Reduced elimination of cyclosporine A in elderly (>65 years) kidney transplant recipients

Transplantation. 2008 Nov 27;86(10):1379-83. doi: 10.1097/TP.0b013e31818aa4b6.

Abstract

Background: Physiologic functions that may affect pharmacokinetics of drugs are altered in elderly patients. The current study was performed to elucidate the effect of age on cyclosporine A (CsA) pharmacokinetics in renal transplant recipients.

Method: Twenty-five renal transplant recipients on CsA treatment were included in the study. CsA doses were adjusted by C2 monitoring. The patients were divided into two groups based on age; elderly: more than 65 years (n=11, mean 73 years) and younger: 18 to 64 years (n=14, mean 43 years). A full 12-hr pharmacokinetic profile was performed during stable phase. CsA whole blood and intracellular T-lymphocytes concentrations (first 6 hr) were measured. Genotyping of the CYP3A5*1/*3 and ABCB1 (C1236T, G2677T, C3435T) polymorphisms and quantification of whole blood mRNA ABCB1 expression were performed in all patients.

Results: Elderly patients achieved target C2 levels with lower CsA doses than the younger patients (4.3+/-0.8 vs. 6.1+/-2.1 mg/day/kg, P=0.025) because of lower clearance of CsA (22.7+/-5.1 vs. 30.5+/-11.1 L/hr, P=0.031). Elderly patients also showed 44% higher intracellular-to-whole blood CsA ratio than younger patients (P=0.02). Neither the CYP3A5*1, the ABCB1 genotypes nor mRNA ABCB1 expression revealed any significant influence on CsA pharmacokinetics.

Conclusion: The clearance of CsA decreased with increasing age. In addition, elderly patients had a significant larger proportion of the whole blood CsA concentration located at the site of action (within T lymphocytes). This indicates that in elderly recipients it might be safe to aim for an even lower whole blood target levels than current guidelines propose.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Adolescent
  • Adult
  • Aged
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Cyclosporine / adverse effects
  • Cyclosporine / blood
  • Cyclosporine / pharmacokinetics
  • Cyclosporine / therapeutic use*
  • Cytochrome P-450 CYP2A6
  • Drug Administration Schedule
  • Gene Expression Regulation
  • Genotype
  • Humans
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / blood
  • Immunosuppressive Agents / pharmacokinetics
  • Immunosuppressive Agents / therapeutic use
  • Kidney Transplantation / immunology*
  • Kidney Transplantation / physiology
  • Metabolic Clearance Rate
  • Middle Aged
  • Pilot Projects
  • Prospective Studies
  • T-Lymphocytes / immunology
  • Young Adult

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Immunosuppressive Agents
  • Cyclosporine
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP2A6