antifungcase

KKGT	Stichting Kwaliteitsbewaking Klinische Geneesmiddelanalyse en Toxicologie

1^stROUND DISCUSSION OF THE PATIENT CASE OF THE INTERNATIONAL INTERLABORATORY QUALITY CONTROL PROGRAM FOR ANTIFUNGAL DRUGS

For preface click here:

CASE DESCRIPTION:
A child (10 years old) diagnosed with AML is submitted for chemotherapy. While in aplasia she developed fever for which simultaneous ceftazidim and vancomycine were started. Her temperature was 38.3°C. The child received phenethicillin 125 mg three times daily, itraconazol oral solution 170 mg once daily, cotrimoxazole 3 times a week and ciprofloxacin 500 mg twice daily. Acetaminophen was given on demand. Two days later, there was an increased oxygen need because of shortness of breath and fatigue, suspected for a pneumonia or ARDS. Because of the persisting fever and typical markings on chest radiograph a fungal infection was suspected upon which voriconazole was started (200 mg two times daily; 08:00 and 20:00u) as empiric treatment. Despite the start of voriconazole no improvement was noticed after five days of therapy.
The physician sends two samples (07:30u = round 1-A and 09:45u = round 1-B).

The sample contains voriconazole, fluconazole, itraconazole, hydroxy-itraconazole and posaconazole.
You are requested to report the analytical results for these components in the table below and to answer the following questions regarding the case description together with the analytical results for voriconazole.

A)         There is no evidence for dosage adjustment; voriconazole is switched to amfotericin B
B)         Voriconazole level is too low; increase dosage to 300mg two times daily and evaluate voriconazole level
C)         Dosage is is too low; increase dosage to 400mg two times daily and evaluate voriconazole level
D)         Other.......

ADVISES REPORTED BY PARTICIPANTS:

N in %	Correct advise: B and C Incorrect advise: A
	N total = 23
	N advise = 15 (=83%)

Additional comment of participants:

	Comment of labs X and Y
	X: Under adequate prophylaxis and after five days of therapy with voriconazole, this patient still has clinical signs of an infection. After five days of therapy voriconazole through levels are too low (≥ 2 mg/l). Because there is the possibility of azole resistance possibly induced by subtherapeutic levels of voriconazole, we recommend to switch to liposomel Amphoterian ß according to the Dutch mycosis guidelines.
	Y: We would also check the mg/kg bodyweight of the patient (not available in the case description)

GENERAL COMMENTS ON THE ROUND A 2008
There is a considerable variability between the measured azole concentrations by the different centres, ranging from 10-200%. Especially itraconazole, voriconazole and posaconazole in the lower range seems difficult to measure for the participants. But also large differences are encountered with the concentrations that lie within the therapeutic range. This indicates the need for further improvement of the method in order to provide a solid advice to the clinicians

COMMENT ON THE CASE:
Itraconazole prophylaxis was continued during voriconazole therapy by the physician, which was stopped after reviewing the medical chart of the patient by the clinical pharmacist. Concomitant use is not advocated as there is no supportive evidence.

Sample A contained voriconazole 0.311 mg/L (trough) and sample B contained 1.32mg/L (peak). Evidence is gathering that plasma concentrations correlate with outcome yielding the need of therapeutic drug monitoring of voriconazole . The plasma concentrations in this case are considered too low ^1-3 . Based on the current expert opinions the trough plasma concentrations aimed for are ≥ 1-2 mg/l.
Answer A is incorrect as in the recent published guideline of treatment of aspergillosis of the Infectious Diseases Society of America therapeutic drug monitoring of voriconazole is advised in case treatment with voriconazole is not successful ⁴ .
Both answers B and C are correct. The next question that should be addressed is: what is the most appropriate dosage increase in this situation. The pharmacokinetics differ between children (near-linear) and adults (non linear) and therefore this has to be taken into account when adjusting the dosage ⁵ . In case of progressive disease or being critically ill (e.g. ICU) a more aggressive approach as in answer C can be preferred. Measuring voriconazole plasma concentrations after dosage adjustment is important as there is a considerable variability in achieved concentration rise.

