title: Temporal decline in sirolimus elimination immediately after pancreatic islet transplantation.
abstract: Pancreatic islet transplantation is a curable treatment for type 1 diabetes and has been put into practice in various countries. In this study, we analyzed the pharmacokinetic characteristics of sirolimus and tacrolimus in six Japanese patients with pancreatic islet transplants immediately after surgery, and monitored efficacy and toxicity. The patients were treated with immunosuppressive therapy based on the Edmonton protocol, that is, sirolimus and low-dose tacrolimus. Pharmacokinetic analyses were performed using the nonlinear mixed-effects modeling program NONMEM. Large inter- and intra-individual variability was observed in the pharmacokinetics of sirolimus and tacrolimus. A model with increased apparent clearance in the postoperative period explained well the intra-individual variability in the pharmacokinetics of both drugs. The most frequent drug-induced toxicity was a decrease in the white blood cell count, and two of six patients required the administration of granulocyte colony-stimulating factor. Clinical laboratory tests immediately before the transplantation and cytochrome P450 3A5 genotype were not related to the high blood concentrations of sirolimus after the loading dose. From these results, the apparent clearance of sirolimus and tacrolimus might temporally decline immediately after pancreatic islet transplantation. A high trough concentration of sirolimus might increase the risk of hematological toxicy, and adjustment of the dosage for immunosuppressive treatment will be necessary in Japanese patients.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University.
authors.forename: Eriko
authors.initials: E
authors.lastname: Sato
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shimomura
authors.forename: Satohiro
authors.initials: S
authors.lastname: Masuda
authors.forename: Ikuko
authors.initials: I
authors.lastname: Yano
authors.forename: Toshiya
authors.initials: T
authors.lastname: Katsura
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Teru
authors.initials: T
authors.lastname: Okitsu
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Iwanaga
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Noguchi
authors.forename: Hideo
authors.initials: H
authors.lastname: Nagata
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Yonekawa
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Inui
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D001774:Blood Chemical Analysis / Q000379:methods; D002851:Chromatography, High Pressure Liquid; D003404:Creatinine / Q000097:blood; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics; D016381:Islets of Langerhans Transplantation; D007958:Leukocyte Count; D008111:Liver Function Tests; D008297:Male; D013058:Mass Spectrometry; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D011110:Polymorphism, Genetic; D020123:Sirolimus / Q000009:adverse effects / Q000493:pharmacokinetics*; D016559:Tacrolimus / Q000009:adverse effects / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D003577:Cytochrome P-450 Enzyme System; D003404:Creatinine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D020123:Sirolimus; D016559:Tacrolimus