The role of antifungal therapeutic
drug monitoring (TDM)?
Dr Livingstone Chishimba BSc, MBChB, MRCP
University Hospital of South Manchester
The University of Manchester
1
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
2
Issues
• Why monitoring?
• Who to monitor?
• What? When? Where ?
• What action?
•
clinically relevant ?
–
exposure–response relationships
–
exposure–toxicity relationships
3
TDM-which drugs?-general
•
compounds with ;
– a narrow therapeutic window
• Warfarin, theophyllins
•
variable pharmacokinetics (PK)
– itra
•
physiological instability
4
Clinical objectives of TDM
Optimise efficacy
Minimise toxicity
5
Hope WW et al. Curr Opin Infect Dis 2008; 21:
580
Clinical use of TDM
•
drug-drug interactions
•
check compliance
•
change of dosage
•
patient failing therapy
6
Antifungal TDM
• Itraconazole
• Voriconazole
• Posaconazole
7
Itraconazole
Itraconazole
8
Two formulations of itraconazole
Capsules
Excipients differ between generic
formulations, and systemic
exposure may differ
Cyclodextrin excipient
20-50% higher bioavailability
Suspension
9
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
10
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
11
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
12
Itraconazole: dose-response relationship in
rabbits with IA
13
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
14
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.
15
Lestner, Clin Infect Dis 2009 In press
Itraconazole: concentration-toxicity
relationship
100
• 216 patients
• mostly capsules
80
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
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)
16
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)
17
Lestner JM et al. Clin Infect Dis 2009; 49: 928
Voriconazole
18
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
19
Walsh TJ et al. Antimicrob Agents Chemother 2004; 48: 2166
Voriconazole - metabolism
•
98% metabolised by liver
•
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
•
Cirrhosis / prior alcohol abuse, likely predictors of slow metabolisers
20
Voriconazole datasheet
Therapeutic drug monitoring may be useful
to optimise therapy for individual patients
9
V or i conazol e C oncent r at i on ( mg/ L)
8
A “fast’ metaboliser with
relatively low concentrations,
who is failing therapy
7
6
5
Dosage escalation from
200 mg bd to 300 mg bd
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 )
21
A “slow’ metaboliser: dosage escalation
may be too risky and this could be
prevented with TDM
9
Dosage escalation from
200 mg bd to 300 mg bd
V ori conazol e C oncent r at i on ( mg/ L)
8
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 )
22
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)
23
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)
24
Chishimba L, denning D et al 2011
(unpublished data)
25
Posaconazole
26
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
27
Krishna G et al. Antimicrob Agents Chemother 2007; 51:
812
Posaconazole as salvage therapy for invasive
aspergillosis: exposure-response relationship
28
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
30
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)
31
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
32
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
33
Posaconazole TDM in clinical practice
•
Targets not well defined
– Trough >0.5mg/L prophylaxis
– Trough 0.5-1.5mg/L therapy
•
Absorption affected by a number of factors:
– frequency of dosage (saturable)
– food, gastric pH and mucosal health
•
Side effects:
– insufficient data to determine if dose-dependent
•
To increase levels:
– may not be any benefit going >800mg/day
– fractionate dose
– give with fatty food
34
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!
35