Effect of glecaprevir/pibrentasvir on weight‐adjusted tacrolimus trough/dose ratios in heart and kidney transplant recipients

Abstract

Objective:The pharmacokinetic implications of direct-acting antiviral (DAA) use on tacrolimus posttransplant are unknown. This study sought to investigate the effects of glecaprevir/pibrentasvir (G/P), a CYP3A4 substrate and inhibitor, on weight-adjusted tacrolimus (FK) trough/dose ratio (T/D) following heart or kidney transplantation. Material and methods:This was a single-center, retrospective analysis of hepatitis C virus (HCV) viremic donors to HCV negative heart or kidney transplant recipients who received 12 weeks of G/P therapy. Weight-adjusted T/D was assessed while patients were at steady-state before, during, and after G/P treatment. Forty-one HCV negative recipients (three heart, 38 kidney) were evaluated. Results:The weight-adjusted T/D significantly increased during G/P treatment (119.31, IQR 88-173.8) compared to before G/P treatment (67.4, IQR 53.4-115.9) (p < 0.01), but decreased after completion of treatment (90.1, IQR 52.9-122.7) (p < 0.01). There was no difference in weight-adjusted T/D before and after G/P treatment (p = 0.42). Four patients experienced acute rejection. Conclusion:Initiation of G/P in heart or kidney transplant recipients induces a reversible change in tacrolimus metabolism. A 33%-50% tacrolimus dose reduction may be considered at the time of G/P initiation. Regardless of tacrolimus dose adjustment, tacrolimus trough levels should be monitored 3 days after initiation of G/P. No clear relationship between HCV viremic organ transplantation and rejection risk was found. Larger studies are warranted to validate these findings

Hepatitis C and heart transplantation: An update

“…If glecaprevir/pibrentasvir is used, given the interaction with tacrolimus, trough levels 3 days after treatment initiation have been recommended. 64 Of note, glecaprevir/pibrentasvir levels were not affected by crushing pills in a study in healthy subjects. 10 Additionally, there are some favorable data in heart transplant patients on the use of crushed sofosbuvir/velpatasvir in a clinical trial, and of ledipasvir/sofosbuvir and elbasvir/grazoprevir in anecdotal reports.…”

“…[57][58][59] Most often though, treatment was deferred to the outpatient setting, with a median time to initiation of 31 to 103 days post-transplant. [60][61][62][63][64][65] Sofosbuvir-based combinations and glecaprevir/pibrentasvir were most frequently used, and grazoprevir/elbasvir less often. Treatment courses lasted ordinarily 8-12 weeks based on HCV genotype, DAA combination, and other factors.…”

“…HCV treatment was initiated upon detection of HCV viremia by a few centers, a strategy often called pre‐emptive treatment, with reported time to DAA initiation ranging from 3 to 11 days post‐transplant in the majority of patients 57–59 . Most often though, treatment was deferred to the outpatient setting, with a median time to initiation of 31 to 103 days post‐transplant 60–65 . Sofosbuvir‐based combinations and glecaprevir/pibrentasvir were most frequently used, and grazoprevir/elbasvir less often.…”

Kidney transplant from HCV viremic donors to HCV‐negative recipients and risk for de novo donor specific antibodies and acute rejection

“…Additionally, DAA therapies could have an interaction with Tacrolimus that affects drug levels and requires dose adjustment. [37][38][39] Glecaprevir/pibrentasvir frequently leads to increase in tacrolimus trough level requiring dose reduction during treatment followed by dose increase post-treatment. Sofosbuvir based therapies could also have an interaction with Tacrolimus.…”

“…However, most of de novo DSA occurred after SVR‐12 was achieved (Figure S1). Additionally, DAA therapies could have an interaction with Tacrolimus that affects drug levels and requires dose adjustment 37–39 . Glecaprevir/pibrentasvir frequently leads to increase in tacrolimus trough level requiring dose reduction during treatment followed by dose increase post‐treatment.…”