Tacrolimus Intra-Patient Variability: The Impact Of Conversion From Immediate (Prograf® ) To Prolonged Release (Advagraf® ) Tacrolimus Formulations In Stable Renal Transplant Patients

Toqa El-Nahhas1, Joyce Popoola2, Rajeshwar Ramkhelawon2, Iain MacPhee2, Atholl Johnston1. 1Clinical Pharmacology Department,William Harvey Research Institute, Barts and The London, Queen Mary University of London, London, UK, 2Cellular & Molecular Medicine-Renal Medicine,George’s Hospital Medical School, London, UK

Background. Once-daily formulation of tacrolimus (Advagraf®) has a similar efficacy and safety profile to twice-daily tacrolimus (Prograf®) (Crespo et.al, 2009).Tacrolimus is a narrow therapeutic index drug, with wide variation between individuals in the blood concentration achieved by a given dose. The within patient variability in tacrolimus exposure was also considered. Variable blood drug concentrations have been shown to be a risk factor for rejection and long-term allograft nephropathy (Borra, 2010).There are very few studies that focused on comparing within-patient variability of tacrolimus formulations.

Objectives. This study investigates the effect of switching stable renal transplant patients from a twice a day formulation of tacrolimus (Prograf®) to a once a day formulation (Advagraf®) on within patient variability in pre-dose blood tacrolimus concentration.

Methods. Sixty five patients aged between 21 to 76 years were included in this study. Switching from Prograf® to Advagraf® was made on a 1mg:1mg basis. Analysis of tacrolimus trough blood concentrations (C0) was made during periods of stable tacrolimus doses. The data were analysed using analysis of variance (ANOVA).

Results. After the switch, there was a highly significant reduction in tacrolimus trough blood concentration (C0) (p < 0.001). The mean tacrolimus C0 concentration fell from 7.51 µg/L SD 1.52 to 6.48 µg/L SD 1.25 with a 13% reduction [90%CI 10 to 17%]. The within-patient percentage coefficient of variation (%CV) of tacrolimus C0 was not significantly different after switching. The mean within patient variability %CV of tacrolimus C0 was 21% SD 14.2 for Prograf® and 23% SD 10.4 for Advagraf® (p > 0.05). In addition, there was no significant change in the tacrolimus mean daily dose before and after switching (p > 0.05). However the tacrolimus dose was reduced in twenty patients (31%) by a mean change of –27% and the dose was increased in 11 patients (17%) by a mean change of +30% with 52% of the patients continuing on the same daily dose.

Conclusions. Switching from immediate to prolonged release tacrolimus formulations in kidney transplant patients was associated with a significantly lower tacrolimus trough concentration (C0), confirming previously published reports but had no influence on within patient variability in contrast to published reports suggesting a reduction following conversion to Advagraf®. While many patients required dose changes, there was no overall increase in the amount of tacrolimus prescribed across the population.

Abbreviations. C0: Trough blood concentrations, ANOVA: Analysis of variance, %CV: Coefficient of variation and CI: Confidence interval.

References.

Borra, L.C . , Roodnat, J.I . , Kal, J.A . , Mathot, R.A . , Weimar, W . , and van Gelder, T. (2010) High within-patient variability in the clearance of tacrolimus is a risk factor for poor long-term outcome after kidney transplantation. Nephrol Dial Transplant, 25(8):2757-63.

Crespo, M . , Mir, M . , Marin, M . , Hurtado, S . , Estadella, C . , Gurí, X . , Rap, O . , Moral, R . , Puig, J.M . , and Lloveras, J .(2009) De novo kidney transplant recipients need higher doses of Advagraf compared with Prograf to get therapeutic levels. Transplant Proc., 41(6):2115-7.