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. 2021 Feb 26:26:e928817.
doi: 10.12659/AOT.928817.

Pharmacodynamic Drug-Drug Interaction on Human Peripheral Blood Mononuclear Cells Between Everolimus and Tacrolimus at the Therapeutic Concentration Range in Renal Transplantation

Masaaki Okihara  1 , Hironori Takeuchi  2 , Shinichi Akiyama  3 , Reichi Yoshinaga  3 , Sayuri Osato  3 , Isao Akashi  1 , Yu Kihara  1 , Osamu Konno  1 , Hitoshi Iwamoto  4 , Takashi Oda  4 , Sachiko Tanaka  5 , Sakae Unezaki  3 , Toshihiko Hirano  5
Affiliations

Pharmacodynamic Drug-Drug Interaction on Human Peripheral Blood Mononuclear Cells Between Everolimus and Tacrolimus at the Therapeutic Concentration Range in Renal Transplantation

Masaaki Okihara et al. Ann Transplant. .

Abstract

BACKGROUND Everolimus (EVL) plus tacrolimus (TAC) therapy is effective and safe in renal transplantation. However, the pharmacokinetic and pharmacodynamic information for EVL combined with TAC is limited. We investigated the pharmacodynamic drug-drug interaction between EVL and TAC at their therapeutic concentration range. MATERIAL AND METHODS Isolated peripheral blood mononuclear cells (PBMCs) from 22 healthy participants aged 22 to 24 years were cultured with concanavalin A (Con A) in the presence of EVL and/or TAC for 4 days, and the proliferation rate of the PBMCs was calculated. RESULTS TAC promoted the inhibitory efficacy of EVL against the mitogen-activated proliferation of PBMCs at the EVL therapeutic concentration range. When 0.175 ng/mL or more of TAC was combined with 30 ng/mL or more of EVL, the antagonistic effect of TAC on the inhibitory efficacy of EVL against the mitogen-activated proliferation of PBMCs was observed. Conversely, when 0.4 ng/mL TAC and 10 ng/mL or more of EVL were combined, the antagonistic effect of EVL on the inhibitory efficacy of TAC against the mitogen-activated proliferation of PBMCs was observed. CONCLUSIONS The pharmacodynamic synergistic efficacy of EVL and TAC in combination on mitogen-activated PBMCs was evident at the therapeutic concentration range, which is used in renal transplantation. However, these drugs antagonize each other to suppress the proliferation of activated PBMCs at concentrations higher than those clinically used.

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Conflict of interest statement

Conflicts of interest

None.

Figures

Figure 1
Figure 1
Concentration-proliferation curves for EVL alone or in combination with TAC against Con A-activated proliferation of PBMCs.
Figure 2
Figure 2
Actual drug–drug interaction of EVL and TAC against the proliferation of Con A-activated PBMCs.
Figure 3
Figure 3
Concentration-proliferation curves for TAC alone or in combination with EVL against Con A-activated proliferation of PBMCs.
Figure 4
Figure 4
The interaction indices of TAC and EVL against Con A-activated proliferation of PBMCs.
See this image and copyright information in PMC

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