Initial posaconazole dosing to achieve therapeutic serum posaconazole concentrations among children, adolescents, and young adults receiving delayed‐release tablet and intravenous posaconazole

Abstract

Posaconazole is a broad‐spectrum antifungal used for prophylaxis and treatment of invasive fungal diseases. There are limited data on the optimal dosing, safety, and efficacy of the DRT and IV formulations in immunocompromised pediatric and adolescent patients. We describe our experience including dosing, plasma trough concentrations, safety, and tolerability. Plasma concentrations ≥.7 µg/mL were considered therapeutic for prophylaxis and ≥1.0 µg/mL for treatment. Fifty‐four patients (median age of 16 years) received DRT or IV formulations of posaconazole. Thirty‐one (57%) patients received posaconazole for treatment and 23 (43%) for prophylaxis. Overall, 36 (67%) patients achieved targeted initial plasma trough concentrations (median 1.3 µg/mL) (Figure 1). The median daily dose among patients <13 years of age who achieved the targeted initial concentrations was 7.3 mg/kg/day for the DRT formulation and 9.8 mg/kg/day for the IV formulation. The median daily dose among patients ≥13 years of age who achieved the targeted initial concentrations was 4.9 mg/kg/day for the DRT formulation and 5.6 mg/kg/day for the IV formulation. Thirty‐six patients (67%) developed transaminitis, mostly grade 1. Our observations show that DRT and IV formulations are safe and effective in immunocompromised children, adolescents, and young adults. Higher dosing per body weight of DRT and IV posaconazole may be required in patients <13 years of age compared with patients 13 years of age and older to achieve therapeutic plasma concentrations. 1FIGURE Distribution of posaconazole plasma trough levels by indication groups

Dose Optimisation of Posaconazole and Therapeutic Drug Monitoring in Pediatric Patients

“…However, the median maintenance dose did not differ significantly between patients aged <6 and 6–12 years old in this study, although a higher trend is shown in patients <6 years old ( Figure 4 ). One possible explanation for the higher doses in patients <13 years is that patients in this group were dosed based on current available data versus patients 13 years and older who were dosed based on package insert recommendations ( Bernardo et al, 2020 ).…”

“…The analytical range was 0.025–5.00 μg mL −1 . For the purpose of this study, plasma concentrations ≥0.7 μg mL −1 were considered therapeutic for prophylaxis and ≥1.0 μg mL −1 for treatment ( Bernardo et al, 2020 ).…”

Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy and haemopoietic stem cell transplant recipients, 2021

“…8,186 Therefore, TDM is indicated for patient groups at risk of low exposure who are receiving prophylaxis with the new posaconazole tablet formulation (e.g. patients with cystic fibrosis, 187 presence of graft-versus-host disease, 10,181 drug-drug interactions including those on concurrent corticosteroids and proton pump inhibitors, 10,188 obese patients, 189,190 young children [191][192][193][194] and patients with gastrointestinal complications including diarrhoea 10,190,195,196 ).…”

In Vitro Antifungal Drug Resistance Profiles of Clinically Relevant Members of the Mucorales (Mucoromycota) Especially with the Newer Triazoles

“…Moreover, the results of direct comparisons of the activity of these two triazoles in vitro are somewhat contradictory, with some studies showing roughly equivalent activities but species-specific variations [11,12], whilst others suggested that posaconazole MICs were generally lower than isavuconazole MICs with the common agents of mucoromycosis [13,14]. Additionally, it remains to be determined whether reported MIC differences between posaconazole and isavuconazole with members of the Mucorales are clinically relevant, given that drug exposures in vivo are usually higher with isavuconazole than with posaconazole [16][17][18][19].…”