Transcript The role of antifungal drug monitoring

The role of antifungal therapeutic
drug monitoring (TDM)?
Dr Livingstone Chishimba BSc, MBChB, MRCP
University Hospital of South Manchester
The University of Manchester
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Outline
• PK affects the antifungal effect
•
Potential indications for TDM-general
• Implications of TDM
– Itra,vori, posa,
• Efficacy and safety
• Studies and evidence
• Clinical implication
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Issues
• Why monitoring?
• Who to monitor?
• What? When? Where ?
• What action?
•
clinically relevant ?
–
exposure–response relationships
–
exposure–toxicity relationships
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TDM-which drugs?-general
•
compounds with ;
– a narrow therapeutic window
• Warfarin, theophyllins
•
variable pharmacokinetics (PK)
– itra
•
physiological instability
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Clinical objectives of TDM
Optimise efficacy
Minimise toxicity
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Hope WW et al. Curr Opin Infect Dis 2008; 21:
580
Clinical use of TDM
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drug-drug interactions
•
check compliance
•
change of dosage
•
patient failing therapy
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Antifungal TDM
• Itraconazole
• Voriconazole
• Posaconazole
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Itraconazole
Itraconazole
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Two formulations of itraconazole
Capsules
Excipients differ between generic
formulations, and systemic
exposure may differ
Cyclodextrin excipient
20-50% higher bioavailability
Suspension
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Itraconazole exhibits nonlinear PK
Itraconazole, ng/mL plasma
Time to steady state ~14 days
Once linear clearance achieved, t1/2 ~24 hours
Hours
Barone JA et al. Antimicrob Agents Chemother 1993; 37: 778
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Itraconazole: PK and variability
• Itraconazole poorly soluble at physiological pH
• Absorption of itraconazole tablets is variable; requires acidic environment,
which is often absent in critically ill patients
• Increased bioavailability with food and cola
• Itraconazole suspension is often poorly tolerated (gastrointestinal),
leading to compliance problems
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Variability in itraconazole PK affects
the antifungal effect
Pulmonary fungal burden
Significant relationship between drug
level and fungal burden
Peak itraconazole concentrations (mg/L)
Berenguer J et al. Antimicrob Agents Chemother 1994; 38: 1303
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Itraconazole: dose-response relationship in
rabbits with IA
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Berenguar et al, AAC 1994;38:1303-8
Itraconazole: incidence of proven invasive
fungal infections
Capsules
• Itraconazole trough concentrations of
<0.5 mg/L associated with higher
mortality (p= 0.039)
Solution
• Easier to get better levels with
suspension
Total
Favours
itraconazole
Favours
control
Glasmacher et al JCO 2003
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100
Toxicity and itraconazole concentrations
80
100
60
40
20
Probability of toxicity (%)
%Toxicity
40
60
80
20
0
0
0
5
0
5
10
15
20
10
15
20
Itraconazole
concentration
mg/L
ITZ plasma
concentration
25
25
NOTE that the highest quintile consists of values ≥ 25.6 mg/L. The line is a logistic regression fit to the
individual measurements.
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Lestner, Clin Infect Dis 2009 In press
Itraconazole: concentration-toxicity
relationship
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• 216 patients
• mostly capsules
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Probability of toxicity
Pro b a b ility o f t o xic ity ( %)
60
40
A range of AE, most common:
•Fluid retention
•Gastrointestinal intolerance
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0
0
5
10
15
20
25
Itra c o n az o le c o n c e n tr at io n m g /L
Trough itraconazole
concentrations (mg/L)
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Lestner JM et al. Clin Infect Dis 2009; 49: 928
Itraconazole: concentration-toxicity
relationship
100
80
Probability of toxicity
Pro b a b ility o f t o xic ity ( %)
60
Probability of toxicity
low<17.1>high
40
20
0
0
5
10
15
20
25
Itra c o n az o le c o n c e n tr at io n m g /L
Trough itraconazole
concentrations (mg/L)
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Lestner JM et al. Clin Infect Dis 2009; 49: 928
Voriconazole
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Voriconazole
• Displays nonlinear PK in adults, with saturable clearance
• Disproportionate changes when dose altered
• ~5 days to achieve steady state concentrations
• Exhibits linear PK in children
• Children may metabolise more quickly
• Dose escalation may be required
Trifilio SM et al. Antimicrob Agents Chemother 2009; 53: 1793
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Walsh TJ et al. Antimicrob Agents Chemother 2004; 48: 2166
Voriconazole - metabolism
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98% metabolised by liver
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Primarily metabolised by CYP2C19 and CYP3A4, less by CYP2C9.
•
Genotype status for CYP2C19 and/or co-administration of drugs that
modulate CYP2C19 or CYP3A4 activities do affect voriconazole
plasma levels.
