Treatment optimization of maintenance immunosuppressive agents in pediatric renal transplant recipients

Abstract

Introduction: Graft survival in pediatric kidney transplant patients has increased significantly within the last three decades, correlating with the discovery and utilization of new immunosuppressants as well as improvements in patient care. Despite these developments in graft survival for patients, there is still improvement needed, particularly in long-term care in pediatric patients receiving grafts from deceased donor patients. Maintenance immunosuppressive therapies have narrow therapeutic indices and are associated with high inter-individual and intra-individual variability.Areas covered: In this review, we examine the impact of pharmacokinetic variability on renal transplantation and its association with age, genetic polymorphisms, drug-drug interactions, drug-disease interactions, renal insufficiency, route of administration, and branded versus generic drug formulation. Pharmacodynamics are outlined in terms of the mechanism of action for each immunosuppressant, potential adverse effects, and the utility of pharmacodynamic biomarkers.Expert opinion: Acquiring abetter quantitative understanding of immunosuppressant pharmacokinetics and pharmacodynamic components should help clinicians implement treatment regimens to maintain the balance between therapeutic efficacy and drug-related toxicity.

Keywords: Graft survival; immunosuppressant; immunosuppression; immunosuppressive agents; kidney transplantation; pediatric; pharmacokinetics; renal transplant.

Figure 1.

Timeline of significant developments in immunosuppressive therapy and initial US approvals of therapies beginning in 1955 through 2011 [54].

Figure 2.

Immunosuppressive therapy from the time of transplant in kidney transplant, Panel A Transplant era (1996 to 2001), Panel B Transplant era (2002–2007), Panel C Transplant era (2008 to 2013) [1].

Figure 3.

Deceased and living donor graft survival at 1-year post-transplant (1991 through 2015) [3,2].

Figure 4.

Mechanism of action for calcineurin inhibitors (cyclosporine, tacrolimus), Inosine-monophosphate dehydrogenase inhibitors (mycophenolic acid), and mTOR inhibitors (sirolimus and everolimus); MPA – mycophenolic acid, MHC – major histocompatibility complex, mTOR – mammalian target of rapamycin inhibitor, FKBP – FK506 binding protein, NFAT – Nuclear factor of activated T-cells, MAPK – mitogen-activated protein kinase, tgfb1 – transforming growth factor-beta 1, Cdk 2 – cyclin-dependent kinase 2, → – path continuation, – | – blocking the pathway. (note, this figure is original and not copied from another source)