*Purpose: An innovative strategy to meet the demands of patients requiring heart or kidney transplantation is the acceptance of hepatitis C viremic organs. Direct acting antivirals (DAAs) are highly effective at curing HCV infection, but the pharmacokinetic implications of DAA use on calcineurin inhibitor therapy post-transplant are unknown. We sought to investigate the effects of glecaprevir/pibrentasvir (G/P), a CYP3A4 substrate and inhibitor, on weight-adjusted tacrolimus (FK) trough/dose (T/D) ratio following isolated heart or kidney transplantation.

*Methods: This was a single-center, retrospective analysis of HCV negative heart or kidney transplant recipients who accepted HCV viremic organs followed by 12-weeks of G/P therapy. Patients received standard triple maintenance immunosuppression with FK, mycophenolate and prednisone. Those initiated on concomitant CYP3A inducers/inhibitors were excluded. Weight-normalized T/D ratio was assessed while patients were on stable doses of FK to achieve steady-state prior to, during, and after G/P treatment. Steady-state was defined by receiving a stable dose of FK without needing adjustment to maintain target trough for 2-3 days.

*Results: Twenty-seven HCV negative organ recipients were evaluated. Median age was 70 years (IQR 66-71). The weight-normalized T/D ratio was greater during G/P treatment (134, IQR 101-195) compared to before treatment (83, IQR 54-129) (P<0.01), but lower after completion of treatment (92, IQR 57-112) compared to during treatment (134, IQR 101-195)(P<0.01). Four patients (3 kidney, 1 heart) experienced acute rejection.

*Conclusions: Initiation of glecaprevir/pibrentasvir in heart or kidney transplant recipients induces a reversible change in tacrolimus metabolism. Based on the results of our study, a 40-50% tacrolimus dose reduction may be considered at the time of glecaprevir/pibrentasvir initiation. No clear relationship of HCV viremic organ transplantation and rejection risk was found. Larger studies are warranted to validate these findings.

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