ABSTRACT
BACKGROUND: 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). MATERIALS AND METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.
Subject(s)
Hematopoietic Stem Cell Transplantation , Triazoles , Antifungal Agents/therapeutic use , Female , Humans , Male , TabletsABSTRACT
BACKGROUND: Therapeutic drug monitoring (TDM) of voriconazole is recommended for personalizing doses. The objective of this study was to compare the enzyme immunoassay developed by ARKTM Diagnostics Inc. for the quantification of voriconazole adapted to the Architect C4000 autoanalyzer (Abbott®) with ultra-performance liquid chromatography using ultraviolet detector (UPLC-UV) method. MATERIALS AND METHODS: Linearity, precision and accuracy of both methods were validated according to the Food and Drug Administration (FDA) and European Medicines Agency guidelines. The limit of quantification (LOQ) of the UPLC-UV method was determined experimentally. Both methods were applied to the analysis of 62 samples from patients. Correlation was evaluated by Passing-Bablok analysis and the concordance by the Bland-Altman method. Dosage recommendations were generated; the discordances according to the technique were evaluated. RESULTS: All validation parameters determined for UPLC-UV met the criteria set out and LOQ of 0.1 µg/mL was established. However, when the enzyme immunoassay was used to determine concentrations ≤1 µg/ml, CVs were >20%. A linear correlation between both methods was found. However, an overestimation of immunoassay (systematic error of 0.39 µg/mL) was detected. In 11.3% of the samples, the differences in concentrations when they were determined by different techniques would imply a different therapeutic regime. These samples had concentrations close to 1 µg/mL. CONCLUSION: Although both techniques can be used for TDM of voriconazole, when a value close to the lower limit of the therapeutic range is determined by the ARKTM immunoassay, it would be better to verify the result by a non-automated technique to avoid possible underdosing.
