Assessing cumulative exposure to maintenance immunosuppressive drugs: Metrics, outcomes, and implications for transplant patients

Immunosuppressive drugs are used in the management of transplant patients to prevent organ rejection. However, immunosuppression can be associated with adverse effects such as infections and cancers. This study aimed to characterize the measures of cumulative immunosuppressive drug exposure (CIDE) used in the literature and their associated outcomes in transplant patients. A literature search was conducted in Ovid MEDLINE, Ovid EMBASE, Cochrane CENTRAL, and Cochrane Database of Systematic Reviews using search terms related to maintenance immunosuppressants and CIDE. Study risk of bias was assessed using the Quality in Prognostic Studies tool. Thirty-one articles were included in this qualitative synthesis. Sixteen articles (52 %) calculated the total dose of immunosuppression over the treatment period, while eight (26 %) used area-under-the-curve of trough level concentrations to quantify CIDE. Five (16 %) articles investigated time-weighted metrics of calcineurin inhibitors and four (13 %) used other metrics that could not be categorized into the previous groups. Most studies investigated CIDE with calcineurin inhibitors and used additive dosing methods. This approach was also popular with corticosteroids and multi-drug exposures. The variety of metrics used in the literature reveals a lack of standardization in the evaluation of CIDE and long-term outcomes. Future studies should validate these metrics for clinical application, especially pertaining to infectious outcomes.