1. Anti-fungal therapeutic drug monitoring and azole dose modification
Tim Felton

2. Contents Triazoles – an overview Therapeutic drug monitoring (TDM)
Specific drugs

3. Triazoles Bind cytochrome P450-enzyme lanosterol 14- demethylase
Inhibits the conversion of lanosterol to ergosterol
Fluconazole
Itraconazole
Voriconazole
Posaconazole
(Isavuconazole)
membrane

4. Emergence of resistance
Therapeutic window

5. Exposure
Peak Concentration
AUC
MIC
Time>threshold

6. Indications for TDM
Variable pharmacokinetics

7. PK-PD: the black arts Survival Resolution of clinical syndrome DOSE
OUTCOME OF CLINICAL INTEREST/IMPORTANCE
BIOMARKER
Quantifiable
Linked to pathogenesis
Linked to an outcome
of clinical interest
Survival
Resolution of clinical syndrome
Conc
Dose
PHARMACOKINETICS
PHARMACODYNAMICS

8. Pharmacokinetic variability
Voriconazole Concentration (mg/L)
Toxic
20 patients given IV voriconazole 4mg/kg
Sub-therapeutic
Time (hours)

9. Pharmacokinetic variability
Monte Carlo simulations from the population pharmacokinetic model for oral (A) and i.v. (B) therapy. Intravenous (i.v.) therapy results in higher measures of drug exposure compared with oral therapy.
Hope WW. AAC In press

10. Pharmacokinetic variability
FIGURE 1 . A Monte Carlo simulation from the population pharmacokinetic model of AbuTarif 17 showing the median along with the 5th and 95th percentiles for concentration-time profiles of 5000 simulated patients throughout the first week of therapy for patients receiving posaconazole 200 mg every 8 hours. A 2-compartment model with the following parameters was used: Ka h-1, elimination rate constant h-1 (between-subject variability 0.221), and V/F 3290 L (between-subject variability 0.156). The simulations were performed using the pharmacokinetic program ADAPT 5.
Howard S. TDM :72-76

11. Pharmacokinetic variability
Absorption
Vomiting
Diet
Genetic differences in drug-transport/gut-metabolism
Concomitant medications
Distribution
Amount of body fat
Presence of extravascular fluid collections
Hypoalbuminaemia
Metabolism
Hepatic dysfunction
Genetic differences in drug-metabolism
Concomitant medications
Excretion
Renal insufficiency
Genetic differences in drug-elimination pathways
Genetic variabilty P-glycoprotein
Concomitant medications - PPI

12. Pharmacogenomics
CYP2C19 status makes a big difference to voriconazole levels, but only accounts for a small portion of observed variance

13. Absorption Suspension (fasted) Suspension (non-fat meal)
Suspension (high-fat meal)
Postprandial posaconazole exposure was greater when administered as a suspension than as a tablet formulation. Compared with the tablet formulation, the oral suspension increased mean posaconazole AUC (0,72 h) by 37% (p = 0.001) and Cmax values by 23% (p = 0.004). All but two of the 20 subjects had increased systemic exposure to posaconazole with the suspension vs the tablet formulation. [Courtney p220]
Mean AUC(0.72 h) and Cmax values of posaconazole suspension were four-fold greater when administered with a high-fat meal than when administered while fasted (p < 0.001). Administration of posaconazole suspension with a non-fat meal also enhanced exposure, with mean AUC(0,72 h) and Cmax values 2.6-fold and three-fold greater than the fasted state, respectively (both P < 0.001). [Courtney p220]
Courtney R et al. Br J Clin Pharmacol 2004;57(2):218–222.
Time (hours)
Courtney R . Br J Clin Pharmacol 2004:218–222. 13

14. Saturation of metabolism
6 mg/kg i.v 2 dosages
4 mg/kg b.d. i.v
200 mg bd oral
And, the PK are nonlinear

15. Saturation of metabolism
Dosage escalation from 200 mg bd to 300 mg bd

16. Indications for TDM Variable pharmacokinetics
Clinically relevant exposure–response relationships

17. Exposure-response relationship
Rabbit Neonatal HCME with anidulafungin
Warn PA. AAC In press

18. Indications for TDM Variable pharmacokinetics
Clinically relevant exposure–response relationships

19. Experimental IPA in rabbits
Berenguar et al, AAC 1994;38:1303-8

20. Exposure-trough conc.
Relationship between the AUC0-12 and the trough concentration at the end of the first week of voriconazole for 43 patients receiving voriconazole (6 mg/kg i.v. for 2 doses followed by 4 mg/kg i.v.). The values are highly positively correlated (Spearman coefficient, 0.977; 43 observations; P < 0.01). Only 7/43 patients had trough concentrations of <1 mg/liter.
Hope WW AAC :

