Switching from Posaconazole Suspension to Tablets Increases Serum Drug Levels in Leukemia Patients without Clinically Relevant Hepatotoxicity

Abstract

cWe evaluated posaconazole serum concentrations and hepatotoxicity in 12 leukemia patients who transitioned from posaconazole suspension to tablets. Patients who switched to tablets had significantly increased posaconazole concentrations (median: suspension, 748 ng/ml; tablet, 1,910 ng/ml; P < 0.01) without clinically relevant hepatotoxicity. Despite concerns of poor bioavailability, posaconazole (POSA) suspension has been used effectively as prophylaxis and as a salvage treatment of invasive fungal infections with rare clinical hepatotoxicity (1). Higher serum concentrations of POSA suspension were associated with higher response rates in treatment of invasive aspergillosis (2). Recent studies (3-6) have suggested that the absorption of the new formulation of POSA delayed-release tablets is minimally affected by food, mucositis, or increased gastric pH and impaired motility and that the new tablet formula also attains higher average concentrations than the suspension does and is well tolerated in healthy subjects. However, no studies about patients who were "bridged" from POSA suspension to tablets have been published to date. We report our early experience in leukemia patients who switched from POSA suspension to delayed-release tablets.Pharmacy databases were queried for adult cancer (Ͼ18 years of age) patients who were switched from POSA suspension (400 mg twice daily or 200 mg 4 times daily) to tablets (300 mg once daily) at The University of Texas MD Anderson Cancer Center from December 2013 to January 2014. Once POSA tablets were added to the formulary, a general trend seen in our hematologic malignancy patient population was that physicians would independently transition almost all current and future patients to tablets despite suspension remaining on the formulary. We identified 12 patients with leukemia who were treated as such. Validated high-performance liquid chromatography (HPLC) assay-tandem mass spectrometry (performed at Mayo Clinic Department of Laboratory Medicine and Pathology, Rochester, MN) was used to measure posaconazole concentrations in blood (7). All patients who had serum POSA levels recorded during both the POSA suspension and tablet periods were identified. POSA concentrations were included in the analysis only if the data were obtained 7 days after POSA administration, as steady state of the drug should be reached at this time for both suspension and tablet (4, 8). The patients' medical records were reviewed for demographic, clinical, and laboratory characteristics (Table 1). Target serum POSA levels were defined as greater than 700 ng/ml for prophylaxis and greater than 1,000 ng/ml for treatment (9). Clinically relevant Underlying condition at the time of sampling, a n (%) ANC of Ͻ500/l 6 (50) Graft-versus-host disease 3 a For measurement of serum POSA levels.

Real-Life Assessment of the Safety and Effectiveness of the New Tablet and Intravenous Formulations of Posaconazole in the Prophylaxis of Invasive Fungal Infections via Analysis of 343 Courses

“…The tablet and intravenous formulations were approved on the basis of safety and pharmacokinetic data, with corresponding phase III data for the tablet formulation recently being published (9). To date, several small, single-center studies have reviewed the initial implementation of PCZ tablets, focusing mainly on pharmacokinetic endpoints (5,6,(10)(11)(12). In agreement with our early experience, those reports also have shown that PCZ tablets yield higher serum concentrations than the suspension formulation and appear to be safe (5).…”

“…To date, several small, single-center studies have reviewed the initial implementation of PCZ tablets, focusing mainly on pharmacokinetic endpoints (5,6,(10)(11)(12). In agreement with our early experience, those reports also have shown that PCZ tablets yield higher serum concentrations than the suspension formulation and appear to be safe (5). Whether there is a subset of patients who have low PCZ levels, despite the use of the new PCZ formulations, remains unclear.…”

“…The recently available intravenous (i.v.) and delayed-release (DR) tablet formulations of PCZ result in significantly higher serum PCZ concentrations and increased attainment of traditional pharmacokinetic targets, compared to the PCZ suspension (5,6). Additionally, the DR formulation has been demonstrated to provide more consistent absorption and is minimally affected by gastric pH and motility (7,8).…”

Chromoblastomycosis

“…In neoplastic patients, this formulation seems to be minimally affected by factors such as food ingestion, increased gastric pH, impaired motility, or mucositis. Recent data revealed that delayed-release PCZ tablets may also achieve higher average plasmatic concentrations than those achieved with the oral solution and are well tolerated in healthy individuals (307,308). The combination of PCZ and 5-FC or TBF may be a potential therapeutic armamentarium for refractory cases.…”

Antifungal stewardship considerations for adults and pediatrics

“…100 The availability of the delayed-release tablet may obviate the need for routine TDM, as serum posaconazole levels are achieved more reliably and without clinically relevant hepatotoxicity in comparison to the oral suspension. 104 There are no recommendations for monitoring serum concentrations of isavuconazole.…”