Pharmacokinetic and pharmacodynamic analysis of cyclosporine A (CsA) to find the best single time point for the monitoring and adjusting of CsA dose using twice-daily 3-h intravenous infusions in allogeneic hematopoietic stem cell transplantation.
Pharmacological study is predictably effective in establishing an optimal monitoring strategy for the usage of cyclosporine A (CsA) to prevent graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation recipients. Pharmacokinetic profiling of 33 recipients administered CsA twice daily by 3-h intravenous infusion revealed that levels peaked 2-3 h after the start of infusion, and an exponential decline of CsA concentrations after the termination of infusion was observed. The correlation between the area under the curve (AUC(0-12)) and CsA concentration at various time points after infusion revealed that C (2) and C (3) correlated best with AUC(0-12) (r (2) = 0.725), while the trough concentration correlated poorly. Ex vivo T cell stimulation followed by intracellular cytokine detection with flow cytometry revealed that the capacity of T cells to produce cytokines upon stimulation was inversely proportional to the CsA concentration, and reached a minimum at about 700 ng/mL with a marginal decrease above this concentration. Extrapolation using the regression equations of this study and the data from our retrospective study leads to the assumption that the dose adjustment of CsA based on maintaining the C (3) concentration above 800 ng/mL may effectively prevent acute GVHD. To confirm this assumption, a prospective clinical study is required.
Division of Bone Marrow Transplantation, Niigata University Medical and Dental Hospital, Asahimachi-dori 1-754, Chuoku, Niigata, Japan. tatsuof@med.niigata-u.ac.jp
Tatsuo
T
Furukawa
Tori
T
Kurasaki-Ida
Masayoshi
M
Masuko
Nobuhiro
N
Tsukada
Kiyoshi
K
Okazuka
Naoko
N
Sato
Toshio
T
Yano
Takashi
T
Abe
Akihito
A
Momoi
Yasuhiko
Y
Shibasaki
Masutaka
M
Higashimura
Kaori
K
Karimata
Masato
M
Moriyama
Takashi
T
Kuroha
Jun
J
Takizawa
Ken
K
Toba
Miwako
M
Narita
Ichiro
I
Fuse
Masuhiro
M
Takahashi
Yoshifusa
Y
Aizawa
D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D016572:Cyclosporine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016903:Drug Monitoring; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010599:Pharmacokinetics; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D055815:Young Adult
D016572:Cyclosporine