Download Is monitoring of azole concentrations of clinical value in patients with

Is monitoring of azole concentrations
of clinical value in patients with
haematological malignancies?
J Peter Donnelly PhD
Department of Haematology
Radboud University Nijmegen Medical Centre
Nijmegen, The Netherlands
Route
Oral, parenteral or
ssssubcutaneousss
Setting
Outpatient
Inpatient
Strategies for treating IFD
Signs &
symptoms
Mycology
EORTC/MSG
Strategy
No
No
Persistent
febrile
neutropenia
Yes
Radiological Radiological
signs
signs
Negative
Positive
biomarker
Negative
Negative
Negative
Positive
Biomarker or
microscopy
or culture
-
-
-
-
Possible
Probable
Prophylaxis
Pre-emptive
therapy
Empirical
therapy
Pre-emptive
therapy
Directed
therapy
Directed
therapy
IV or oral azole
ECIL recommendations
Azole
Itraconazole
Prophylaxis
Oral
BI
IV
Voriconazole
Oral
Oral
Salvage therapy
IV then oral
IV then Oral
CIII
Oral
IV then oral
IV
Posaconazole
1st line therapy
Oral
AI
Oral
Oral
AI
CIII
CIII
IV then oral
Oral
BII
Oral
BII
Some questions to ask
!  oral or IV administration of the azole?
!  treatment or prophylaxis?
! 
If treatment
!  is it for fever, suspected IFD, possible IFD or
probable/proven IFD?
!  is
there no other alternative to the azole?
Clinical value
TDM
harms
helps
What do we want to know?
!  Is the patient taking the medication?
!  Is the patient absorbing the medication?
!  Are the levels likely to result in toxicity?
!  Are the levels optimum for efficacy?
is the patient taking the azole?
Are you taking the medication?
Minimum levels
Azole
Trough levels
Itraconazole
1- 2 mg/L
Voriconazole
1 – 2 mg/L
Posaconazole
0.5 – 1.5 mg/L
Consequences of non compliance
You taken
your
medication?
Yep but it sure
is hard to
swallow!
Is the azole being absorbed?
Posaconazole levels and prophylaxis
Lebeaux et al. Antimicrob Chemother Ag 2009; 53: 5224-5229
Improving the absorption of posaconazole
High fat
Carbonated drinks
PPIs
TDM of oral voriconazole
Ueda et al Int J Hematol. 2009;89:592-9
Consequences of low levels
Azole
Action
Itraconazole
Increase dose or switch to IV
Voriconazole
Increase dose or switch to IV
Posaconazole
Increase dose
Levels likely to result in toxicity
Toxic levels
Azole
Trough levels
Itraconazole
>10 mg/L
Voriconazole
> 6 mg/L
Posaconazole
No data
Voriconazole levels and toxicity
Pascual et al. Clin Infect Dis 2008; 46: 201-11
Voriconazole levels and toxicity
Ueda et al Int J Hematol. 2009;89:592-9
Dosage and levels of patients
Pascual et al. Clin Infect Dis 2008; 46: 201-11
Dosage and levels of patients
Pascual et al. Clin Infect Dis 2008; 46: 201-11
Consequences of “toxic” levels
Azole
Action
Itraconazole
Lower dose, suspend treatment
OR change to another drug
Voriconazole
Lower dose, suspend treatment
OR change to another drug
Posaconazole
Lower dose, suspend treatment
OR change to another drug
Levels optimum for efficacy
Therapeutic levels
Azole
Trough levels
Itraconazole
>1-2 - <10 mg/L
Voriconazole
>1-2 - <6 mg/L
Posaconazole
>0.5 – 1.5 mg/L
Dosage and levels of patients
Pascual et al. Clin Infect Dis 2008; 46: 201-11
Voriconazole levels and outcome
Pascual et al. Clin Infect Dis 2008; 46: 201-11
Consequences of toxic levels
Azole
Action
Itraconazole
Increase dose or switch to IV
Voriconazole
Increase dose or switch to IV
Posaconazole
Increase dose
What is needed for effective monitoring
Dutch voriconazole study
am
pm
1
6
6
2
4
4
3
4
4
4
4
!"#$
%
!"#$%$!"&
'
!"($$%$#
(
(
#$$%$#"(
$&&'&$#(
#"($$%$)
&(
&"(
(
))$$%$*"(
*(
&
Action: increase
**"($%$(
( ( dose *to 5 mg/kg
+(
)
Dutch voriconazole study
am
pm
1
6
6
2
4
4
3
4
4
4
5
5
5
5
5
6
5
5
7
5
!"#$
!"#$%$!"&
!"($$%$#
#$$%$#"(
#"($$%$)
(
)$$%$*"(
*(
)&&'&*#(
*"($%$(
*( (
+(
%
'
(
(
&(
&"(
&+
*
)
Action: decrease dose to 4 mg/kg
Dutch voriconazole study
am
pm
1
6
6
2
4
4
3
4
4
4
5
5
5
5
5
6
5
5
7
5
4
8
4
4
9 10 11 12 1 31 14
4 4
4
Twice weekly if in hospital
Cost-effectiveness of TDM of azole drugs
TDM of voriconazole is useful (C3)
TDM of itraconazole can be useful (C3)
TDM of posaconazole (no data)
Recommendations:
!  Voriconazole therapy must be guided by TDM.
!  TDM can be useful to guide therapy of itraconazole.
Touw et al. EJHP Science 2007; 4: 283-91
Clinical ordering of voriconazole levels
!  Lack of information on dose and sample timing
!  Delay in delivery to the laboratory
!  Lack of clinical details
!  No follow up samples
!  Problem with Fridays
!  Lack of synchronisation between sample cycling
and dosing cycling
!  Failure to see TDM as a care pathway
Miyakis et al. Ther Drug Monit 2010; epub
Care pathway for TDM
azole
level
Too
oo low
In rang
range
Too high
hig
Increase
Incre
se exposure
ex
Decrease
se ex
exposure
osure
Increase dose
Switch to IV
Decrease dose
Suspend therapy
level to other drug
If all else fails switch
Too
oo low
In rang
range
Too high
hig
Final question
Will the results of the azole assay add more to
the clinical decision making process than sound
clinical judgment alone?
!  Yes for compliance
!  Yes for absorption
!  No for efficacy
!  Perhaps for toxicity