J Kamp, A Gelinck, M Lyousoufi, S Meziyerh, H S Spijker, V A L Huurman, P J M van der Boog, A P J de Vries, D J A R Moes
We successfully developed two separate population PK models for tacrolimus in SPK and KT recipients together with a combined SPK and KT model, showing a significantly reduced tacrolimus oral absorption rate in SPK recipients. In addition, our data suggested that SPK recipients might need higher C0 target concentrations to obtain a similar tacrolimus exposure as KT recipients.
BACKGROUND AND OBJECTIVES: Simultaneous pancreas kidney transplantation (SPK) is a preferred option for type 1 diabetes (T1DM) patients with end-stage renal disease (ESRD). Most transplant centers use kidney transplant (KT) protocols target trough concentrations (C0) to dose tacrolimus in SPK recipients, due to a lack of evidence for optimal tacrolimus C0 in SPK recipients. However, tacrolimus pharmacokinetics (PK) might be altered in SPK recipients due to diabetic gastroparesis or complications from intraperitoneal surgery and/or enteric drainage. We therefore aimed to compare oral tacrolimus PK in SPK versus KT recipients as a first step to define the optimal target tacrolimus concentrations in SPK recipients.
METHODS: A retrospective observational study was performed to describe and compare tacrolimus population PK in SPK and KT recipients. Relevant demographic and PK data were extracted from our local transplantation database for patients transplanted between 2005 and 2020 at our hospital. Pharmacokinetic data were analyzed using nonlinear mixed effect modeling in NONMEM. Furthermore, simulations were performed to assess potential differences in AUC0-12h to C0 ratios between SPK and KT recipients.
RESULTS: Tacrolimus population PK in SPK and KT recipients were best described by two-compartmental models. The combined SPK and KT model showed a significantly reduced oral absorption rate for SPK recipients, compared to KT recipients (0.231 h-1 vs 0.336 h-1 respectively). Simulations indicated a 10% (95% CI 8.8%-11.1%) lower AUC0-12h to C0 ratio in SPK recipients compared to KT recipients.
CONCLUSIONS: We successfully developed two separate population PK models for tacrolimus in SPK and KT recipients together with a combined SPK and KT model, showing a significantly reduced tacrolimus oral absorption rate in SPK recipients. In addition, our data suggested that SPK recipients might need higher C0 target concentrations to obtain a similar tacrolimus exposure as KT recipients.