Best single time points as surrogates to the tacrolimus and mycophenolic acid area under the curve in adult liver transplant patients beyond 12 months of transplantation

Vartan Mardigyan, Jean Tchervenkov, Peter Metrakos, Jeffrey Barkun, Marc Deschenes, Marcelo Cantarovich
Clinical Therapeutics 2005, 27 (4): 463-9

BACKGROUND: Tacrolimus and mycophenolate mofetil (MMF) are immunosuppressive agents used for the prevention of allograft rejection in liver transplant recipients. Therapeutic drug monitoring (TDM) of tacrolimus is routinely performed using the trough (predose; time 0) plasma drug concentration (C0). In kidney and heart transplant recipients, TDM of MMF has proved to be effective in preventing acute rejection. Some studies have shown that C0 is a poor predictor of drug exposure (represented by AUC), and that concentrations measured after dosing may have a stronger correlation with AUC. However, routine TDM of MMF has not been widely accepted and dose adjustments are usually performed based on adverse effects.

OBJECTIVE: The aim of the present study was to determine whether plasma drug concentrations measured after dosing would be better correlated with the tacrolimus and mycoplasmic acid (MPA) (the active metabolite of MMF) AUC(0-12) values compared with C0 in liver transplant recipients > or = 12 months after transplantation.

METHODS: This study was conducted at the Multi-Organ Transplant Program research suite, Royal Victoria Hospital, McGill University Health Center, Montréal, Quebéc, Canada. Liver transplant recipients aged > or = 18 years receiving tacrolimus and MMF > or = 12 months after transplantation were enrolled. The plasma tacrolimus and MPA concentrations were measured before the first morning dose (C0) and at 30 minutes (MPA only) and 1, 2, 3, 4, 6, 8, and 12 hours after the first morning dose (C(30 min), C1, C2, C3, C4, C6, C8, and C12, respectively).

RESULTS: The study population consisted of 14 patients (7 women, 7 men; mean [SD] age, 57 [16] years; mean [SD] body weight, 75.4 [20.7] kg [range, 44-107 kg]; mean time posttransplant, 42 [30] months). All postdose concentrations (except C(30 min) [MPA]) were better correlated with AUC(0-12) values for tacrolimus and MPA compared with C0. For tacrolimus, the correlations of C0, C2, C3, and C4 with AUC(0-12) were 0.67, 0.83, 0.84, and 0.88, respectively, and for MPA, they were 0.46, 0.73, 0.69, and 0.68, respectively. For tacrolimus, the concentration best correlated with AUC(0-12) was C4. For MPA, the concentration best correlated with AUC(0-12) was C8.

CONCLUSION: This study in adult liver transplant recipients suggests that for both tacrolimus and MPA, C2, C3, and C4 are better surrogates of AUC(0-12) compared with C0.

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