Posaconazole bioavailability of the solid oral tablet is reduced during severe intestinal mucositis

Anouk M.E. Jansen, Eline W. Muilwijk, Walter J.F.M. van der Velden, Johan A. Maertens, Robina Aerts, Angela Colbers, David Burger, Paul E. Verweij, Rob ter Heine, Nicole M.A. Blijlevens, Roger J.M. Brüggemann

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

2 Citaten (Scopus)

Samenvatting

Objectives: This study aimed to describe the absolute oral bioavailability of the solid oral formulation of posaconazole and the impact of severe intestinal mucositis in haematology patients. This study also aimed to describe posaconazole protein binding in haematology patients. Methods: A pharmacokinetic study was performed of patients receiving induction chemotherapy or a haematopoietic cell transplantation who were randomized to receive 7 days of intravenous posaconazole therapy followed by 9 days of oral therapy, or vice versa. Patients received a posaconazole licensed dose until day 12, after which a reduced once-daily dose of 200 mg was given. At days 7, 12, and 16, blood samples were obtained for pharmacokinetic curves, and trough samples were collected on all other days. Total and unbound posaconazole pharmacokinetics were analyzed by population pharmacokinetic modelling. The presence of severe intestinal mucositis was assessed by plasma citrulline levels and analyzed as a binary covariate using 10 μmol/L as the cut-off. Monte Carlo simulations were performed to simulate posaconazole exposure at a steady state. Results: Twenty-three patients were included for analysis, with 581 total posaconazole concentrations and 91 paired unbound concentrations. Absolute bioavailability in the final model was estimated at 51.4% (percentage relative standard error (%RSE): 56.5) and 67.6% (%RSE: 75.0) in patients with and without severe intestinal mucositis, respectively. Posaconazole unbound fraction was estimated at 2.7% (%RSE: 3.9). Discussion: Posaconazole bioavailability is reduced in haematological patients with severe intestinal mucositis, requiring an increase in oral posaconazole dose to 400 mg twice daily on day 1, followed by 400 mg once daily or a switch to intravenous therapy.

Originele taal-2Engels
Pagina's (van-tot)1003-1009
Aantal pagina's7
TijdschriftClinical Microbiology and Infection
Volume28
Nummer van het tijdschrift7
DOI's
StatusGepubliceerd - jul. 2022
Extern gepubliceerdJa

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