Posaconazole in Saliva: Feasibility of a Noninvasive Monitoring Approach in Immunocompromised Children

To the Editors: Therapeutic drug monitoring (TDM) is necessary for optimizing triazole antifungal therapy in immunocompromised children. However, frequent blood sampling can be invasive and distressing, and particularly burdensome for children undergoing intensive cancer treatments or recipients of hematopoietic cell transplants (HCT).1 Noninvasive TDM methods, such as saliva sampling, offer a promising alternative due to their ease of collection and accessibility.2,3 To date, no published studies have investigated the feasibility of measuring posaconazole concentrations using saliva. Therefore, we aimed to determine whether posaconazole can be detected in the saliva of children undergoing cancer therapy or allogenic HCT. In a 2-year prospective pharmacokinetic study (2023–2025), paired serum and saliva samples were collected after written informed consent from oncology or HCT patients aged 1–<18 years receiving posaconazole during their inpatient stay at the Royal Children’s Hospital Melbourne (ethics approval HREC 81867). Children with oral mucositis, bleeding or infection were excluded. Serum and unstimulated saliva samples were collected within 15 minutes of each other at posaconazole steady state, defined as 5–7 days after daily dosing. Saliva was collected using an oral synthetic swab and passive drool method (0.5–2 mL, Salimetrics, State College, PA). Posaconazole levels were measured using ultra-performance liquid chromatography–tandem mass spectrometry in positive electrospray ionization mode. Overall, 10 children, median age 14.1 years (range 8.1–17.8), were enrolled with a median of 2 serum (range 2–5) and 2 saliva samples (range 2–5) taken from each (Table 1). The median time between serum and saliva samples was 5 minutes (range 0–10). Posaconazole was undetectable (<0.05 mg/L) in 25/26 (96%) saliva samples, despite many patients having therapeutic serum concentrations (median 1.4 mg/L, range 0.1–5.0) (Table 1). Only 1 saliva sample had a detectable posaconazole concentration (0.06 mg/L, with paired serum concentration of 5.0 mg/L). TABLE 1. - Posaconazole Results Age (yr), Sex Posaconazole Sample Number Serum (mg/L) Saliva (mg/L) Saliva Collection Method Dose (mg) Frequency Formulation 14.2F 300 daily IV 1 1.45 <0.05 S 2 1.45 <0.05 D 3 1.41 <0.05 S 10.4M 300 daily IV 1 2.71 <0.05 S 2 3.52 <0.05 S 8.1M 300 daily IV 1 3.98 <0.05 S 2 3.98 <0.05 D 3 1.36 <0.05 S 4 1.36 <0.05 D 14.9M 200 daily DRT 1 1.81 <0.05 S 2 1.03 <0.05 S 14.1M 300 daily DRT 1 0.61 <0.05 S 2 0.73 <0.05 S 3 0.73 <0.05 D 4 0.91 <0.05 S 5 0.91 <0.05 D 17.8F 300 daily DRT 1 0.88 <0.05 S 2 1,73 <0.05 S 13.6M 300 daily IV 1 3.11 <0.05 S 2 4.99 0.06 S 9.4M 300 daily DRT 1 2.75 <0.05 S 2 1.51 <0.05 S 14.8M 300 daily DRT 1 2.1 <0.05 S 2 1.21 <0.05 S 16.0M 300 daily DRT 1 0.25 <0.05 S 2 0.11 <0.05 S D indicates passive drool; DRT, delayed release tablet; IV, intravenous; S, saliva swab. The undetectable salivary concentrations of posaconazole in our study may be explained by its high protein binding (>98%) in comparison to voriconazole (~58%) and fluconazole (~10%).4 A recent review found that both voriconazole and fluconazole can be reliably detected in saliva.3 For fluconazole, saliva-to-serum concentration ratios averaged 1.21 (±0.31 standard deviation; range: 0.99–1.45). Itraconazole is structurally like posaconazole, has high protein binding (>99%) and has poor detectability in saliva. Two studies in adults detected itraconazole in saliva after oral suspension but not with capsules, likely due to the topical effect. In addition, the active metabolite of itraconazole was not detected, limiting the use of saliva for monitoring this antifungal.3 Overall, our findings show that saliva testing is not feasible for noninvasive TDM of posaconazole in immunocompromised children.