Population pharmacokinetics of a posaconazole tablet formulation in transplant adult allogeneic stem cell recipients

• Published in: European journal of pharmaceutical sciences Vol. 168; p. 106049
• Main Authors: Peña-Lorenzo, Diego, Rebollo, Noemí, Sánchez-Hernández, José Germán, Zarzuelo-Castañeda, Aránzazu, Vázquez-López, Lourdes, Otero, María José, Pérez-Blanco, Jonás Samuel
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-01-2022
• Subjects: Allogeneic hematopoietic stem cell transplant; Antifungal Agents - therapeutic use; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Model-informed precision dosing; Population pharmacokinetics; Posaconazole; Tablets; Triazoles; Population pharmacokinetics; Posaconazole; Allogeneic hematopoietic stem cell transplant; Model-informed precision dosing
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2021.106049

•A popPK model of posaconazole tablets in allogeneic SCT adult recipients is presented.•Gender and serum proteins showed a significant impact on posaconazole elimination.•A nomogram based on PKPD criteria for MIPD of posaconazole has been developed.
Posaconazole is an antifungal agent extensively used as a prophylaxis for invasive fungal infections (IFIs) in allogeneic stem cell transplant (SCT) recipients. Low posaconazole concentrations have been associated with reduced clinical response. The aim of this study was to develop a population pharmacokinetic (popPK) model of a posaconazole tablet formulation in allogeneic SCT adult recipients for supporting model-informed precision dosing (MIPD).
Prospective observational study performed in adult allogeneic SCT recipients receiving posaconazole as prophylaxis for IFIs and followed up by a therapeutic drug monitoring (TDM) program. Posaconazole plasma concentrations were quantified using an ultra-high-performance liquid chromatography (UPLC) with UV detector. A popPK model was developed using NONMEM v.7.4.0. Deterministic and stochastic simulations were carried out with the final model to evaluate the differences across physiological variables with impact on drug exposure.
A one-compartment model with sequential absorption (zero and first order) and first order elimination described adequately 55 posaconazole concentrations from 36 patients. Higher doses of posaconazole were found to be required by males and patients with lower values of total serum proteins. A nomogram to estimate the posaconazole daily dose based on pharmacokinetic/pharmacodynamic (PKPD) criterion for males and females for different values of total proteins was developed.
Gender and total serum proteins have been identified as covariates influencing posaconazole CL/F in adult allogeneic SCT recipients receiving the delay-released tablet formulation. Additional studies are required to better characterize the absorption of posaconazole and implications on dosage recommendations together with potential safety concerns.
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