Plasma exposures following posaconazole delayed-release tablets in immunocompromised children and adolescents

Abstract

Background Posaconazole is a recommended option for antifungal prophylaxis in paediatric patients >12 years of age. However, little is known about plasma exposures and safety following administration of the delayed-release tablets (DRTs) in children and adolescents. Methods In a retrospective observational study, we analysed steady-state trough concentrations of posaconazole in all paediatric patients who had received the DRT formulation between May 2015 and December 2018 for antifungal prophylaxis. Dosing was guided by a published population pharmacokinetic model with weight-based dosing. Drug concentrations in plasma were measured by a validated tandem MS method. Liver function and drug discontinuations due to adverse effects were also assessed. Results A total of 34 patients (21 male, 13 female; median age 12 years, range 5–17 years; median body weight 43.5 kg, range 16–84 kg) undergoing treatment for haemato-oncological disorders (n=23) or immunosuppression for polyarthritis (n=1) or post-allogeneic HSCT (n=11) received posaconazole DRTs for a median of 70 days (range 9–391 days). The median first steady-state trough plasma concentration following model-derived dosing was 1607 ng/mL (range 501–8485 ng/mL) with trough concentrations being above the dosing target of ≥700 ng/mL in 32/34 patients (94%). Considering all (first and subsequent) trough concentrations, target attainment was 90% (63/70 samples). Posaconazole was well tolerated without adverse event-related discontinuations or breakthrough infections. Conclusions Administration of posaconazole DRTs to paediatric patients guided by a population pharmacokinetic-derived dosing algorithm resulted in predictable and potentially effective exposures and was well tolerated over prolonged time periods.

Pharmacokinetics and Pharmacodynamics of Posaconazole

“…While the posaconazole oral formulations are approved in patients older than 13 years (USA) or 18 years (Europe), the intravenous form is only labeled for patients older than 18 years, due to potential toxicity to brain ventricle development observed in juvenile dogs [2,30]. However, many studies have reported its off-label use in pediatric patients, which could be attributed to the promising efficacy and safety profile in adults [132][133][134]. A recent population pharmacokinetic model was developed for 171 pediatric immunocompromised patients aged between 5 month and 18 years receiving one of the oral formulations, with nearly 96% of the samples being obtained after administration of the suspension [70].…”

“…Experience with the posaconazole delayed-release tablet in pediatric patients is limited. A model-derived dosing strategy was applied in 34 children and adolescents (range 5-17 years) receiving the posaconazole delayed-release tablet, and more than 90% of the patients were reported to have steady-state trough concentrations above the target of 0.7 mg/L [134]. However, to implement such size-based dosing approaches in younger children, the delayed-release tablet displays an unattractive prospect as it is indivisible and large in size.…”

“…Based on the model-based simulations, this study recommended different dosing regimens for different age groups for both prophylactic and treatment purposes in children patients aged < 13 years. Due to the poor and saturable bioavailability of the suspension, the delayed-release tablet formulation is considered a superior choice compared to the oral suspension once the children are able to take it [70,99,134].…”

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

“…In this study, patients weighing between 31 and 50 kg received 300 mg twice‐daily loading doses on day 1 and 300 mg once daily for maintenance; patients weighing between 21 and 30 kg received a 300 mg loading dose and daily maintenance doses alternating between 200 mg and 300 mg; and patients weighing between 10 and 20 kg received a 200 mg loading dose and 200 mg daily maintenance doses. The median first plasma trough concentration was 1.607 µg/mL (range .501‐8.485 µg/mL) 13 …”

Posaconazole delayed‐release tablets in paediatric haematology–oncology patients

“…The steady‐state trough PPC of DRT used as prophylaxis has been also evaluated recently in a retrospective study involving in 34 paediatric patients (median age 12 years, range 5‐17) 12 . Posaconazole DRTs were administered for a median of 70 days (range 9‐391 days) in paediatric patients undergoing treatment for haemato‐oncological disorders (n = 23) or immunosuppression for polyarthritis (n = 1) or postallogeneic HSCT (n = 11).…”