TY - JOUR
T1 - Effects of Letermovir and/or Methylprednisolone Coadministration on Voriconazole Pharmacokinetics in Hematopoietic Stem Cell Transplantation
T2 - A Population Pharmacokinetic Study
AU - Suetsugu, Kimitaka
AU - Muraki, Shota
AU - Fukumoto, Junshiro
AU - Matsukane, Ryosuke
AU - Mori, Yasuo
AU - Hirota, Takeshi
AU - Miyamoto, Toshihiro
AU - Egashira, Nobuaki
AU - Akashi, Koichi
AU - Ieiri, Ichiro
N1 - Funding Information:
This work was supported by JSPS KAKENHI Grant number JP20K16078.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021
Y1 - 2021
N2 - Objective: The aim of this study was to identify factors affecting blood concentrations of voriconazole following letermovir coadministration using population pharmacokinetic (PPK) analysis in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Methods: The following data were retrospectively collected: voriconazole trough levels, patient characteristics, concomitant drugs, and laboratory information. PPK analysis was performed with NONMEM® version 7.4.3, using the first-order conditional estimation method with interaction. We collected data on plasma voriconazole steady-state trough concentrations at 216 timepoints for 47 patients. A nonlinear pharmacokinetic model with the Michaelis–Menten equation was applied to describe the relationship between steady-state trough concentration and daily maintenance dose of voriconazole. After stepwise covariate modeling, the final model was evaluated using a goodness-of-fit plot, case deletion diagnostics, and bootstrap methods. Results: The maximum elimination rate (Vmax) of voriconazole in patients coadministered letermovir and methylprednisolone was 1.72 and 1.30 times larger than that in patients not coadministered these drugs, respectively, resulting in decreased voriconazole trough concentrations. The developed PPK model adequately described the voriconazole trough concentration profiles in allo-HSCT recipients. Simulations clearly showed that increased daily doses of voriconazole were required to achieve an optimal trough voriconazole concentration (1–5 mg/L) when patients received voriconazole with letermovir and/or methylprednisolone. Conclusions: The development of individualized dose adjustment is critical to achieve optimal voriconazole concentration, especially among allo-HSCT recipients receiving concomitant letermovir and/or methylprednisolone.
AB - Objective: The aim of this study was to identify factors affecting blood concentrations of voriconazole following letermovir coadministration using population pharmacokinetic (PPK) analysis in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Methods: The following data were retrospectively collected: voriconazole trough levels, patient characteristics, concomitant drugs, and laboratory information. PPK analysis was performed with NONMEM® version 7.4.3, using the first-order conditional estimation method with interaction. We collected data on plasma voriconazole steady-state trough concentrations at 216 timepoints for 47 patients. A nonlinear pharmacokinetic model with the Michaelis–Menten equation was applied to describe the relationship between steady-state trough concentration and daily maintenance dose of voriconazole. After stepwise covariate modeling, the final model was evaluated using a goodness-of-fit plot, case deletion diagnostics, and bootstrap methods. Results: The maximum elimination rate (Vmax) of voriconazole in patients coadministered letermovir and methylprednisolone was 1.72 and 1.30 times larger than that in patients not coadministered these drugs, respectively, resulting in decreased voriconazole trough concentrations. The developed PPK model adequately described the voriconazole trough concentration profiles in allo-HSCT recipients. Simulations clearly showed that increased daily doses of voriconazole were required to achieve an optimal trough voriconazole concentration (1–5 mg/L) when patients received voriconazole with letermovir and/or methylprednisolone. Conclusions: The development of individualized dose adjustment is critical to achieve optimal voriconazole concentration, especially among allo-HSCT recipients receiving concomitant letermovir and/or methylprednisolone.
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U2 - 10.1007/s40268-021-00365-0
DO - 10.1007/s40268-021-00365-0
M3 - Article
C2 - 34655050
AN - SCOPUS:85117149016
SN - 1174-5886
JO - Drugs in R and D
JF - Drugs in R and D
ER -