1995 Fiscal Year Final Research Report Summary
Population Analysis of Pharmacokinetics and Pharmacodynamics of an Immunosuppresive Agent
| Project/Area Number |
06672140
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Physical pharmacy
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| Research Institution | Tokyo Medical and Dental University (1995)
Kyoto University (1994) |
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Principal Investigator |
YASUHARA Masato Tokyo Medical & Dental Univ., Med., Prof., 医学部, 教授 (00127151)
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| Co-Investigator(Kenkyū-buntansha) |
HASHIMOTO Yukiya Kyoto Univ., Med., Lecturer, 医学部, 講師 (90228429)
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| Project Period (FY) |
1994 – 1995
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| Keywords | Immunosuppressive agent / Population analysis / Tacrolimus / Pharmacokinetics / Pharmacodynamics / Hepatic extraction / Living-related donor liver transplantation |
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| Research Abstract |
The establishment of reliable postoperative immunosuppressive therapy is essential to improve the outcome of organ transplantation. We have investigated the pharmacokinetics and pharmacodynamics of tacrolimus (FK506), a new immunosuppressive agent, in patients receiving living-related donor liver transplantations (LRLT) at the Second Department of Surgery, Kyoto University Hospital.
1.Of the 55 patients receiving LRLT,6 had and episode of hepatic dysfunction, which was suspected to the liver allograft rejection. The onset of rejection was associated with lower blood concentration of tacrolimus. On the other hand, most of the adverse effects, such as hyperkalemia, renal dysfunction and hyperglycemia, occurred at the blood concentration higher than 20 ng/ml. Thus, the therapeutic effect and toxicity of tacrolimus were related to trough blood concentrations and the therapeutic blood concentration of tacrolimus ranged from nearly 10 to 20 ng/ml for impatients after LRLT.
3.The pharmacokinetics of tacrolimus after i.v.infusion and oral administration was analyzed with an one-compartment model using the NONMEM program developed for population analysis. NONMEM analysis showed that the clearance of tacrolimus was related to body weight and days after operation and that the availability was about 19%.
3.The careful dose adjustment based on TDM is essential because of the large inter-and intra-individual variability in the pharmacokinetics of tacrolimus.
4.The animal experiment indicated that the clearance and hepatic extraction of tacrolimus reduced significantly in rats with hepatic dysfunction.
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