What is the primary reason for routine posaconazole (Posaconazole) therapeutic drug monitoring (TDM) during its use for prophylaxis and treatment of invasive fungal infections (Invasive Fungal Infections, IFIs)?

Primary Reason for Routine Posaconazole Therapeutic Drug Monitoring

The bioavailability of oral formulations is variable, with a high rate of subtherapeutic trough concentrations, especially with the immediate-release oral suspension.

Evidence Supporting Variable Bioavailability as Primary Reason

Therapeutic drug monitoring (TDM) for posaconazole is primarily recommended due to the significant variability in bioavailability of its oral formulations, particularly the immediate-release oral suspension. This variability leads to unpredictable and often subtherapeutic drug levels, which can compromise clinical efficacy in preventing and treating invasive fungal infections (IFIs).

Pharmacokinetic Variability of Posaconazole

• The IDSA guidelines highlight that posaconazole levels using the suspension formulation are commonly low (<0.7 μg/mL) in patients with documented invasive aspergillosis receiving salvage treatment 1

• Posaconazole suspension demonstrates highly variable absorption that is significantly affected by:

  • Food intake (absorption increased up to 400% when taken with high-fat meals) 1
  • Gastric pH (proton pump inhibitors reduce absorption) 1
  • Gastrointestinal function (diarrhea, mucositis) 1

• A multicenter study found that patients with breakthrough fungal infections had significantly lower median posaconazole concentrations (289 ng/ml) compared to those without infections (485 ng/ml) 2

Formulation Differences and Impact on TDM Need

The need for TDM varies by posaconazole formulation:

Immediate-Release Oral Suspension

• Demonstrates highly variable and often poor bioavailability
• Only 47.1% of patients reach the minimal target concentration of 0.7 mg/L 3
• Breakthrough aspergillosis occurred in 8.7% of patients using the suspension formulation 3
• TDM is strongly recommended for this formulation

Delayed-Release Tablet and IV Formulation

• Show improved and more predictable bioavailability
• 92% of patients reach the target concentration of 0.7 mg/L with the tablet formulation 3
• NCCN guidelines note that TDM may not be necessary for prophylaxis with these formulations as a dose of 300 mg/day results in at least 0.5 μg/mL in >95% of patients 1
• However, TDM may still be valuable in certain high-risk situations

Target Concentrations and Clinical Outcomes

• For prophylaxis: Target concentration of ≥0.7 μg/mL (with some studies suggesting ≥0.5 μg/mL may be effective) 1
• For treatment of established infections: Target trough concentration of ≥1 μg/mL 1
• Multiple studies have demonstrated a clear relationship between posaconazole plasma concentration and clinical efficacy 4

Risk Factors for Subtherapeutic Levels

Even with the improved tablet formulation, certain factors increase risk of subtherapeutic levels:

• Diarrhea (83% of patients with subtherapeutic levels) 5
• Concurrent proton pump inhibitor use (93% of patients with subtherapeutic levels) 5
• Weight >90 kg (48% of patients with subtherapeutic levels) 5
• Other factors: mucositis, early post-transplant period in HSCT recipients 2

Clinical Implications

The Society of Infectious Diseases Pharmacists (SIDP) and other expert groups recommend routine TDM for posaconazole primarily because of the variable bioavailability leading to subtherapeutic concentrations. This variability directly impacts clinical outcomes, with subtherapeutic levels associated with breakthrough fungal infections, which carry significant morbidity and mortality.

TDM allows for dose adjustments to ensure adequate drug exposure, particularly in high-risk patients with factors that may further compromise absorption or in those receiving treatment (rather than prophylaxis) for established infections.