Primary Reason for Routine Posaconazole Therapeutic Drug Monitoring
The bioavailability of oral posaconazole formulations is variable, with a high rate of subtherapeutic trough concentrations, especially with the immediate-release oral suspension. 1, 2
Variability in Posaconazole Bioavailability
The NCCN guidelines clearly identify that posaconazole, particularly the oral suspension formulation, demonstrates significant variability in bioavailability that necessitates therapeutic drug monitoring (TDM) 1. This variability is influenced by several key factors:
- Food effect: Administration with or after a high-fat meal can enhance absorption up to 400% 1
- Gastric pH: Proton pump inhibitors can reduce plasma concentrations due to increased gastric pH 1, 3
- Gastrointestinal function: Conditions like diarrhea or mucositis significantly impact absorption 4, 3
Evidence Supporting Subtherapeutic Concentrations as Primary Concern
Multiple studies have demonstrated the relationship between subtherapeutic posaconazole concentrations and breakthrough fungal infections:
- A multicenter study found that patients who developed breakthrough fungal infections had significantly lower median posaconazole concentrations (289 ng/ml) compared to those who did not (485 ng/ml) 4
- In a study of patients receiving the oral suspension, 53% failed to achieve the target concentration of 0.7 mg/L, resulting in an 8.7% rate of breakthrough aspergillosis 5
- Even with the improved tablet formulation, 18% of patients still had subtherapeutic concentrations (<700 ng/mL) in one study 3
Target Concentrations and Monitoring Recommendations
The guidelines establish clear target concentrations for posaconazole:
- For prophylaxis: ≥0.7 μg/mL (with some studies suggesting ≥0.5 μg/mL may be effective) 1
- For treatment of established infections: ≥1 μg/mL 1
TDM should be performed on day 5 of therapy or soon thereafter to ensure adequate exposure 1. While the delayed-release tablet and intravenous formulations have improved bioavailability compared to the suspension, TDM may still be valuable in high-risk situations 1, 2.
Formulation Differences
The guidelines note important differences between posaconazole formulations:
- Oral suspension: Highly variable absorption, significantly affected by food, gastric pH, and GI function 1, 2
- Delayed-release tablet: Improved absorption and more predictable bioavailability; not affected by gastric pH or proton pump inhibitors 1
- Intravenous formulation: Similar pharmacokinetics and safety compared to the delayed-release tablet 1
Risk Factors for Subtherapeutic Levels
Even with the improved tablet formulation, certain risk factors are associated with subtherapeutic concentrations:
- Diarrhea (83% of patients with subtherapeutic levels) 3
- Concomitant proton pump inhibitor use (93% of patients with subtherapeutic levels) 3
- Weight >90 kg (48% of patients with subtherapeutic levels) 3
Clinical Implications
The primary concern with variable bioavailability is the risk of treatment failure due to subtherapeutic concentrations. Breakthrough fungal infections are significantly more common in patients with low posaconazole levels 5, 4, directly impacting morbidity and mortality outcomes.
While supratherapeutic concentrations are also a concern, the evidence predominantly focuses on the risk of subtherapeutic levels as the primary driver for routine TDM of posaconazole.