What is the best course of action for a patient with a subtherapeutic posaconazole trough concentration of 0.4 mg/L while on posaconazole (Antifungal medication) therapy for invasive fungal infection (IFI) prophylaxis after an allogenic hematopoietic cell transplant?

Management of Subtherapeutic Posaconazole Levels in Post-Transplant Prophylaxis

Increasing the dosage to posaconazole 300 mg as delayed-release tablets twice daily is the most appropriate recommendation for this patient with a subtherapeutic trough concentration of 0.4 mg/L.

Assessment of Current Situation

The patient is a 21-year-old with acute myelogenous leukemia who underwent an allogenic hematopoietic cell transplant 2 weeks ago and is currently receiving posaconazole 300 mg daily (delayed-release tablets) for invasive fungal infection (IFI) prophylaxis. The measured trough concentration of 0.4 mg/L is below the recommended therapeutic target.

Target Posaconazole Concentrations

• For prophylaxis: Target trough concentration should be ≥0.7 μg/mL (0.7 mg/L) 1
• For treatment of established infections: Target trough concentration should be ≥1.0 μg/mL (1.0 mg/L) 2

Rationale for Dose Increase to 300 mg Twice Daily

1. Subtherapeutic level: The current trough concentration (0.4 mg/L) is significantly below the recommended prophylactic target of ≥0.7 mg/L 2, 1

2. Formulation considerations:

   • The delayed-release tablet formulation has better bioavailability than the oral suspension 1
   • Maintaining the same formulation while increasing the dose is preferred over switching to suspension, which has more variable absorption 1

3. Evidence for dose adjustment strategy:

   • According to research, dose adjustment to 200 mg twice daily successfully achieved target concentrations in 89% of patients with initially subtherapeutic levels 3
   • For this patient with a very low level (0.4 mg/L), a higher dose of 300 mg twice daily is warranted to ensure therapeutic levels are achieved 2

Why Other Options Are Less Appropriate

1. Switching to posaconazole immediate-release suspension 200 mg PO every 8 hours:

   • The suspension formulation has more variable absorption and is more affected by food intake, gastric pH, and GI function 1
   • This would be a step backward in terms of reliable drug delivery 2

2. Increasing to posaconazole 400 mg as delayed-release tablets orally daily:

   • Single daily dosing may not provide as consistent drug levels throughout the day as divided dosing 3
   • Research supports divided dosing for patients with subtherapeutic levels 3

3. Switching to posaconazole 300 mg IV daily:

   • While IV formulation ensures 100% bioavailability, it's typically reserved for patients unable to take oral medications
   • The patient can take oral medications, and the issue can be addressed with oral dose adjustment
   • IV administration introduces unnecessary risks (line infections, etc.) when an oral option is viable

Risk Factors for Subtherapeutic Levels to Assess

Several factors may contribute to the patient's low posaconazole levels:

• Body weight: Patients weighing >90 kg are more likely to have subtherapeutic levels 4, 5
• Gastrointestinal issues: Diarrhea significantly reduces posaconazole absorption 4, 3, 6, 5
• Medication interactions: Proton pump inhibitors can reduce posaconazole levels 6, 5
• Metoclopramide use: Regular use is associated with subtherapeutic levels 3

Monitoring Recommendations

1. Repeat posaconazole trough level 5-7 days after dose adjustment 2, 1
2. Target trough concentration should be ≥0.7 mg/L for prophylaxis 2, 1
3. Monitor for adverse effects, particularly with higher doses
4. Assess for and address any contributing factors (diarrhea, drug interactions)

Conclusion

Doubling the daily dose by administering posaconazole 300 mg delayed-release tablets twice daily is the most appropriate intervention to achieve therapeutic drug levels in this post-transplant patient requiring effective fungal prophylaxis. This approach maintains the advantages of the delayed-release formulation while providing a more consistent drug exposure throughout the day.