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

Article highlights

• Developmental differences in pediatric renal transplant patients influences treatment plan decisions and overall patient outcomes.

• Maintenance phase immunosuppressant protocols have evolved over the last several decades.

• Toxicities and adverse drug reactions associated with immunosuppressant therapy can be minimized by controlling therapeutic target concentration attainment based on therapeutic drug monitoring.

• Individual patient factors (e.g. age, weight, hematocrit, and pharmacogenetics) should be considered when implementing immunosuppressant treatment plans.

• Studies comparing the bioequivalence of generic formulations to brand formulations are ongoing.

Acknowledgments

The authors would like to thank Luzviminda (Luz) Sinha, Medical and Research Librarian at Dayton Children’s Hospital, for her helpful retrieval of literature in addition to her edits and review.

Declaration of interest

CMS, RMW, JR, SSK, SMI, and KMJ received funding through a grant (1U01FD005191) from the US FDA. Otherwise, the authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

KMJ, JKR, RMW, JS, and CMS contributed to the conception, design, and initial preparation of the manuscript. JKR, EYE, SMI, SSK, JR, TF, JS outlined the initial literature review and interpretation of published data. KMJ, JMR, EYE, SMI, SSK, JR, JS, and CMS undertook the initial literature review and interpretation of published data. KMJ, JMR, EYE, SMI, SSK, JR, RMW, TF, JS, and CMS made substantial contributions in drafting the manuscript and revising it critically for valuable intellectual content. All authors have read and approved the final submitted version of the manuscript.

Additional information

Funding

This study was supported in part by a grant Pharmacometric Modeling of Immunosuppressants For Evaluation of Bioequivalence Criteria (1U01FD005191-270) from the US FDA. Views expressed here are the authors’ and do not reflect the official.