Relationship Between Change Rate of Tacrolimus Clearance During Continuous Intravenous Infusion and Recipient Recovery a
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ORIGINAL RESEARCH ARTICLE
Relationship Between Change Rate of Tacrolimus Clearance During Continuous Intravenous Infusion and Recipient Recovery at an Early Stage After Living Donor Liver Transplantation Junichi Nakagawa1 · Keinosuke Ishido2 · Yuka Tono1 · Norihisa Kimura2 · Taiichi Wakiya2 · Yuji Okamura1 · Kenichi Hakamada2 · Takenori Niioka1,3
© Springer Nature Switzerland AG 2020
Abstract Background and Objective Tacrolimus clearance (CL) is significantly altered according to recovery of liver function at an early stage after living donor liver transplantation (LDLT). In this study, we aimed to examine the impact of the change rate from postoperative day (POD) 1 in CL (ΔCL) of tacrolimus during continuous intravenous infusion (CIVI) on recipient recovery. Methods A tacrolimus population pharmacokinetic model on POD1 after LDLT was developed using Phoenix NLME 1.3. The CLPOD1 was calculated using the final model. The CLPOD4–7 was calculated by dividing total daily tacrolimus dose by the area under the concentration-time curve from 0 to 24 h. Results Data were obtained from 57 LDLT recipients, along with 540 points (177 points on POD1, 363 points on POD4–7) of tacrolimus whole blood concentrations at CIVI. The median tacrolimus CL decreased from POD1 to POD4 (from 2.73 to 1.40 L/h) and was then stable until POD7. Stepwise Cox proportional hazards regression analyses showed that the graft volume (GV)/standard liver volume (SLV) ratio (GV/SLV) and the tacrolimus ΔCLPOD6 were independent factors predicting early discharge (within 64 days median value) of recipients after LDLT [hazard ratio (HR) = 1.041, P = 0.001 and HR = 1.023, P = 0.004]. Conclusions The tacrolimus ΔCL during CIVI immediately after LDLT in each recipient was a useful indicator for evaluation of recovery at an early stage after LDLT.
1 Introduction Tacrolimus is a calcineurin inhibitor commonly used for prevention of rejection in solid organ transplantation [1, 2]. However, the use of tacrolimus is complicated by its narrow Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13318-020-00628-2) contains supplementary material, which is available to authorized users. * Takenori Niioka t‑niioka@hirosaki‑u.ac.jp 1
Department of Pharmacy, Hirosaki University Hospital, 53 Hon‑cho, Hirosaki, Aomori 036‑8563, Japan
2
Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu‑cho, Hirosaki, Aomori 036‑8562, Japan
3
Department of Pharmaceutical Science, Hirosaki University Graduate School of Medicine, 53 Hon‑cho, Hirosaki, Aomori 036‑8563, Japan
therapeutic index and wide intra- and inter-recipient variability in pharmacokinetics [3]. High tacrolimus blood concentrations are associated with nephrotoxicity and neurotoxicity, whereas low blood concentrations may lead to rejection of the transplanted organ [3]. Therefore, therapeutic drug monitoring (TDM) of tacrolimus is required to achieve the target whole blood concentration ( Cwb) in transplant
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