1. The role of antifungal therapeutic drug monitoring (TDM)?
Dr Livingstone Chishimba BSc, MBChB, MRCP
University Hospital of South Manchester
The University of Manchester

2. Outline PK affects the antifungal effect Implications of TDM
Potential indications for TDM-general
Implications of TDM
Itra,vori, posa,
Efficacy and safety
Studies and evidence
Clinical implication

3. Issues Why monitoring? Who to monitor? What? When? Where ?
What action?
clinically relevant ?
exposure–response relationships
exposure–toxicity relationships

4. TDM-which drugs?-general
compounds with ;
a narrow therapeutic window
Warfarin, theophyllins
variable pharmacokinetics (PK)
itra
physiological instability

5. Clinical objectives of TDM
Optimise efficacy
Minimise toxicity
Hope WW et al. Curr Opin Infect Dis 2008; 21: 580

6. Clinical use of TDM drug-drug interactions check compliance
change of dosage
patient failing therapy

7. Antifungal TDM
Itraconazole
Voriconazole
Posaconazole

8. Itraconazole
Itraconazole

9. Two formulations of itraconazole
Excipients differ between generic formulations, and systemic exposure may differ
Capsules
Cyclodextrin excipient
20-50% higher bioavailability
Suspension

10. Itraconazole exhibits nonlinear PK
Time to steady state ~14 days
Once linear clearance achieved, t1/2 ~24 hours
Itraconazole, ng/mL plasma
Hours
Barone JA et al. Antimicrob Agents Chemother 1993; 37: 778

11. 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

12. Variability in itraconazole PK affects the antifungal effect
Significant relationship between drug level and fungal burden
Pulmonary fungal burden
Peak itraconazole concentrations (mg/L)
Berenguer J et al. Antimicrob Agents Chemother 1994; 38: 1303

13. Itraconazole: dose-response relationship in rabbits with IA
Berenguar et al, AAC 1994;38:1303-8

14. Itraconazole: incidence of proven invasive fungal infections
Capsules
Itraconazole trough concentrations of <0.5 mg/L associated with higher mortality (p= 0.039)
Easier to get better levels with suspension
Solution
Total
Favours itraconazole
Favours control
Glasmacher et al JCO 2003

15. Toxicity and itraconazole concentrations
Itraconazole concentration mg/L
Probability of toxicity (%)
NOTE that the highest quintile consists of values ≥ 25.6 mg/L. The line is a logistic regression fit to the individual measurements. 5 10 15 20 25
100 80 60 40
Lestner, Clin Infect Dis 2009 In press

16. Itraconazole: concentration-toxicity relationship
216 patients
mostly capsules
Probability of toxicity
A range of AE, most common:
Fluid retention
Gastrointestinal intolerance
Trough itraconazole concentrations (mg/L)
Lestner JM et al. Clin Infect Dis 2009; 49: 928

17. Itraconazole: concentration-toxicity relationship
Probability of toxicity
Probability of toxicity
low<17.1>high
Trough itraconazole concentrations (mg/L)
Lestner JM et al. Clin Infect Dis 2009; 49: 928

18. Voriconazole

19. 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
Walsh TJ et al. Antimicrob Agents Chemother 2004; 48: 2166

20. 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
Voriconazole datasheet

21. Therapeutic drug monitoring may be useful to optimise therapy for individual patients
A “fast’ metaboliser with relatively low concentrations, who is failing therapy
Dosage escalation from 200 mg bd to 300 mg bd

22. A “slow’ metaboliser: dosage escalation may be too risky and this could be prevented with TDM
Dosage escalation from 200 mg bd to 300 mg bd

23. 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)

24. 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)
Chishimba L, denning D et al 2011 (unpublished data)

25. Chishimba L, denning D et al 2011 (unpublished data)

26. Posaconazole

27. Posaconazole Saturation of absorption above 800mg/day
Displays linear PK with dosages of mg
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
Krishna G et al. Antimicrob Agents Chemother 2007; 51: 812

28. Posaconazole as salvage therapy for invasive aspergillosis: exposure-response relationship
Walsh TJ et al. Clin Infect Dis 2007; 44: 2

29. 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
2005

30. Antifungal TDM-Which drug to monitor?
Necessary
Itraconazole
Voriconazole (especially IV, children, complex case)
Flucytosine

31. Antifungal TDM-Which to drug to monitor?
Unnecessary
Amphotericin B
Echinocandins (not much data though)
Fluconazole (unless short gut and oral administration, or compliance)
Desirable
Posaconazole (probably)

32. 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

33. 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

34. Posaconazole TDM in clinical practice
Targets not well defined
Trough >0.5mg/L prophylaxis
Trough mg/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
Andes D et al. Antimicrob Agents Chemother 2009; 53: 24

35. 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!