (bioassay/HPLC)
CYP3A4
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Itraconazole
• Exposure–response relationship
– Peak itraconazole levels and successful outcome of
mucosal candidiasis in patients with AIDS
– In vivo data
• Exposure–toxicity relationship
– Gastrointestinal intolerance, hypokalaemia, fatigue,
ankle oedema, cardiac failure and deranged LFTs
– Nausea more common with suspension (cyclodextrin)
Advances Against Aspergillosis
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Itraconazole
• TDM target
– 200mg b.i.d.
– Trough concentration
– Lower level
• Prophylaxis in neutropenia & treatment of oesophageal
candidasis in HIV
• 0.5mg/L HPLC or 5mg/L bioassay
– Upper level
• 17mg/L (bioassay)due to high probability of toxicity
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Itraconazole
• Tips to improve low levels
–
1.
2.
3.
4.
5.
6.
Usually poor absorption
Capsule with food or acid drink?
Stop PPI or H2-antagonist (if possible)
Compliance
Consistently prescribe the same preparation
Check for drug interactions
Increase to capsule 300mg twice daily or change to
suspension 200mg twice daily
7. Check serum levels again!
Advances Against Aspergillosis
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Itraconazole
• Tips to reduce high levels +/- toxicity
–
1.
2.
3.
Usually saturated clearance
Stop drug for 1-2 weeks
Re-start at a lower dose
Check serum levels again!
Advances Against Aspergillosis
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Voriconazole
• Indication
– Disseminated candidasis
– IPA and CPA
• Pharmacology/pharmacokinetics
–
–
–
–
–
–
Excellent bioavailabilty (96%)
IV preparation – cyclodextrin (potentially nephrotoxic)
Marked PK variability (100-fold)
Sex, age and CYP2C19 genotype only partially explain
Weight important in paediatric patients
CYP2C19, 3A4 and 2C9 substrate
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Herbrecht R. NEJM. 2002. 347:408-15
Voriconazole
• Exposure–response relationship
– In-vivo, in-vitro and clinical data
• Exposure–toxicity relationship
– Gradual increase in probability with increasing
concentration
– Abnormal LFTs, visual disturbance, photosensitivity,
confusion etc
Advances Against Aspergillosis
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Pascual et al. CID. 2008:46;201-11
Voriconazole
• TDM target
– 200mg b.i.d. (i.v. loading dose)
– Trough concentration
– Lower level
• Trough 1mg/L associated with 70% probability of
success
– Upper level
• Less well established
• >6mg/L associated with high probability of CNS toxicity
and hepatitis
Advances Against Aspergillosis
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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
Advances Against Aspergillosis
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Posaconazole
• Indication
– Salvage therapy IPA
– Prophylaxis neutropenia and HSCT
• Pharmacology/pharmacokinetics
–
–
–
–
–
–
Only oral suspension
Linear PK to 800mg/day
Absorption saturated above 800mg/day
Better absorption with fatty food and low stomach pH
Long t½ with comparable average and trough levels
Variability
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Felton TW. CID. 2010;51:1383-1391
Posaconazole
• Exposure–response relationship
– In-vivo (mouse IC and rabbit IPA)
– Increased clinical response with increasing average and
trough concentration
• Exposure–toxicity relationship
– GI intolerance, abnormal LFT
– No dose dependent
Advances Against Aspergillosis
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Walsh T. CID. 2007. 44. 2-12
Posaconazole
• TDM target
– 400mg b.i.d
– Trough concentration (but long t½ life)
– Lower level
• >0.7mg/L
• Higher might be better if formulation/cost allowed!
– Upper level
• Not known/defined
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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
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Indications for TDM
1.
2.
3.
4.
5.
6.
7.
8.
9.
Variable pharmacokinetics
Clinically relevant exposure–response relationships
Clinically relevant exposure–toxicity relationships
Narrow therapeutic window
Unable to rapidly assess response
Serious/poor prognostic disease
Drug–drug interactions
Compliance
Dosage adjustment
Advances Against Aspergillosis
Istanbul, 2012
1.0
0.9
Probability
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
2
Therapeutic window
Emergence of resistance
0.8
3
4
5
Drug exposure
Advances Against Aspergillosis
Istanbul, 2012
Response
Toxicity
6
7
8
Conclusions
• TDM required for itraconazole and voriconazole
• Probably for posaconazole
• TDM should
– Improve outcomes
– Reduce emergence of resistance
– BUT there is an associated cost
Advances Against Aspergillosis
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