Mami Iwasaki1,2, Ikuko Yano1,3, Sachio Fukatsu1, Sachiyo Hashi1, Yuki Yamamoto1, Mitsuhiro Sugimoto1, Masahide Fukudo1, Satohiro Masuda1, Shunsaku Nakagawa1, Atsushi Yonezawa1, Toshimi Kaido4, Shinji Uemoto4, Kazuo Matsubara1. 1. Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan. Dr. Fukudo is now with the Department of Pharmacy and Pharmacology, Asahikawa Medical University, Japan. Dr. Masuda is now with the Department of Pharmacy, Kyushu University Hospital, Japan. 2. Department of Clinical Trial Management, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan. 3. Department of Pharmacy, Kobe University Hospital, Kobe, Japan. 4. Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Abstract
BACKGROUND: This study investigates the pharmacokinetics and pharmacodynamics of tacrolimus using the once-daily (OD) formulation in the early stage after living donor liver transplantation (LDLT) in comparison with those using the twice-daily (TD) formulation. METHODS: Nine patients undergoing primary LDLT and treated with the OD tacrolimus formulation were included. The trough blood concentration (C0) of tacrolimus was monitored every day for 3 weeks after LDLT. A time course study of the blood tacrolimus concentrations and calcineurin (CN) phosphatase activity in peripheral blood mononuclear cells was performed 3 weeks after LDLT. Pharmacokinetic and pharmacodynamic parameters were compared with previously reported data using the TD formulation. RESULTS: The interindividual variability in the daily dose of tacrolimus was significantly larger in the OD formulation than in the TD formulation (P < 0.001). In the time course study, the tacrolimus blood concentrations at 4, 8, and 12 hours after administration and the area under the concentration-time curve from 0 to 24 hours (AUC0-24) in the OD group were significantly higher than in the TD group, although the C0 was equivalent. In addition, the C0 was not significantly correlated with the AUC0-24 in the OD formulation. The apparent clearance and the pharmacodynamic parameters examined were not significantly different between the OD and TD groups. CONCLUSIONS: The C0 monitoring of the OD formulation may not be optimal in patients at the early stage after LDLT because the C0 was not correlated with the AUC0-24. If clinicians target the same C0 using the OD and TD formulations, the exposure of tacrolimus can be higher in the OD formulation, and excessive immunosuppression should be noted. Particular attention should be paid to the patients in the early stage after LDLT in the use of the OD oral formulation of tacrolimus.
BACKGROUND: This study investigates the pharmacokinetics and pharmacodynamics of tacrolimus using the once-daily (OD) formulation in the early stage after living donor liver transplantation (LDLT) in comparison with those using the twice-daily (TD) formulation. METHODS: Nine patients undergoing primary LDLT and treated with the OD tacrolimus formulation were included. The trough blood concentration (C0) of tacrolimus was monitored every day for 3 weeks after LDLT. A time course study of the blood tacrolimus concentrations and calcineurin (CN) phosphatase activity in peripheral blood mononuclear cells was performed 3 weeks after LDLT. Pharmacokinetic and pharmacodynamic parameters were compared with previously reported data using the TD formulation. RESULTS: The interindividual variability in the daily dose of tacrolimus was significantly larger in the OD formulation than in the TD formulation (P < 0.001). In the time course study, the tacrolimus blood concentrations at 4, 8, and 12 hours after administration and the area under the concentration-time curve from 0 to 24 hours (AUC0-24) in the OD group were significantly higher than in the TD group, although the C0 was equivalent. In addition, the C0 was not significantly correlated with the AUC0-24 in the OD formulation. The apparent clearance and the pharmacodynamic parameters examined were not significantly different between the OD and TD groups. CONCLUSIONS: The C0 monitoring of the OD formulation may not be optimal in patients at the early stage after LDLT because the C0 was not correlated with the AUC0-24. If clinicians target the same C0 using the OD and TD formulations, the exposure of tacrolimus can be higher in the OD formulation, and excessive immunosuppression should be noted. Particular attention should be paid to the patients in the early stage after LDLT in the use of the OD oral formulation of tacrolimus.
Authors: Jong Man Kim; Pyoung-Jae Park; Geun Hong; Dong Jin Joo; Kwan Woo Kim; Je Ho Ryu; Young Seok Han; Jai Young Cho; Gi-Won Song; Bong-Wan Kim; Dong-Sik Kim; Seong Hoon Kim; Sang Tae Choi; Young Kyoung You; Kyung-Suk Suh; Yang-Won Na; Koo Jeong Kang; Jae-Won Joh Journal: Korean J Transplant Date: 2021-09-30
Authors: Pere Fontova; Helena Colom; Raül Rigo-Bonnin; Lisanne N van Merendonk; Anna Vidal-Alabró; Nuria Montero; Edoardo Melilli; Maria Meneghini; Anna Manonelles; Josep M Cruzado; Juan Torras; Josep Maria Grinyó; Oriol Bestard; Nuria Lloberas Journal: Front Pharmacol Date: 2021-03-17 Impact factor: 5.810