21. In-vitro alveolus model of IPA
Jeans. A. JID In press

22. Clinical IPA
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Probability effect
Effect 1 2 3 4 5 6 7 8 9 10
Voriconazole trough concentrations (mg/L)
181 measurements with high-pressure liquid chromatography were performed during 2388
treatment days in 52 patients. A
Pascual et al. CID :201-11

23. Indications for TDM Variable pharmacokinetics
Clinically relevant exposure–response relationships
Clinically relevant exposure–toxicity relationships

24. Concentration-toxicity
—Predicted probability of an adverse event vs. concentrations of itraconazole, from the logistic regression model. Data are mean values (95% confidence intervals) for the study population within 5 quintiles (determined by plasma itraconazole concentration level). The highest quintile includes values ⩾25.6 mg/L. The solid line represents a logistic regression model fitted to the measurements from each patient. The parameters for logistic regression are as follows: intercept, −0.111; coefficient, 0.151; odds ratio, (95% confidence interval, ; P<.001
Lestner J M. CID :

25. Clinical IPA 1 2 3 4 5 6 7 8 9 10
Voriconazole trough concentrations (mg/L)
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Probability effect or toxicity
Effect
Toxicity
181 measurements with high-pressure liquid chromatography were performed during 2388
treatment days in 52 patients. A
Pascual et al. CID :201-11

26. Indications for TDM Variable pharmacokinetics
Clinically relevant exposure–response relationships
Clinically relevant exposure–toxicity relationships
Narrow therapeutic window

27. Clinical IPA Therapeutic window 1 2 3 4 5 6 7 8 9 101 2 3 4 5 6 7 8 9 10
Voriconazole trough concentrations (mg/L)
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Probability effect or toxicity
Effect
Toxicity
181 measurements with high-pressure liquid chromatography were performed during 2388
treatment days in 52 patients. A
Pascual et al. CID :201-11

28. Indications for TDM Variable pharmacokinetics
Clinically relevant exposure–response relationships
Clinically relevant exposure–toxicity relationships
Narrow therapeutic window
Unable to rapidly assess response
Serious/poor prognostic disease
Drug–drug interactions
Compliance
Dosage adjustment
PD of hyper/hypotension

29. Specific dugs Fluconazole Itraconazole Voriconazole Posaconazole
Indication
Pharmacology/pharmacokinetics
Exposure–response relationship
Exposure–toxicity relationship
TDM target
membrane

30. Fluconazole Indication Pharmacology/pharmacokinetics
Prophylaxis
Empirical therapy
Treatment of superficial and invasive candidiasis
Pharmacology/pharmacokinetics
Linear PK
High bioavailability
Exposure–response relationship
Well defined
Patients with mucosal candidiasis
Rodríguez-Tudela J L. AAC :

31. Fluconazole Exposure–toxicity relationship TDM target
High LFTs, nausea, vomiting, seizures at high dosages
TDM target
Wide therapeutic index
Treatment of isolates with reduced susceptibility
Poor absorption
Paediatric patients

32. Itraconazole Indication Prophylaxis of IFI Treatment of IPA
Treatment of CPA
Treatment of ABPA
Hydroxyitraconazole produced in a 1:1 ratio

33. Itraconazole Pharmacology/pharmacokinetics
Highly lipophilic and protein bound
 capsule solubility in acidic environment
Different manufactures' capsules behave differently
 absorption with PPI and H2-antagonists
Suspension (cyclodextrin) 20-50% higher bioavailability
Non-linear (probably)
Extensive variability
Active metabolite (OH-itraconazole) (bioassay/HPLC)
CYP3A4
Poorly soluble
Hydroxyitraconazole produced in a 1:1 ratio

34. Itraconazole Exposure–response relationship
Peak itraconazole levels and successful outcome of mucosal candidiasis in patients with AIDS
In vivo data
Exposure–toxicity relationship
Gastrointestinal intolerance, hypokalaemia, fatigue, ankle oedema, cardiac failure and deranged LFTs
Nausea more common with suspension (cyclodextrin)

35. Itraconazole TDM target 200mg b.i.d. Trough concentration Lower level
Prophylaxis in neutropenia & treatment of oesophageal candidasis in HIV
0.5mg/L HPLC or 5mg/L bioassay
Upper level
17mg/L (bioassay)due to high probability of toxicity

