Therapeutic Drug Monitoring of Posaconazole in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome

Abstract

Posaconazole is a broad-spectrum triazole antifungal available as an oral suspension. Pharmacokinetic data showed a high variability of plasma posaconazole concentrations (PPCs) in patients, suggesting a potential interest in drug monitoring. The aim of our prospective study was to measure the PPCs in prophylactically treated patients to evaluate the impact of different factors on these concentrations. In 40 patients treated prophylactically with posaconazole for acute myeloid leukemia or myelodysplastic syndrome between February 2009 and August 2010, PPCs were measured at day 7 of treatment and then twice weekly. Demographic data, clinical data (including gastrointestinal disorders, comedications, and treatment compliance), caloric and fat intake, and biological data were collected and evaluated. We obtained 275 measurements of PPCs, with a median of 430 ng/ml. PPCs were significantly lower in patients with mucositis (P < 0.001), nausea (P ‫؍‬ 0.03), diarrhea (P ‫؍‬ 0.03), or vomiting (P ‫؍‬ 0.05). PPCs were higher in patients with a higher caloric intake (P ‫؍‬ 0.02), while the proportion of fat intake had no influence on PPCs (P ‫؍‬ 0.84). The concomitant use of proton pump inhibitors decreased the PPCs (P ‫؍‬ 0.02), while the use of tacrolimus increased the PPC (P ‫؍‬ 0.03). In the multivariate analysis, the factors influencing the PPCs independently were the concomitant use of tacrolimus (P < 0.001), the presence of mucositis (P ‫؍‬ 0.01), and food intake (P ‫؍‬ 0.02). Our study confirmed the high variability of posaconazole bioavailability and showed the significant influence of gastrointestinal disorders, food intake, and concomitant medication on the PPCs. However, the optimal PPCs still remain to be defined and correlated with clinical efficacy.

How we treat invasive fungal diseases in patients with acute leukemia: the importance of an individualized approach

“…103 Upon response, we add posaconazole if the organism is susceptible and continue both agents for 1 week to ensure steady-state plasma posaconazole concentrations (PPCs) and then discontinue L-AMB. The PPCs in patients with A-Leuk are significantly decreased in the presence of mucositis or diarrhea, 56,104,105 poor food intake, 105 and concomitant receipt of proton pump inhibitors 56 or chemotherapeutic agents. 105 Lower PPCs have been associated with increased IFDs.…”

“…The PPCs in patients with A-Leuk are significantly decreased in the presence of mucositis or diarrhea, 56,104,105 poor food intake, 105 and concomitant receipt of proton pump inhibitors 56 or chemotherapeutic agents. 105 Lower PPCs have been associated with increased IFDs. 104 Compared with oral posaconazole solution, a once-daily tablet significantly improves bioavailability.…”

Treatment Principles for the Management of Mold Infections

“…Several studies have documented that the risk of neurological adverse effects during voriconazole therapy increases exponentially at trough concentrations .5 mg/L (Pascual et al , 2012. For posaconazole, a target serum trough concentration of 0.5 -0.7 mg/L has been suggested for prophylaxis (Dolton et al 2012;Vaes et al 2012), with trough concentrations The major dose-limiting adverse effects during antifungal therapy are renal toxicity, which is manifested by acute tubular necrosis and impaired glomerular filtration with AMB formulations, and hepatic toxicity, which can occur with all antifungal medications. Renal toxicity is a well-known side effect of AMBbased regimens that can be reduced or delayed by avoiding other nephrotoxins, ensuring adequate hydration of the patient, and by administering lipid or liposomal formulation (Saliba and Dupont 2008).…”

Posaconazole Plasma Concentrations on Days Three to Five Predict Steady-State Levels

“…The major drawbacks of the oral solution are its limited bioavailability, particularly when mucositis, gastrointestinal GVHD, or diarrhea is present, and its nonlinear pharmacokinetics (15,16). Multiple other variables may also affect PCZ absorption, giving rise to significant inter-and intrapatient variability in the bioavailability of the PCZ oral solution (15,(17)(18)(19)(20)(21)(22).…”

“…The major drawbacks of the oral solution are its limited bioavailability, particularly when mucositis, gastrointestinal GVHD, or diarrhea is present, and its nonlinear pharmacokinetics (15,16). Multiple other variables may also affect PCZ absorption, giving rise to significant inter-and intrapatient variability in the bioavailability of the PCZ oral solution (15,(17)(18)(19)(20)(21)(22).Given that subtherapeutic PCZ plasma concentrations (PPCs) may be associated with breakthrough invasive fungal infections (IFIs) (21,23,24), therapeutic drug monitoring (TDM) of PCZ has been recommended for the PCZ oral solution (25). There remain many clinical and practical issues that affect PCZ TDM, in particular the length of time required to reach steady state, which may be 7 to 10 days (23,(26)(27)(28).…”