Factors affecting the pharmacokinetics of tacrolimus (FK506) in hematopoietic cell transplant (HCT) patients

• Published in: Bone marrow transplantation (Basingstoke) Vol. 28; no. 8; pp. 753 - 758
• Main Authors: JACOBSON, P, NG, J, RATANATHARATHORN, V, UBERTI, J, BRUNDAGE, R. C
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.10.2001
• Subjects: Administration, Oral; Adolescent; Adult; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Bilirubin; Bioavailability; Biological and medical sciences; Biological Availability; Bone marrow; Bone marrow transplantation; Bone marrow, stem cells transplantation. Graft versus host reaction; Creatinine; Creatinine - blood; Female; FK506; Graft versus host disease; Graft vs Host Disease - etiology; Graft vs Host Disease - prevention & control; Graft-versus-host reaction; Hematologic Neoplasms - blood; Hematologic Neoplasms - therapy; Hematopoietic Stem Cell Transplantation - adverse effects; Hepatic Veno-Occlusive Disease - etiology; Humans; Hyperbilirubinemia - metabolism; Immunomodulators; Immunosuppression; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - blood; Immunosuppressive Agents - pharmacokinetics; Infusions, Intravenous; Intravenous administration; Male; Medical sciences; Metabolic Clearance Rate; Middle Aged; Models, Biological; Parameter identification; Patient Compliance; Patients; Pharmacokinetics; Pharmacology; Pharmacology. Drug treatments; Population statistics; Retrospective Studies; Stem cell transplantation; Tacrolimus; Tacrolimus - administration & dosage; Tacrolimus - blood; Tacrolimus - pharmacokinetics; Toxicity; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplantation; Transplantation, Homologous - adverse effects; Transplants & implants; Veno-occlusive disease; United States; North America; America; Human; Venoocclusive disease; Intravenous administration; Stem cell; Estimation; Hematopoietic cell; Lactone; Graft versus host reaction; Concentration; Macrocycle; Prevention; Whole blood; Therapeutic drug monitoring; Immunosuppression; Tacrolimus; Interindividual comparison; Models; Immunosuppressive agent; Pharmacokinetics
• ISSN: 0268-3369; 1476-5365
• DOI: 10.1038/sj.bmt.1703224

Tacrolimus is an immunosuppressant commonly used in the prevention of graft-versus-host disease (GVHD) following allogeneic HCT. Unfortunately, the use of tacrolimus is associated with variable immunosuppression and toxicity. The purpose of this study was to describe tacrolimus population pharmacokinetic parameters, to identify relationships between clinical covariates and pharmacokinetic estimates, and to develop a model to predict tacrolimus clearance in HCT patients. Steady-state whole blood tacrolimus concentrations (n = 1625) obtained during intravenous and oral therapy were analyzed in 122 patients. Population clearance (CL) was 5.22 l/h and bioavailability (F) was 0.28. The influence of clinical covariates on population estimates of CL and F of tacrolimus were tested with nonlinear mixed effects models (NONMEM). CL was significantly reduced by elevations in total bilirubin 2.0-9.9 mg/dl (CL * 0.797), bilirubin > or = 10 mg/dl (CL * 0.581), serum creatinine > or = 2 mg/dl (CL * 0.587), grade III/IV graft-versus-host disease (CL * 0.814) and veno-occlusive disease (CL 0.814). No covariates were predictive of oral F. The interindividual variabilities in CL and F were 33% and 44%, respectively. Residual variability was 27.5% and 16.8% at tacrolimus concentrations of 10 microg/l and 20 microg/l, respectively. These models may be used to predict tacrolimus clearance and doses in adult patients following HCT.