Reply to lab X
Despite using itraconazole oral solution in a few cases absorption is not adequate and therefore prophylaxis will probably fail. The induction of azole resistance within the short period of therapy is not likely. However, resistance of Aspergillus to azole drugs is emerging and should be taken into account when therapy is failing. The choice for a lipid formulation of amphotericin B is then appropriate.

Reply to lab Y
The dosage of voriconazole is according to product information leaflet: two times daily 200 mg oral for children aged 2-12 years. In this case the girl weighed 29 kg.

Reference List

¹D. W. Denning, et al., "Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis," Clin. Infect. Dis. 34(5), 563 (2002).

²Andres Pascual, et al., "Voriconazole Therapeutic Drug Monitoring in Patients with Invasive Mycoses Improves Efficacy and Safety Outcomes," 46(2), 201 (2008).

³J. Smith, et al., "Voriconazole therapeutic drug monitoring," Antimicrob. Agents Chemother. 50(4), 1570 (2006).

⁴T. J. Walsh, et al., "Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America," Clin. Infect. Dis. 46(3), 327 (2008).

⁵T. J. Walsh, et al., "Pharmacokinetics and safety of intravenous voriconazole in children after single- or multiple-dose administration," Antimicrob. Agents Chemother. 48(6), 2166 (2004).

2^ndROUND DISCUSSION OF THE PATIENT CASE OF THE INTERNATIONAL
INTERLABORATORY QUALITY CONTROL PROGRAM FOR ANTIFUNGAL DRUGS

CASE DESCRIPTION:

A 30-year male patient is diagnosed as HIV positive since June 2004. In February 2008 the patient reports at the outpatient clinic for routine clinical check-up. The patients’ current medication is lamivudine/ zidovudine (Combivir® 300/150 mg bid) and lopinavir/ritonavir (Kaletra®, 400/100mg bid). His laboratory analysis shows a low CD4+ cell count (180 cells/ml) and the patient is complaining of frequent diarrhea.
Upon these results his antiretroviral drugs are changed to lamivudine/ zidovudine (Combivir®, 300/150 mg bid) and efavirenz (Stocrin®, 600 mg qd).
A month later he reports again at your outpatient clinic. He is in bad condition and states that he is suffering from pain in his eyes. The ophthalmologist finds an invasive Aspergillus fumigatus for which she starts with oral voriconazole twice daily 400 mg for 24 hours, followed by 200 mg twice daily. After 3 days a trough concentration (half hour before the next dose) (round 2-A) and a sample 3 hours after oral intake (round 2-B) is taken.
The sample contained voriconazole, fluconazole, itraconazole, hydroxy-itraconazole and posaconazole.
You were requested to report the analytical results for these components in the table below and to answer the following questions regarding the case description together with the analytical results for voriconazole.

A) Concomitant administration of voriconazole and efavirenz must be avoided
B) voriconazole concentration is too low; increase dosage to 400 mg twice daily and evaluate voriconazole level
C) voriconazole concentration is too high; decrease dosage to 150 mg twice daily and evaluate voriconazole level
D) Other.......

ADVISES PARTICIPANTS:

	Correct advise: b
	N total = 21
	N advise = 18 (=86%)

