A Prospective Study to Evaluate the Effect of Therapeutic Drug Monitoring-Based Posaconazole Prophylaxis on Invasive
Mounika Boppana1,2, Manju Sengar3,4, Hasmukh Jain3
1Department of Medical Oncology, Tata Memorial Centre, Affiliated to Homi Bhabha National Institute, E Borges Road, Mumbai, Maharashtra 400 012 India.
Abstract:
Invasive fungal infections (IFIs) are a significant cause of morbidity and mortality in de-novo acute myeloid leukemia patients receiving induction chemotherapy. Despite using posaconazole, a broad-spectrum antifungal, for IFI prophylaxis, the breakthrough IFI rate is high in the real-world setting. One of the reasons could be frequent suboptimal plasma posaconazole levels. In the present study, we evaluated if therapeutic drug monitoring (TDM) guided posaconazole prophylaxis can reduce the IFI rates in comparison to a historical cohort. We enrolled 90 patients, > / = 16 years of age, without baseline IFIs, planned for remission induction therapy. All patients were started on posaconazole suspension 200 mg TDS and the dose was increased in a stepwise manner if trough levels were found to be suboptimal (< 350 ng/ml for day 2 or < 700 ng/ml subsequently). The TDM based approach resulted in a significant decline in breakthrough IFI rates (18% versus 52%, P < 0.0001) A total of 69 patients (78%) required dose escalation. Thirty-one patients required change in antifungals due to either suboptimal levels, persistent fever, diarrhoea or vomiting. We could not demonstrate an exposure-response relationship but the difference in IFI rates in patients with a median posaconazole level > / = 700 ng/ml (0%) and < 700 ng/ml (21.6%) was clinically meaningful. Posaconazole levels were found to be significantly lower in patients on antacids and prokinetics. The incidence of posaconazole-related grade 3 toxicity was low (2.3%). Thus TDM-based dosing of posaconazole helps reduce breakthrough IFI rate and should be a part of posaconazole prophylaxis.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s12288-023-01709-3.
Insights
Therapeutic drug monitoring (TDM) for posaconazole significantly reduced breakthrough invasive fungal infections (IFIs) in acute myeloid leukemia patients. This approach optimizes antifungal prophylaxis, improving patient outcomes and potentially lowering IFI rates.
Area of Science:
- Hematology
- Infectious Diseases
- Pharmacology
Background:
- Invasive fungal infections (IFIs) are a major cause of mortality in acute myeloid leukemia (AML) patients undergoing induction chemotherapy.
- Standard posaconazole prophylaxis often results in high rates of breakthrough IFIs due to suboptimal drug levels in real-world settings.
- Optimizing posaconazole dosing is crucial for effective IFI prevention in this vulnerable patient population.
Purpose of the Study:
- To evaluate if therapeutic drug monitoring (TDM)-guided posaconazole prophylaxis can decrease breakthrough IFI rates compared to a historical cohort.
- To assess the impact of TDM on posaconazole dosing and identify factors influencing drug levels.
Main Methods:
- A cohort of 90 adult de-novo AML patients received posaconazole prophylaxis during induction chemotherapy.
- Posaconazole trough levels were monitored, with dose adjustments made to maintain target concentrations (≥350 ng/ml on day 2, ≥700 ng/ml subsequently).
- Breakthrough IFI rates were compared to a historical control group.
Main Results:
- TDM-guided posaconazole prophylaxis significantly reduced breakthrough IFI rates from 52% in the historical cohort to 18% (P < 0.0001).
- Dose escalation was required in 78% of patients, and 31 patients needed a change in antifungal therapy.
- While an exposure-response relationship was not definitively shown, patients with median posaconazole levels ≥700 ng/ml had 0% IFI rates versus 21.6% in those with levels <700 ng/ml. Lower levels were observed with antacids and prokinetics. Grade 3 toxicity was low (2.3%).
Conclusions:
- Therapeutic drug monitoring-guided posaconazole dosing is effective in reducing breakthrough IFIs in AML patients.
- TDM should be integrated into posaconazole prophylaxis protocols to optimize antifungal therapy and improve patient outcomes.
- Factors like concomitant medications can influence posaconazole levels, highlighting the importance of individualized monitoring.
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