Pharmacokinetic Boosting of Calcineurin Inhibitors in Transplantation: Pros, Cons, and Perspectives

The concept of pharmacokinetic (PK) boosting of calcineurin inhibitors (CNI) emerged after the FDA approval of cyclosporine-A. Several studies followed, and the proof of concept was well established by the late 1990s. This also continued for the next blockbuster immunosuppressant, tacrolimus. The driver for such research was an endeavor to save costs, as both drugs were expensive due to patent protection. Two CYP inhibitors, ketoconazole and diltiazem, have been extensively studied in this context and continue to be prescribed off-label along with the CNI. It has been observed that using ketoconazole reduces the dose requirement of tacrolimus by about 50% and 30% with diltiazem, which is in conformity with their pharmacological actions. Off-label co-prescription of these drugs with CNI is often encountered in low and middle-income countries. The foremost reason cited is economic. This article collates the evidence from the clinical studies that evaluate the PK-boosting effects of CNI and also reviews the gaps in the current evidence base. The current knowledge prevents the transplant community from making meaningful inferences about the risks and benefits of such strategies. Although the PK-boosting strategy can lead to serious adverse events, emerging evidence suggests that it may be advantageous for individuals with high CNI dose requirements. Hence, PK boosting may be an unmet need in the therapeutics of CNI. Nevertheless, there are several unanswered questions surrounding such use, and therefore, this merits testing in well-designed clinical studies. Moreover, drugs with better safer profiles and a history of successful PK boosting may be considered for evaluation with CNI.