Purpose: Evaluation of mammalian target of rapamycin inhibitor (mTORi)-related adverse events (AEs) and drug trough levels (C₀) at onset may aid their management in liver transplant recipients (LTRs). Here, we investigate time to onset, drug C₀, and related discontinuations due to select mTORi (everolimus [EVR])-associated AEs from the pivotal H2304 (NCT00622869) study.

Methods: In this 24-month, multicenter, open-label, controlled study, de novo LTRs were randomized (1:1:1) at 30 (±5) days posttransplant to EVR+rTAC (EVR C₀: 3-8 ng/mL; tacrolimus (TAC) C₀: 3-5 ng/mL); TAC withdrawal (EVR_mono [EVR C₀: 6-10 ng/mL; TAC withdrawal by Month 4]); or TAC control (TAC-C: C₀: 6-10 ng/mL) arms. Time to onset from randomization, EVR C₀ at onset (before/at/after event), and reported rates of concomitant medication use and treatment discontinuation for hyperlipidemia, proteinuria, stomatitis, and wound healing events (WHE) were assessed.

Results: Hyperlipidemia was the most frequent AE in all 3 arms. Median onset time of WHE was shorter than that of the other 3 AEs in both EVR arms, whereas that of hyperlipidemia was shortest in TAC-C arm. Median EVR C₀ at onset in the EVR arms was within target range regardless of AE. Median TAC C₀ at onset was above (hyperlipidemia and proteinuria) or near (stomatitis and wound healing) the upper limit of target range in the EVR+rTAC arm. In the EVR_mono arm, median onset time of all AEs, except proteinuria (198 days), was shorter than the TAC discontinuation target of 4 months. In both EVR arms, most hyperlipidemia, stomatitis, and wound healing (70%-77%) events were treated with concomitant medications. Events requiring treatment discontinuation were low (0%-8%), except for proteinuria in the EVR+rTAC (8/13; 61.5%) and EVR_mono (3/12; 25%) arms.

Conclusion: In LTRs receiving EVR-based regimens, most related AEs could be managed by adjusting of EVR C₀ and/or use of concomitant medications. Treatment discontinuation was mostly required with proteinuria.

CITATION INFORMATION: Fung J., Saliba F., Schlitt H., Junge G., McCague K., Patel D., Charlton M. Association between Everolimus Trough Levels, Onset of Related Adverse Events, and Treatment Discontinuation after Liver Transplantation: 24-Month Results from the H2304 Study Am J Transplant. 2017;17 (suppl 3).

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