Pharmacokinetic/pharmacodynamic analysis of romidepsin used as an HIV latency reversing agent
Por:
Molto, J, Rosas-Umbert, M, Miranda, C, Manzardo, C, Puertas, MC, Ruiz-Riol, M, Lopez, M, Miro, JM, Martinez-Picado, J, Clotet, B, Brander, C, Mothe, B and Valle, M
Publicada:
1 abr 2021
Resumen:
Objectives: To develop a population pharmacokinetic model for romidepsin given as an HIV Latency reversing agent (LRA) and to explore the relationship between romidepsin exposure and its in vivo effects on viral gene expression and antiviral immunity.
Methods: A population pharmacokinetic analysis was performed in 15 HIV-1-infected patients who received three weekly infusions of romidepsin (5 mg/m(2)) within the BCN02 clinical trial. A full pharmacokinetic profile was obtained for each participant at the first dose, and additional samples thereafter. A population pharmacokinetic model was developed. Bayesian estimates of the individual pharmacokinetic parameters of romidepsin were used to simulate individual time-concentration curves on each occasion. The relationship between romidepsin AUC(0-infinity) and its in vivo effects was assessed.
Results: Romidepsin pharmacokinetics were best described by a three-compartment model with Linear kinetics. Body weight influenced romidepsin disposition. A significant relationship was observed between romidepsin AUC(0-infinity) and increases in expression of exhaustion markers by CD4+ and CD8+ T cells and apoptosis markers in CD4+, but not with histone acetylation Levels or HIV-1 cell-associated RNA in CD4+ T cells. For each increase of 100 ng.h/mL in romidepsin AUC(0-infinity), CD4+ counts decreased by a mean (95% CI) of 74 (42-94) cells/mm(3) after dosing.
Conclusions: A population model describing the pharmacokinetics of romidepsin as an HIV LRA was developed. Higher exposure to romidepsin resulted in higher expression of apoptosis markers and declines in CD4+ count but did not increase viral reactivation Levels. These observations have important implications for the optimization of effective kick-and-kill strategies for an HIV-1 cure.
Filiaciones:
:
Fundacio Lluita Sida, Badalona, Spain
Hosp Badalona Germans Trias & Pujol, Infect Dis Dept, Badalona, Spain
:
IrsiCaixa AIDS Res Inst HIVACAT, Badalona, Spain
Univ Autonoma Barcelona UAB, Dept Cellular Biol Physiol & Immunol, Barcelona, Spain
:
Fundacio Lluita Sida, Badalona, Spain
Manzardo, C:
Univ Barcelona, Hosp Clin IDIBAPS, Infect Dis Dept, Barcelona, Spain
:
IrsiCaixa AIDS Res Inst HIVACAT, Badalona, Spain
:
IrsiCaixa AIDS Res Inst HIVACAT, Badalona, Spain
:
Fundacio Lluita Sida, Badalona, Spain
Miro, JM:
Univ Barcelona, Hosp Clin IDIBAPS, Infect Dis Dept, Barcelona, Spain
:
IrsiCaixa AIDS Res Inst HIVACAT, Badalona, Spain
Univ Vic Cent Univ Catalonia UVic UCC, Fac Med, Vic, Spain
ICREA, Barcelona, Spain
:
Fundacio Lluita Sida, Badalona, Spain
Hosp Badalona Germans Trias & Pujol, Infect Dis Dept, Badalona, Spain
IrsiCaixa AIDS Res Inst HIVACAT, Badalona, Spain
Univ Vic Cent Univ Catalonia UVic UCC, Fac Med, Vic, Spain
:
IrsiCaixa AIDS Res Inst HIVACAT, Badalona, Spain
Univ Vic Cent Univ Catalonia UVic UCC, Fac Med, Vic, Spain
ICREA, Barcelona, Spain
:
Fundacio Lluita Sida, Badalona, Spain
Hosp Badalona Germans Trias & Pujol, Infect Dis Dept, Badalona, Spain
IrsiCaixa AIDS Res Inst HIVACAT, Badalona, Spain
Univ Vic Cent Univ Catalonia UVic UCC, Fac Med, Vic, Spain
Valle, M:
Univ Autonoma Barcelona UAB, Barcelona, Spain
St Pau Inst Biomed Res IIB St Pau, PKPD Modeling & Simulat, Barcelona, Spain
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