36. Itraconazole Tips to improve low levels Usually poor absorption
Capsule with food or acid drink?
Stop PPI or H2-antagonist (if possible)
Compliance
Consistently prescribe the same preparation
Check for drug interactions
Increase to capsule 300mg twice daily or change to suspension 200mg twice daily
Check serum levels again!
(enzyme inducers - rifampicin, phenytoin, carbamazepine)

37. Itraconazole Tips to reduce high levels +/- toxicity
Usually saturated clearance
Stop drug for 1-2 weeks
Re-start at a lower dose
Check serum levels again!

38. Voriconazole Indication Pharmacology/pharmacokinetics
Disseminated candidasis
IPA and CPA
Pharmacology/pharmacokinetics
Excellent bioavailabilty (96%)
IV preparation – cyclodextrin (potentially nephrotoxic)
Marked PK variability (100-fold)
Sex, age and CYP2C19 genotype only partially explain
Weight important in paediatric patients
CYP2C19, 3A4 and 2C9 substrate
(polymorphisms present in  4% whites,  20% Asian patients)
High levels in poor hepatic function, critical ill- ness, poor metabolizer CYP2C19 genotype and the elderly.
Herbrecht R. NEJM :408-15

39. Voriconazole Exposure–response relationship
In-vivo, in-vitro and clinical data
Exposure–toxicity relationship
Gradual increase in probability with increasing concentration
Abnormal LFTs, visual disturbance, photosensitivity, confusion etc
Pascual et al. CID. 2008:46;201-11

40. Voriconazole TDM target 200mg b.i.d. (i.v. loading dose)
Trough concentration
Lower level
Trough 1mg/L associated with 70% probability of success
Upper level
Less well established
>6mg/L associated with high probability of CNS toxicity and hepatitis

41. Voriconazole Tips on use Tips to improve low levels
Loading dose
Switch IV to oral
Tips to improve low levels
Dosage escalation carefully by 50mg daily
Check levels every 1-2/52
Tips to reduce high levels +/- toxicity
Stop for 1 week or by TDM then reduce dosage
Stop omeprazole
Check levels

42. Posaconazole Indication Pharmacology/pharmacokinetics
Salvage therapy IPA
Prophylaxis neutropenia and HSCT
Pharmacology/pharmacokinetics
Only oral suspension
Linear PK to 800mg/day
Absorption saturated above 800mg/day
Better absorption with fatty food and low stomach pH
Long t½ with comparable average and trough levels
Variability
1 week to reach steady state
Felton TW. CID. 2010;51:

43. Posaconazole Exposure–response relationship
In-vivo (mouse IC and rabbit IPA)
Increased clinical response with increasing average and trough concentration
Exposure–toxicity relationship
GI intolerance, abnormal LFT
No dose dependent
Walsh T. CID

44. Posaconazole TDM target 400mg b.i.d
Trough concentration (but long t½ life)
Lower level
>0.7mg/L
Higher might be better if formulation/cost allowed!
Upper level
Not known/defined

45. Posaconazole Tips to improve low levels
Fatty foods, milk or fatty food supplements
Stop enzyme inducers
Stop PPIs
Can try fractionating the regimen
Dosage escalation unhelpful above 800mg/day
Serum level changes are unpredictable
Rifampacin, carbamazepine, phenytonin etc

46. Indications for TDM Variable pharmacokinetics
Clinically relevant exposure–response relationships
Clinically relevant exposure–toxicity relationships
Narrow therapeutic window
Unable to rapidly assess response
Serious/poor prognostic disease
Drug–drug interactions
Compliance
Dosage adjustment
PD of hyper/hypotension

47. Emergence of resistance
Therapeutic window

48. Conclusions TDM required for itraconazole and voriconazole
Probably for posaconazole
TDM should
Improve outcomes
Reduce emergence of resistance
BUT there is an associated cost
(especially in more severe disease with less therapeutic options

49. Fungal infection and allergy
Invasive fungal infection
High mortality and morbidy
Chronic fungal infection
Fungal allergy
High morbidy
Could do 2 slides with graphs

50. Fungal infection and allergy
Triazole are the most commonly used treatment
Increasing levels of triazole resistance
Could do 2 slides with graphs

51. Saturation of metabolism
Voriconazole i.v. switching to 300 mg po bd

52. Saturation of metabolism
Voriconazole i.v. switching to 400 mg po bd