Episode #57 – Fun-Gals Just Want to Have Fun: Antifungal with SIDP Breakpoints

Agent

Ashok et al. (10.1007/s12281-022-00430-4)

Chau et al. (10.1111/imj.15587)

Kably et al. (10.1097/FTD.0000000000000952)

Itraconazole

Treatment:

Routine for treatment irrespective of formulation

Prophylaxis:

Capsules – Routine for prophylaxis

Solution – Routine for prophylaxis

SUBA-Itra – Selected cases at risk of low exposure (e.g. DDIs)

Other:

TDM for patients who initiate/discontinue interacting med, undergo a formulation change, or demonstrate lack of response or sign of toxicity

Ranges:

Treatment – >1-1.5 mg/L

Prophylaxis – >0.25-0.5 mg/L

Toxicity – 3-5 mg/L

Timing:

5-7 days (loading dose); troughs

10-14 days (no loading dose); troughs

Thereafter, every 1-2 weeks once steady state achieved

Indication:

To ensure adequate absorption; therapeutic concentration

Treatment:

Routine for treatment irrespective of formulations

Prophylaxis:

Capsules – Routeine for prophylaxis

Solution – Routine for prophylaxis

SUBA-Itra – Recommended in selected cases at risk of low exposure (e.g. DDIs, GI complications, and young children)

Ranges:

Treatment – 1-4 mg/L (HPLC) (AII for efficacy, BIII for toxicity)

Prophylaxis – 0.5-4 mg/L (HPLC) (AII for efficacy, BIII for toxicity)

Timing:

5-7 days (loading dose); troughs

10-14 days (no loading dose); troughs

Adjustment:

–               If subtx, increase dose by 25-50%

–               If taking capsules, also consider switch to solution or SUBA-Itra

–               Ensure capsule taken with food, avoid H2RA/PPIs

–               Ensure solution on empty stomach

“ITZ TDM is still recommended, but the benefit-to-risk ratio for prolonged prophylaxis in CF is a matter of debate.”

TDM Recommendation:

>0.5-1 mg/L (various references)

Voriconazole

Treatment:

Routine for treatment irrespective of formulation

Prophylaxis:

Limited evidence for routine TDM in prophylaxis

Ranges:

Treatment – >1.7-2 mg/L; >2 mg/L if high risk, poor prognosis, bulky disease

Prophylaxis – not established

Toxicity – 4-6 mg/L; routine LFT monitoring and for clinical signs of neurotoxicity recommended

Timing:

Within 2-5 days of initiating therapy

Repeat at 3-5 days may be warranted in: Critical illness, suspected treatment failure, DDIs, or change in dosing

Indication:

To detect therapeutic and toxic concentrations

Treatment:

Routine for treatment

Prophylaxis:

Recommended for prophylaxis

Ranges:

Treatment – 1-5.5 mg/L (AII); CNS infection, bulky disease, multifocal infection > 2 mg/L (BIII)

Prophylaxis – 1-5.5 mg/L (AII)

Timing:

2-5 days; trough

Adjustments:

–               0.0–0.49 mg/L: increase by 50%

–               0.5–0.99 mg/L: increase by 25%

–               1.0–5.5 mg/L: no change

–               > 5.5 mg/L and asymptomatic: decrease dose by 25%

–               > 5.5 mg/L with drug-related toxicities: hold one dose and decrease subsequent doses by 50%

“VRZ is the most challenging. There is a large consensus that the drug must be detectable with a trough level .1 mg/L, but contradictory findings have been reported concerning the upper range for trough level. In patients with normal hepatic function, outside the loading dose period, in the absence of significant metabolic inhibition, trough levels .4 mg/L (the peak value established after the PK exploitation of pivotal trials) is unlikely to be achieved with the standard 200 mg ·2 dose. Moreover, safety issues limit the maintenance of high exposures and doses in clinical practice.367–369 The 1-5.5-6 mg/L trough target recommended on the basis of weak evidence is frequently applied as a 1–4 mg/L target, resulting, in clinical practice, in a median or average trough exposure of 1–3 mg/L.”

