C0h/C2h monitoring of the pharmacodynamics of cyclosporin plus mycophenolate mofetil in human heart transplant recipients.
Pharmacokinetic (PK) parameters like C2h have improved efficacy of immunosuppressive therapy. However, drug interactions, toxicities, and individual differences to drug effects still remain challenging. Therefore, this study was designed to assess pharmacodynamic (PD) effects of the combination cyclosporin (CsA) plus mycophenolate mofetil (MMF) on lymphocyte functions in peripheral blood of stable heart transplant recipients (HTx) using our established FACS assays.


METHODS
Blood from 25 HTx patients was drawn before (C0h) and 2 hours after dosing (C2h). CsA and mycophenolic acid (MPA) concentrations were measured by EMIT. FACS assessed expression of cytokine production (IL-2, TNF-alpha), lymphocyte proliferation (PCNA), and T-cell activation (CD25, CD95).


RESULTS
Evening doses of CsA (25/50/75 or 100 mg) and MMF (250/500 or 1000 mg) produced C0h levels as follows: CsA, 162 +/- 12 ng/mL; MPA, 1.7 +/- 0.2 mg/L. Morning doses of CsA (50/75 or 100 mg) and MMF (250/500/1000 or 1500 mg) produced C2h-levels as follows: CsA, 589 +/- 56 ng/mL and MPA, 7.4 +/- 1.3 mg/L. PD effects at C0h/C2h (% expression +/- SEM, all P < .05) were IL-2, 18 +/- 3/10 +/- 2; TNF-alpha, 12 +/- 2/7 +/- 1; PCNA, 8 +/- 1/5 +/- 1; CD25, 26 +/- 4/13 +/- 2; CD95, 23 +/- 4/11 +/- 2). Correlations (r2) at time point C2h between inhibition of lymphocyte functions (PD) with drug concentrations (PK) and with drug doses were CsA-PK, 0.71 to 0.91; MMF-PK, 0.55 to 0.76; CsA-dose, 0.73 to 0.87; MMF-dose, 0.61 to 0.80.


CONCLUSIONS
For the first time, the immunosuppressive effects of the combination CsA plus MMF were quantified in whole blood of human HTx at different time points. PD assays may offer the opportunity to optimize clinical immunosuppressive drug therapy.
Barten
M J
MJ
University Leipzig, Department of Cardiac Surgery, Leipzig Heart Center, Leipzig, Germany. bartenm@medizin.uni-leipzig.de
Rahmel
A
A
Garbade
J
J
Richter
M
M
Bittner
H B
HB
Dhein
S
S
Mohr
F W
FW
Gummert
J F
JF
D015703:Antigens, CD / Q000097:blood; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D016027:Heart Transplantation / Q000276:immunology / Q000502:physiology*; D006801:Humans; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D018809:Proliferating Cell Nuclear Antigen / Q000097:blood
D015703:Antigens, CD; D018809:Proliferating Cell Nuclear Antigen; D016572:Cyclosporine; D009173:Mycophenolic Acid