Therapeutic drug monitoring following crushed administration of delayed-release posaconazole tablets via enteral feeding tubes

Abstract

Posaconazole, a triazole antifungal commonly used for the treatment and prevention of invasive fungal infections, is available in IV, oral suspension and oral delayed-release (DR) tablet formulations.1–3 Of the oral formulations, the DR tablet is favoured owing to its superior bioavailability, once-daily dosing and reliable absorption regardless of gastric acidity.4 Even when dosed appropriately, posaconazole oral solution often does not achieve therapeutic levels.5 This complicates administration in patients unable to swallow tablets whole and in whom long-term IV administration is undesirable. Posaconazole DR tablets are labelled as ‘do not crush,’ largely due to extrapolated concern that crushing the DR matrix may lead to a ‘dose dump’ and altered bioavailability.6,7 Recently, several case series have demonstrated success with crushing and administering the DR tablets via enteral feeding tubes, thus prompting a practice change across our health system.8–10 In August 2022, following the report by Dieringer et al.,9 our electronic health record entry for the DR tablets was modified to permit selection of per feeding tube routes and modification of the administration instructions to facilitate administration of crushed posaconazole DR tablets by feeding tube, when necessary. Between 1 August 2022 and 18 November 2022 a total of 22 adult patients received at least one dose of posaconazole DR tablets crushed and administered via feeding tube. This included 13 patients receiving the agent for antifungal prophylaxis and 9 patients receiving therapy for confirmed or suspected fungal infections. Ten patients had sufficient documentation confirming administration of the crushed DR tablets and therapeutic drug monitoring (TDM) performed. Of these, one patient was receiving crushed tablets per gastric tube upon hospital admission and had this continued, four patients were switched from alternative formulations to the crushed tablets, and five patients were initiated on new therapy with the crushed DR tablets. Patient age/sex, indications for therapy, previous formulation dosing regimens, crushed DR tablet regimens and routes, and TDM for the 10 included patients are displayed in Table 1. Patients receiving crushed posaconazole DR tablets per feeding tube M, male; F, female; N/A, not applicable; bid, twice daily; G-tube, gastric tube; J-tube, jejunum tube; aAM, every morning; qPM, every evening; Patient had previously received posaconazole; however, had been off therapy for 29 days at time of reinitiation. Patient had previously received posaconazole; however, had been off therapy for 10 days at time of reinitiation. Patient was eventually switched back to solid tablets at twice-daily dosing and developed an elevated serum level necessitating transition back to daily dosing regimen of solid tablets. Two patients failed to achieve therapeutic concentrations. Both were initially started on 300 mg DR crushed per gastric tube once daily. Patient 2 was switched to an alternative antifungal agent (voriconazole) upon return of a subtherapeutic concentration and Patient 7 had the dose increased to 400 mg orally (PO) daily but expired due to non-infectious causes prior to obtaining repeat levels. The remaining eight patients were able to achieve therapeutic serum concentrations. Two of these, both receiving posaconazole for prophylaxis, obtained therapeutic concentrations on 300 mg crushed DR per tube once daily. The remaining six patients were all transitioned to twice-daily dosing prior to achieving therapeutic levels. It bears noting that two patients (patients 4 and 9) had their dose doubled from 300 mg daily to twice daily and subsequently demonstrated slowly increasing serum concentrations on this formulation over time, likely attributable to the large dose increase and prolonged half-life of the agent. Additionally, two patients (Patients 3 and 6) were transitioned from twice-daily regimens on crushed DR tablets to equivalent doses administered whole. Both patients subsequently developed serum concentrations >3000 ng/mL (3090 and 3370 ng/mL, respectively), prompting dose reductions of the non-crushed tablets back to 300 mg PO DR daily. Our limited experience adds to the available literature suggesting that crushing posaconazole DR tablets for administration by feeding tube is a viable alternative to the suspension in patients where absorption of the liquid formulation may be impaired. In our cohort, we found that daily administration of crushed DR tablets commonly resulted in initial levels that were subtherapeutic, prompting dose increases. Patients were most often changed to twice-daily regimens, with a maximum of 300 mg twice daily, aligning with prior publications.8,9 Conversely, Manesh et al.10 found that crushed posaconazole DR tablets given per feeding tube at a dose of 300 mg daily produced therapeutic levels after 2 weeks of therapy in 19 of 19 patients receiving treatment for rhino-orbito-cerebral mucormycosis.10 Many factors can impact drug levels of crushed posaconazole DR tablets, spanning from the obvious patient factors (i.e. absorption) to terminal tube placement (e.g. J-tube versus G-tube) or the more nuanced factors (preparation and administration technique). The literature supporting this practice is evolving, but still limited. It is currently unknown how different manufacturers’ DR matrices may impact serum concentrations if crushed, or how crushed DR tablets would compare in a head-to-head comparison against the oral suspension. Our experience adds to the growing body of evidence suggesting that crushing and administering posaconazole DR tablets via enteral feeding tubes is safe and often results in therapeutic levels. Importantly, doses may likely need to be up- or down-titrated when switching to or from the formulation of crushed posaconazole DR tablets, respectively. Clinicians should consider this route of administration, when necessary, in conjunction with careful dose titration and frequent TDM. No funding was supplied for the support of this work. None of the authors have any conflicts of interest to disclosure.

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