Deconvolution Analysis of the Interaction between Tacrolimus and Ketoconazole

Signature Grand, Davie, Florida, USA

Objective. To improve the precision of the point estimate and develop predictors of tacrolimus bioavailability, alone and when administered concomitantly with CYP3A and P-gp inhibitors. Background. Tacrolimus (TAC) has been used for immunosuppresion after solid organ transplant for over ten years. Despite numerous pharmacokinetic studies of TAC the absolute bioavailability (F) remains poorly defined. Methods. Subjects were 19 adult renal transplant recipients receiving TAC as part of an immunosuppression regimen. TAC was administered by intravenous (IV) infusion after a 24-hr washout period; a single oral (po) dose of KT (400 mg) was administered followed by the same IV dose of TAC. Whole blood was drawn to provide pharmacokinetic (PK) profiles after IV administration. Steady state oral TAC PK profiles with and without KT were similarly obtained. A two-compartment model for intermittent IV infusion and po dosing at steady state were simultaneously fit and deconvolution analysis was performed using WinNonLin Professional V 5.2. Percent change in F and the Ln transformed KT/TAC po dose ratio were fit to a sigmoid Emax model. Results. Systemic clearance of TAC was not altered by 400 mg of oral KT (control 0.102 L/h/kg (0.089-0.114) Vs keto 0.088 L/H/kg (0.072-0.103) p = 0.15). TAC F was altered by KT (14 %(11-17) ctrl; 35% (26-44) KT; p=0.0006) in a dose dependent fashion (Emax 350 %, EC50 = 4.2 mg keto /mg TAC, γ = 15). Conclusion. TAC F is altered by KT, not by changing systemic clearance, but rather by increasing absorption from jejunal and ileal sites.