Posaconazole therapeutic drug monitoring:
Precision vs. pragmatism?





Russell E. Lewis, Pharm.D., FCCP
Associate Professor of Infectious Diseases
Department of Molecular Medicine
University of Padua

Disclosures


  • Royalities: UptoDate

  • Research support: Gilead Inc.

  • Speaking: Avir, Gilead, F2G, Pfizer

  • Advisory: Gilead, F2G, Synexis, Basilea, Cidara

Timeline of posaconazole TDM

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timeline
section Suspension era- <br>TDM essential for all patients
  2006: Suspension formulation approved by the FDA, EMA
  2007: Prophylaxis and refractory IA data: Cornely et al. NEJM: Ullmann et al. NEJM: Walsh et al. CID : Treatment > 1000 ng/mL
  2010: TDM targets- prophylaxis > 700 ng/mL: Jang et al. CP&T 
  2012: "Real-life" validation of 500-700 ng/mL: Dolton et al. AAC: Many other single and multi centre retrospective studies : TDM incorporated in treatment guidelines
section Gastro-resistant tablet/IV era- <br> TDM still essential?
  2013: FDA/EMA approval of posaconazole ER tablets 
  2015: FDA/EMA approval of posaconazole IV formulation: Cornely et al. JAC
  2020: Toxicity threshold? : Nguyen et 2020: Pseudo- <br>hypo- <br>aldosteronism, hepatotoxicity > 3000 ng/mL
  2021: Phase III treatment data: Maertens et al. Lancet 
  2023: No observed ER relationship: Maertens et al.  <br>Clin Drug Investig
section Targeted TDM- <br> which patients?
  2025: Wide PK variability in ICU : Roberts et al. <br> SAFE-ICU <br> Inten Care Med

Case #1: Posaconazole prophylaxis post HSCT


  • 56 year-old female patient with AML undergoing haploidentical HSCT with myeloablative BuFLU -thiotepa

  • Prophylaxis:

    • Micafungin 50 mg/day starting at neutropenia onset until completion of PTCy on days +3,+4

    • Posaconazole ER tablets 300 mg BID day #1, then 300 mg daily starting day+5

    • Patient is also started on letermovir, tacrolimus, mycophenolate, valacyclovir

  • On day +9 of transplant when patient has ANC 50 and mucositis (still can swallow solid food), a posaconazole trough concentration is ordered

  • Result= 450 ng/mL (Target > 700 ng/mL)

What should we do?


  1. No change in dose, repeat TDM in 7 days
  2. Increase dose of posaconazole ER tablets to 400 mg daily, repeat TDM in 7 days
  3. Switch to IV posaconazole (if available)
  4. Switch to oral isavuconazole or IV isavuconazole

Mucositis grading system

(Sonis et al., 1999)

Reduced bioavailibility in the setting of
intestinal mucositis

Dose-escalation during mucositis?


  • Use IV formulation (if available)

  • Pragmatic increase of loading dose to 400 mg BID on day 1, then 400 mg daily

    • Higher doses are generally well-tolerated during treatment of triazole-resistant isolates

      • Hepatotoxicity, pseudohyperaldosteronism (serum levels > 3000 ng/mL)

  • Not always easy to predict who develops severe mucositis-
    citrulline biomarker not routinely used in clinic

    • Follow oral food intake/ Visual assessment?

  • Will higher doses reduce the risk of breakthrough fungal disease?

Delayed attainment of target posaconazole
trough concentrations after HSCT

Study design

Primary study endpoint: Incidence of breakthrough IFIs

Delayed attainment of target posaconazole
trough concentrations after HSCT

Delayed attainment of target posaconazole
trough concentrations after HSCT

(Cao et al., 2024)

Case #2: Posaconazole precision dosing?



  • 65 year-old patient with AML, fever, severe respiratory difficulty following consolidation chemotherapy -absolute neutrophil count 250
  • Patient was receiving voriconazole, but switched to isavuconazole following development of mental status changes
  • Influenzae A positive- oseltamivir
  • Bronchoscopy positive for Aspergillus terreus, galactomannan 3.1

Aspergillus terreus antibiogram


Antifungal MIC (mg/L) EUCAST interpretation
Amphotericin B 4 IE
Anidulafungin >4 IE
Caspofungin >4 IE
Micafungin >4 IE
Isavuconazole 2 R
Voriconazole 1 IE, ECOFF=2
Posaconazole 0.06 S, breakpoint= 0.25

Clinical management



  • Patient is switched to posaconazole ER tablets 300 mg BID day 1, then 300 mg daily
  • After 5 days a posaconazole trough is sent, result =710 ng/mL
  • Patient is clinically stable, improving respiratory status and afebrile

What do you do?


  1. No change in dose, repeat TDM in 7 days
  2. Increase dose of posaconazole ER tablets to 400 mg daily, repeat TDM in 7 days
  3. Use combination therapy
  4. Explore options for olorofim, fosmanogepix?

Do we need to increase the dose?

Or just assume the MIC is 0.25 mg/L?

(Mouton et al., 2018)

One other twist….


  • Patient has a serum albumin of 2.2 mg/dL
  • Trough treatment target 1000-3750 ng/L: free drug (99% protein bound) 10-37.5 ng/mL
  • In theory, her total serum posaconazole concentrations are decreased, but unbound concentration is the same and percent unbound actually increases ~ 2 fold
  • Because TDM results are not reported as free drug, should we “correct” posaconazole results for low albumin?

Corrected total concentration of posaconazole
in this patient?


\[ C_{corr}= C_{obs}\frac{1}{\left( 0.01 + 0.99\frac{Alb}{4.4} \right)} \]

simplified equation as Fu is negligible in denomiator :

\[ C_{corr}= C_{obs}\frac{4.4}{Alb} \]

corrected concentration:

\[ C_{corr}= 1400 ng/mL \]

Are the assumptions valid or close enough?

Percent unbound posaconazole versus unbound concentrations

Percent unbound posaconazole versus unbound concentrations

(Jansen et al., 2022b)

Posaconazole dosing models work!

The reality?

(Salmanton-García et al., 2023)

References

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