N in %

Additional comment of labs

La	Comment
A.	Advise B and decrease efavirenz to 1 dd 300 mg
B.	Advise B. The through concentration is very low, which can be caused by non-compliance of the patient or an increased clearance of the drug. Assuming good compliance the estimated half-life is short (<2,5h). Concerning the patient’s co-medication, a possible induction of CYP₃A₄ by efavirenz is suspected, which could explain the short half-life and the low through concentrations. However, the 3-hour concentration as measured is quite high. This is in contrast to the substantially reduced peak concentrations as reported for combination therapy of efavirenz with voriconazole. Thus, patient compliance should be questioned. Interindividual variability of voriconazole pharmacokinetics is large and the therapeutic range is still not well defined. However, indirect evidence suggests that voriconazole efficacy at plasma concentrations > 2,05 mg/l is higher particularly if more resistant fungi as in this case have to be treated. To reach these concentrations voricinazole doses should be increased to 2 x 400 mg/d. Because of the nonlinearity of voricinazole pharmacokinetics in some patients, voriconazole concentrations should be reassessed 2-3 days after dose adjustments. In addition, dose reduction of efavirenz (e.g. 300 mg per day) during voriconazole therapy should be considered since an increased exposure to efavirenz during co-treatment with voriconazole has been reported.
C	Advise B. Voriconazole concentration is too low; increase dosage to 400 mg twice daily and evaluate voriconazole level and adjust efavirenz to 300 mg qd. (Damle et al. Br J Clin Pharmacol. 2008)
D	Advise B. Reduce efavirenz to 400 mg/day and evaluate efavirenz concentration.
E	Advise B. Increase dosage of voriconazole to 400 mg bid and evaluate voriconazole level, decrease dosage of efavirenz to 300 mg qd.
F	Advise D. Voriconazole is too low, increase dosage to 300 mg and remeasure voriconazole level. Efavirenz exposure probably too high, so dose must be reduced to 300 mg qd.
G.	Advise B. Co-administration of standard dose voriconazole and efavirenz results in a substantial decrease in voriconazole levels, while concurrently increasing efavirenz levels. When co-administered, voriconazole dose should be increased to 400 mg q 12 h in order to provide systemic exposures similar to standard-dose monotherapy. (Damle B et al. Br J Clin Pharmacol 2008, 65 (4): 523-30)
H	Advise B. Voriconazole concentration is too low; increase dosage to 400 mg twice daily; decrease efavirenz dosage to 300 mg qd and evaluate voriconazole level.
I	Advise B and monitoring of efavirenz blood levels for possible efavirenz dose adjustment.
J.	Advise B and decrease efavirenz dosage with 50%. Evaluate both efavirenz and voriconazole levels.

Comment on the case:

Voriconazole plasma concentrations were:
Sample taken 3 hours after dosing: 2.18 mg/L
Trough sample= 0.105 mg/L

Voriconazole is co-administered with efavirenz. Efavirenz is an non-specific inducer of cytochrome P450 enzymes and will decrease exposure of voriconazole. Voriconazole will cause an increase in efavirenz exposure most probably due to inhibition of cytochrome P450 3A4. (Damle et al, Br J Clin Pharmacol 2008).
The bioavailability of voriconazole when given alone is >90%, but when co-administered with efavirenz, this drug will effect the gastrointestinal enzymatic processes resulting in a decreased Cmax and thus a lower bioavailability. The exact extend on voriconazole bioavailability is not known since equivalent dosages are not compared. The plasma concentration at 3 hours post dose is a little higher than expected based on population data but since interindividual variation is large it is considered within a normal range.
Due to induction of cytochrome P450 enzymes the clearance of voriconazole will be higher resulting in a shorter terminal half life of voriconazole. Plasma trough concentrations will be lower.
Evidence for cut-off points for efficacy and toxicity of voriconazole is gathering (Pascual et al, CID 2008). Plasma trough concentrations of > 1 mg/L are pursued for efficacy when the focus of the infection is in the lung and > 2mg/L for sanctuary sites.
Management: Voriconazole trough concentrations are too low. Voriconazole dosage should be adjusted to 400 mg twice daily to attain these targets. Furthermore the dose of efavirenz should be reduced to 300 mg QD (tablets) or 400 mg QD (oral suspension, because of 20% lower bioavailability; SmPC Stocrin/ Sustiva) and concentrations should be monitored by therapeutic drug monitoring. Voriconazole trough plasma concentrations after dose-adjustments can best be reassessed after 2 or 3 days but preferably within one week.

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