•
–
PC BRASS,
–
OAK DEVICESS
3-5% caucasians, 15-20% Asians have genetic polymorphism of
CYP2C19 - slow metabolisers
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Cirrhosis / prior alcohol abuse, likely predictors of slow metabolisers
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Voriconazole datasheet
Therapeutic drug monitoring may be useful
to optimise therapy for individual patients
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V or i conazol e C oncent r at i on ( mg/ L)
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A “fast’ metaboliser with
relatively low concentrations,
who is failing therapy
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6
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Dosage escalation from
200 mg bd to 300 mg bd
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3
2
1
0
0
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116
145
174
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232
261
290
319
348
T i m e (h o u rs )
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A “slow’ metaboliser: dosage escalation
may be too risky and this could be
prevented with TDM
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Dosage escalation from
200 mg bd to 300 mg bd
V ori conazol e C oncent r at i on ( mg/ L)
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7
6
5
4
3
2
1
0
0
29
58
87
116
145
174
203
232
261
290
319
348
T i m e (h o u rs )
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Voriconazole:
exposure-response relationships
• There have been REAL difficulties linking drug exposure with effect
because:
– Good PK was not done in the trials (trough, random, mean levels)
– Assessing patient outcome is really tough
• Random levels of < 2.05 mg/L associated with poorer outcome (Smith et
al AAC 2006)
• 15% of patients in recent studies have no detectable levels of drug in
serum! (Trifilio et al 2007)
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Efficacy and safety of voriconazole
• 26 patients (ABPA, n=21, SAFS=5)
• Poor relationship between dose and
– Clinical efficacy
• ?Good relationship between
– Dose, TDL and AEs
Chishimba L, denning D et al 2011
(unpublished data)
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Chishimba L, denning D et al 2011
(unpublished data)
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Posaconazole
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Posaconazole
• Displays linear PK with dosages of 50-800mg
• Saturation of absorption above 800mg/day
• ~7-10 days to achieve steady state concentrations
• Minimal differences between peak and trough levels
• Similar blood concentrations found in juveniles with comparable efficacy and
safety
Courtney R et al. Antimicrob Agents Chemother 2003; 47: 2788
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Krishna G et al. Antimicrob Agents Chemother 2007; 51:
812
Posaconazole as salvage therapy for invasive
aspergillosis: exposure-response relationship
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Walsh TJ et al. Clin Infect Dis 2007; 44: 2
Posaconazole: concentration-response
relationship from prophylaxis studies
Clinical failure of
25% at levels of
0.71mg/L
Clinical failure:
• death
• fungal infection
• drug stopped
• use of other antifungals
http://www.fda/cder/foi/nda/2006/022003s000_Noxafil_ClinPharR.pdf. 2005
Antifungal TDM-Which drug to
monitor?
Necessary
• Itraconazole
• Voriconazole (especially IV, children, complex case)
• Flucytosine
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Antifungal TDM-Which to drug to monitor?
Desirable
• Posaconazole (probably)
Unnecessary
• Amphotericin B
• Echinocandins (not much data though)
• Fluconazole (unless short gut and oral administration,
or compliance)
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Itraconazole TDM: clinical practice
• Targets
– HPLC: >0.5 mg/L
– Bioassay >5 mg/L
• Low levels with capsules usually due to suboptimal absorption
– Administer with food or cola
– Stop H2 antagonists, PPIs
– Check for drug interactions (rifampicin, phenytoin, carbamazepine).
– Can increase from 200 mg b.i.d to 300 mg b.i.d
• Change to suspension
– Monitor compliance
– Understand variance
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Voriconazole TDM in clinical practice
• Target: pre-dose (only) should be monitored
– greater than 1.0 and less than ~5.5mg/L
• Monitor for duration of therapy
• Give loading dose
– preferably iv
• Look for and expect nonlinear behaviour when adjusting dose
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Posaconazole TDM in clinical practice
•
Targets not well defined
– Trough >0.5mg/L prophylaxis
– Trough 0.5-1.5mg/L therapy
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Absorption affected by a number of factors:
– frequency of dosage (saturable)
– food, gastric pH and mucosal health
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Side effects:
– insufficient data to determine if dose-dependent
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To increase levels:
– may not be any benefit going >800mg/day
– fractionate dose
– give with fatty food
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Andes D et al. Antimicrob Agents Chemother 2009; 53: 24
Take home message
• Linear PK: itra and posa
• None linear PK: vori
• Dose alteration not only on TDL but on clinical response, Aes
• Consider drug interactions
– PPI, antiepileptics , macrolides
• time-diet timing etc if not able to achieve TDL but clinical outcome most
important.
– frequency of dosage (saturable)
– food, gastric pH and mucosal health
• but much more work required using population PK modelling to reach the
goal of truly individualising therapy!
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