Pharmacological considerations for azole antifungal drug management in cystic fibrosis lung transplant patients

Abstract

This paper aims to present our experience in the pharmacological approach of the management of azole antifungal drugs in cystic fibrosis lung transplant patients. Cystic fibrosis (CF) lung transplantation is associated with multi-factorial care management, because of immunosuppressive requirements, risk of infections, frequency of gastro-oesophageal reflux disease, hepatic alterations and CF pharmacokinetics (PK) specificities that result in important PK variability. CF is associated with frequent colonization of the airways by filamentous fungi, especially by Aspergillus species. Today the antifungal therapeutic arsenal offers several possibilities for long-term oral therapy including azole drugs (itraconazole, voriconazole and posaconazole). Therefore, nephrotoxic amphotericin B should be avoided. The liver is important in the pharmacological profile of azole drugs, due to metabolic elimination, hepatotoxicity and PK drug-drug interaction (DDI) involving CYP3A4 metabolic inhibition. Targets for such DDI are numerous, but immunosuppressive drugs are of major concern, justifying combined therapeutic drug monitoring (TDM) of both azoles (inhibitors) and immunosuppressants (targets) on an individualized patient basis to adjust the coprescription quantitatively. The risk of long under-dosed periods, frequently addressed in this population, could justify, on a PK basis, the need for combination with an exclusive parenteral antifungal while waiting for azole relevant drug level. High PK variability, the risk of low exposure, therapeutic issues and DDI management in this complex underlying disease justify close monitoring with systematic combined TDM of azole and immunosuppressants, in case of coprescription.

Comparing Azole Plasma Trough Levels in Lung Transplant Recipients: Percentage of Therapeutic Levels and Intrapatient Variability

“…Billaud et al recommended dose escalation in patients with cystic fibrosis LTx of 35%–45% compared with standard recommended dose, which is in line with our results. 53 …”

Concentration of Antifungal Agents within Host Cell Membranes: a New Paradigm Governing the Efficacy of Prophylaxis

“…Voriconazole is a relatively polar molecule, and it concentrates minimally within host cells (1,5,8). Serum levels of voriconazole between 1 g/ml and 5 g/ml have been reported to correlate well with efficacy both in the treatment of IFI (3,(23)(24)(25) and in prophylaxis (31). In contrast, posaconazole is significantly more lipophilic and while its serum levels are lower than those reported with voriconazole, posaconazole has been reported to concentrate to high levels within cells (up to 40-to 50-fold) (5).…”

Practical Approach to Emergencies in Lung Transplant Recipients: How We Do It

“…Certain proton pump inhibitors (PPIs) also interact with cyclosporine; thus, it is not advisable to switch PPIs unless exceptional reasons exist and close TDM can be performed [39]. For similar reasons, we do not change or permanently stop giving drugs with known interactions, even if a new drug is introduced to treat an intercurrent problem (infection).…”

“…These situations require frequent TDM and dose adjustments. In situations of increased risk of invasive fungal infections (augmented IS) or documented fungal infection, we consider treating temporarily with caspofungin, bearing in mind that it does not cover zygomycosis infection [39]. In contrast to guidelines and common practice elsewhere, we hardly ever use fluconazole or voriconazole [40,41,42].…”

“…This is a common pitfall for physicians not familiar with the treatment concepts established for LTRs. The need for accurate pancreas enzyme replacement therapy in cystic fibrosis (CF) patients following lung transplantation requires particular attention; variations in dosing and stool frequency may strongly influence intestinal drug uptake and therefore change drug levels [39]. If insufficient drug levels for IS or antifungal prophylaxis are observed in these patients, intravenous IS and antifungal treatment must be considered in order to prevent allograft rejection or fungal infection [43].…”