Aspergillosis Patients Support Meeting April 2011 - Caroline Moore

Led by Graham Atherton
Supported by
Georgina Powell, Marie Kirwan & Debbie Kennedy
NAC Centre Manager Chris Harris
Talks given by Nicola Duddy and Caroline Moore
Mycology Diagnostics Lab
UHSM, Manchester
National aspergillosis centre
UHSM
Manchester
Support Meeting for Aspergillosis Patients
Fungal Research Trust

Antifungal drugs – are you getting enough?
Dr Caroline B. Moore
Mycology Reference Centre
University Hospital of South Manchester
The University of Manchester

Are you getting enough?
Or too much?

Checking antifungal drug levels……Therapeutic Drug Monitoring or TDM

When would we need TDM?
Maximise effectiveness
Minimise side-effects
Our goal:
Some drugs have a relationship between:
- concentration (in blood) and improvement
- concentration (in blood) and side-effects
Hope WW et al. Curr Opin Infect Dis 2008; 21: 580

drugs with a narrow range that is effective but not toxic (therapeutic window)
where we see variation within and between patients

if we suspect drug interactions
to check whether patient is taking the drug (compliance)
if we change the dose
if we think the drug isn’t working

Drugs levels not satisfactory?
Low levels
- worsening of disease
- development of Aspergillus resistance
High levels
developing/worsening of side-effects
more serious side-effects

A few explanations…
each drug has a pharmacokinetic profile:
- what the body does to the drug
- how the drug gets into, through and out of the body
Rate of
Elimination
drugs have linear or non-linear kinetics
Blood drug conc.
Blood drug conc.
Rate of
Elimination
non-linear
linear

Drugs have to reach steady state:
rate of elimination = rate of administration
what’s going in equals what’s coming out!
drugs take different amounts of time to get to steady state

Sample types:
Pre-dose: just before the next dose is due
Post-dose: a set period of time after the drug has been taken, often 2 or 4 hours
Random: at any other time

How do we measure drug levels?
Machines very expensive
Automated methods:
- mass spectrometry
- HPLC
Manual methods:
- bioassay
Time-consuming

Itraconazole

Itraconazole exhibits nonlinear kinetics
Time to steady state
~14 days
Itraconazole, ng/mL plasma
Hours
Barone JA et al. Antimicrob Agents Chemother 1993; 37: 778

Variation in itraconazole kinetics
Less than 0.5mg/L
Variation in post-dose concentrations
Aspergillus in the lung
~17mg/L
Post-dose itraconazole concentrations (mg/L)
Berenguer J et al. Antimicrob Agents Chemother 1994; 38: 1303

Variation affects how well the drug works
Lots of Aspergillus
Relationship between drug level and amount of Aspergillus
Aspergillus in the lung
Less Aspergillus
Post-dose itraconazole concentrations (mg/L)
Berenguer J et al. Antimicrob Agents Chemother 1994; 38: 1303

Itraconazole: relationship between drug level and side-effects
17.1mg/L
Probability of side-effects
Probability of side-effects increase as drug level increases
Pre-dose itraconazole concentrations (mg/L)
Lestner JM et al. Clin Infect Dis 2009; 49: 928

Itraconazole audit
~20% too high
~40% too low
Only ~ 40% of levels were satisfactory

Voriconazole

Voriconazole
Displays nonlinear kinetics in adults
Disproportionate changes when dose altered
Time to steady state ~5 days
Trifilio SM et al. Antimicrob Agents Chemother 2009; 53: 1793
Walsh TJ et al. Antimicrob Agents Chemother 2004; 48: 2166

Voriconazole concentrations in adults receiving 3mg/kg BID
100,000
extensive variation
10,000
1000
High levels:
poor liver function
critical illness
elderly
Log 10 [Concentration (µg/L)]
100
10
1
0
70
140
210
280
days after first dose
Data from Denning DW et al. Clin Infect Dis 2002; 34: 563

Voriconazole: relationship between drug level and success
SUCCESS
1
0.8
0.6
Probability
Pre-dose level greater than 1.0mg/L was significantly better
0.4
0.2
LACK OF RESPONSE
0
0.125
0.25
0.5
1
2
4
8
16
Voriconazole pre-dose blood level, mg/L
Pascual et al. Clin Infect Dis 2008; 46: 201

Voriconazole: relationship between drug level and neurological side-effects
NEURO-LOGICAL
TOXICITY
1
Pre-dose level greater than 5.5mg/L was significantly more toxic
90% probability
at 8mg/L
0.8
0.6
Probability
0.4
0.2
15% probability
at 5.5mg/L
ABSENCE OF
TOXICITY
0
0.125
0.25
0.5
1
2
4
8
16
Voriconazole pre-dose blood level, mg/L
Pascual et al. Clin Infect Dis 2008; 46: 201

Posaconazole

Posaconazole
Displays linear kinetics up to 800mg
Time to steady state ~7-10 days
Minimal differences between pre- and post-dose levels
Courtney R et al. Antimicrob Agents Chemother 2003; 47: 2788
Krishna G et al. Antimicrob Agents Chemother 2007; 51: 812

Posaconazole levels measured by a United States laboratory
Range 0 - 6.57mg/L
16% had undetectable levels
Posaconazole serum level (mg/L)
Number of serum levels (n=202)
Thompson et al. Antimicrob Agents Chemother 2009; 53: 2223

Posaconazole audit
34% of levels <1mg/L: too low
25% of levels >2mg/L
~40% of levels between 1 and 2mg/L

So keep taking your tablets!

Thank you to the Mycology team:
Professor Malcolm RichardsonDr Caroline MooreNichola DuddyElaine TaylorPatrycja Kent
Rebecca CollinsMartin McHughEmma DaviesMonika PergeJoanne Gill
And to you!
www.mycologymanchester.org

Aspergillosis Patients Support Meeting April 2011 - Caroline Moore

by Graham Atherton on Jul 28, 2011

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Aspergillosis Patients Support Meeting April 2011 - Caroline Moore — Webinar Transcript