TDM Recommendation

1-2 to 4-6 mg/L (various references)

Posaconazole

Treatment:

Routine for treatment (not required for intravenous)

Prophylaxis:

Suspension– Routine for prophylaxis

Tablets – Selected cases at risk for low exposure

Intravenous – Not required

Ranges:

Treatment – >1-1.25 mg/L

Prophylaxis – >0.5 mg/L

Toxicity – > 4 mg/L associated with PIPH

Timing:

7 days

Indication:

To ensure adequate absorption; therapeutic conecntration

Treatment:

Routine for treatment irrespective of formulations

Prophylaxis:

Suspension – Routine for prophylaxis

Tablets – Recommended for selected cases at risk of low exposure (e.g. DDIs, GI complications, young children)

Ranges:

Treatment – > 1 mg/L (AII)

Prophylaxis – > 0.5 (AII for susp.; BII for tabs)

Timing:

After 5-7 days; troughs preferred, untimed concentrations usable given steady serum concentration over time

Early monitoring (e.g. day 2) may be predictive of steady-state concentration

Adjustments:

Suspension:

Prophylaxis: if subtherapeutic, increase to 200 mg four times daily or 300 mg three times daily

Treatment: if subtherapeutic, increase to 400 mg three times daily

Ensure patient taking suspension with food and/or acidic beverage, and avoid H2 antagonists and proton pump inhibitors

Switch to modified-release formulation if patient can swallow tablets

Tablets:

If subtherapeutic, increase to 400 mg daily

Consider administering with high fat meal if previously taken tablets in fasted state

Intravenous:

No data

“PSZ TDM is recommended, especially in curative situations. However, even recent recommendations refer to initial exposure achieved with the oral suspension and do not consider the new tablet formulation. In cases of prophylaxis, the low rate of events limits the demonstration of a clinically relevant threshold. The initial 0.5 or 0.7 mg/L threshold seems appropriate and the question as to whether less than 300 mg can be used with tablets is justified.”

TDM Recommendation

> 1 mg/L (various references)

Fluconazole

Treatment: Consider in select circumstances for IFD treatment:

–               Critical illness

–               Renal replacement

–               CNS infection

–               Treatment failure

Ranges:

Efficacy – Trough of 10-15 mg/L (or AUC/MIC > 50). However, not well elucidated.

Toxicity – Threshold not well established. 

Timing:

Optimal timing unclear

“We recommend against routine TDM of fluconazole (Not recommended, Level II evidence).”

Table:

Timing/Ranges:

None specified

Considerations:

May be utilised in certain clinical circumstances for IFD treatment (e.g. critically ill patients with sepsis, patients with altered renal function, sanctuary site infections such as CNS, treatment failure or concerns for medication noncompliance)

“There is no major new insight regarding TDM for 5FC, FCZ, AmB, and echinocandins. […] The usual targets for FCZ are consistent over time, but the low level of recommendation for TDM raises a number of issues, particularly in cases of IV administration, impaired renal function, and ICU settings.”

TDM Recommendation:

10-15 mg/mL (PMID: 32026399, 32535150)

Isavuconazole

Treatment: Consider in select circumstances for IFD treatment:

–               Critical illness

–               Renal replacement

–               CNS infection

–               Treatment failure

–               GVHD

–               ECMO

–               Obesity

Ranges:

Efficacy – Not well elucidated.

Toxicity – 5 mg/L, not consistently demonstrated. 

Timing:

Single trough once steady state has been achieved (2-3 weks); value of repeat testing unclear

“No significant relationship was identified between drug exposure and mortality, clinical responses, overall response or safety outcomes in the SECURE study. However, interindividual variation exists and one trial has demonstrated exposure-related gastrointestinal side-effects, with increased incidence for steady-state concentrations between 4.87 and 5.13 mg/L.”

mrda

Table:

“No”

“ISZ TDM is not generally recommended. However, ISZ use is frequently based on particular clinical features identified as beneficial by TDM.”

TDM Recommendation:

> 1 mg/L (PMID: 32535150)