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Exposure-Response Relationship of Posaconazole Suspension in Theprophylaxis of Invasive Fungal Infections in Patients with Acute Myeloid Leukemia

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Indian Journal of Hematology and Blood Transfusion Aims and scope Submit manuscript

Abstract

Purpose

Antifungal prophylaxis with posaconazole has demonstrated a reduction in the risk of death due to Invasive fungal infections (IFI)in patients with acute myeloid leukemia (AML) during induction therapy. However, various factors affect the plasma levels of posaconazole and can potentially limit its efficacy. Therapeutic drug monitoring (TDM) can help optimize the dose, but literature is scant from centers with a high IFI burden. This study aimed to evaluate the proportion of de-novo AML patients on induction who could achieve the target level of 700ng/mL with posaconazole prophylaxis,factors that can influence the plasma levels, and the impact of plasma posaconazole levels on incidence of IFI.

Methods

Patients with AML on induction therapy with no baseline IFI were enrolled at our tertiary cancer center which has high prevalence of IFI. These patients received posaconazole suspension as prophylaxis. Daily plasma levels were measured from Day 4 till Day 12 of posaconazole prophylaxis. All patients were monitored for the development of IFI. The data on adverse events, concomitant drugs, mucositis, vomiting, and diarrhea were recorded.

Results

A total of 411 samples from fifty patients were collected. Only 177 out of 411 samples had levels > 700 ng/mL. The median trough level was 610 ng/mL (range30-3000 ng/mL). The median time to achieve target trough concentration was four days (range 4–12 days) from the start of induction.Thirty-eight (76%) patients achieved target plasma levels by day 12 of induction.The median plasma level on day 12 was 690 ng/mL (range,30-1270) in patients who achieved target levels as compared to 340 (50–560) ng/mL in those who did not. Twenty-six (52%) patients had IFI in our study, and the median time to develop breakthrough IFI was 14 days (range 4–24 days). Median and range of plasma levels were 690 ng/ml (30-2410; n = 22) in those who developed IFI, while 590 ng/mL (50-2300 n = 24) in those who did not. The odds of developing IFI in patients who did not achieve the threshold trough concentration of 700 ng/mL was 7.14 (95% CI; 1.35–37.75, p = 0.0206). Occurrence of vomiting (p = 0.02), diarrhea (p = 0.0008), mucositis (p = 0.003) had adverse impact on achievement of target plasma posaconazole levels.

Conclusion

A significant proportion of patients receiving posaconazole prophylaxis fail to achieve target plasma levels which can result in high risk of development of IFI. Occurrence of diarrhea, vomiting and mucositis can adversely affect the achievement target plasma levels.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

We would like to acknowledge the contributions of Naina Morajkar, Mangesh Kadam, and Supriya Adak.

Funding

The study was funded by intramural grants of the Tata Memorial Centre.

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Authors and Affiliations

  1. Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National University, Dr. E. Borges Road, Parel, 400012, Mumbai, Maharashtra, India

    Manju Sengar

  2. Kasturba Medical College, Manipal University, 203, Light House Hill Rd, 575001, Mangalore, Hampankatta, Mangalore, Karnataka, India

    Hasmukh Jain

  3. Tata Memorial Centre, Homi Bhabha National University, Dr.E Borges Road, Parel, 400 012, Mumbai, India

    Sanyo D’souza, Sadhana Kannan & Smruti Mokal

  4. ACTREC, Tata Memorial Centre, 410210, Kharghar, Navi Mumbai, Maharashtra, India

    Murari Gurjar & Madhavi Ambotkar

  5. Tata Memorial Centre, Dr. E Borges Road, Parel, 400 012, Mumbai, India

    Neha Sharma

  6. Department of Medical Oncology, Krishna Institute of Medical Sciences, Hyderabad, India

    Mounika Boppanna

  7. Clinical Pharmacology, ACTREC, Tata Memorial Centre, Homi Bhabha National University, Kharghar, Navi Mumbai, 410210, Mumbai, Maharashtra, India

    Vikram Gota

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Contributions

HJ, MS, SD, SK, and SM designed the research study. HJ, MS, VG, and SD conducted the study. VG, MG, and MA contributed in performing essential tests and providing laboratory results. HJ, MS, VG, SD, SK, MG, MA, and SM analyzed the data. HJ, MS, VG, SD, SK, MB, and SM wrote the paper.

Corresponding author

Correspondence to Manju Sengar.

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Sengar, M., Jain, H., D’souza, S. et al. Exposure-Response Relationship of Posaconazole Suspension in Theprophylaxis of Invasive Fungal Infections in Patients with Acute Myeloid Leukemia. Indian J Hematol Blood Transfus 39, 200–207 (2023). https://doi.org/10.1007/s12288-022-01568-4

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