Conversion to Once-daily Tacrolimus Results in increased p38MAPK Phosphorylation in T-lymphocytes of Kidney Transplant Recipients

Background: The once-daily formulation of tacrolimus (TACOD) has been developed to overcome adherence problems. Conversion from the twice-daily TAC (TACBID) formulation to TACOD on a 1:1 basis, however, often leads to a decrease of TAC predose concentrations, which averages ~15%. Switching between the two TAC formulations may thus influence drug efficacy and necessitates therapeutic drug monitoring. As an additional tool in transplantation diagnostics, phospho-specific flow cytometry was used to study the biological effects of conversion on p38MAPK phosphorylation, a kinase involved in T-lymphocyte activation.

Methods: Stable renal transplant recipients (n = 12), at least 1 year after their transplantation, were converted from TACBID to TACOD on 1:1 mg for mg base. Comedication consisted of mycophenolate mofetil (n = 10) and prednisolone (n = 3). TAC whole-blood predose concentrations were determined by immunoassay before and 3 months after conversion. P38MAPK phosphorylation was measured in T lymphocytes by whole-blood phospho-specific flow cytometry.

Results: Three months after conversion, no significant decreases in TAC predose concentrations (C0) were found (P = 0.54), whereas p38MAPK phosphorylation increased with 11.4% (P < 0.05) in CD4+ and with 15.6% (P < 0.05) in CD8+ T lymphocytes. The TAC C0 during treatment with TACBID correlated inversely with p38MAPK phosphorylation in T lymphocytes (rs = -0.638; P < 0.05).

Conclusions: These results suggest that the measurement of p38MAPK phosphorylation status in T lymphocytes is a sensitive method to determine the biological effects of TAC before and after conversion from TACBID to TACOD. This method could be a more sensitive tool for therapeutic drug monitoring of TAC.