Early Use of Long-acting Tacrolimus in Lung Transplant Recipients

Lung transplantation is a life-saving therapy for patients with end-stage lung disease refractory to medical treatment, providing an improvement in both survival and quality of life.\[1,2\] Despite the benefits, patients are at risk for myriad side effects including infection, malignancy, neurologic complications (headache, tremor, seizures), gastrointestinal distress and renal failure, to name a few.\[3\] Many of these are related to the requisite need for life-long immunosuppression. Current standard immunosuppressive regimens for lung transplant recipients include calcineurin inhibitors (tacrolimus preferred over cyclosporine), antiproliferative agents (mycophenolate mofetil vs. azathioprine) and corticosteroids; calcineurin inhibitors serve as the backbone of immunosuppression.\[4\] Renal dysfunction is perhaps the most prevalent complication after lung transplantation, affecting up to 90% of post-transplant recipients.\[5\] By 5-year post-transplant, \~8% of patients may require renal replacement therapy and/or renal transplantation.\[6\] Renal dysfunction tends to occur early on in the post-transplant period. Monnier and colleagues showed in a single-center analysis that the incidence of acute kidney injury within the index hospitalization was \~75%; the median loss of glomerular function within the first year was \~45%.\[7\] Moreover, Canales and colleagues showed that \>55% of patients in a cohort of 219 lung transplant recipients had a doubling of their pre-transplant serum creatinine, the majority occurring within the first year post-transplant.\[8\] Early renal dysfunction in lung transplant recipients is associated with a poor overall prognosis. Broelkroleof and colleagues demonstrated that loss of renal function within he first month post-transplant is predictive of chronic kidney disease.\[9\] Moreover, chronic kidney disease is associated with a five times increased risk of mortality.\[5\] Perhaps the greatest contributor to the development of CKD in solid-organ transplant recipients are the calcineurin inhibitors (CNIs).\[10\] CNIs cause renal compromise (calcineurin inhibitor nephropathy, CIN) via acute and chronic mechanisms. Acute CIN is due to potent vasoconstriction of afferent arterioles in the kidney, resulting in ischemia.\[11,12\] Chronic CIN is thought to be largely mediated by interstitial fibrosis as the end-result of arteriolar sclerosis, oxygen free-radical injury, and upregulation of pro-fibrotic pathways including PDGF, renin-angiotensin-aldosterone signaling, TGFB and matrix metalloproteinase-9.\[11,13\] Attempts at utilizing CNI-free or CNI-reduced regimens in the lung transplantation population has been understudied and/or unsuccessful to date. Belatacept, a CTLA4-fusion molecule that prevents CD28-mediated co-stimulation to activate T-lymphocytes, has been well-studied in renal transplantation as an alternative to CNIs. The BENEFIT Trial, a phase III clinical study of Belatacept vs. Cyclosporine in renal transplant recipients, demonstrated improvement in patient and allograft survival, and mean eGFR (\~70 cc/min vs \~45cc/min) at seven years. However, rates of biopsy proven acute cellular rejection were twice as much with Belatacept.\[14\] Case reports of Belatacept as rescue therapy in lung transplant recipients intolerant of CNIs are mixed; there are reports of increased ACR and fulminant acute respiratory distress syndrome.\[15,16\] The mTOR inhibitor class of immunosuppression has also been incorporated into regimens in an effort to ameliorate CNI-toxicity. Villanueva and colleagues assessed outcomes of conversion to Sirolimus and reduced Tacrolimus in 49 patients with bronchiolitis obliterans syndrome (chronic rejection) or CNI-intolerance; there was no difference in renal function one year following sirolimus initiation.\[17\] Conversely, Shitrit and colleagues demonstrated that sirolimus plus low-dose tacrolimus led to an improvement in GFR of 10 mL/min, compared to control maintenance immunosuppression in a pilot study of sixteen lung allograft recipients.\[18\] More recently, Gottlieb and colleagues demonstrated that conversion to quadruple immunosuppression therapy with low-dose CNI (target tacrolimus trough 3-5) led to improvements in eGFR of 10cc/mL compared to standard immunosuppression (tacrolimus trough \>5). There was no considerable difference in biopsy-proven acute rejection, chronic rejection and death.\[20\] The conversion for those in the 4-drug experimental group occurred on average 11 months following transplant, which may account for the muted benefit; perhaps an earlier change in immunosuppression management would have led to more clinically significant results. Notably, discontinuation rates of sirolimus in case reports are variable, with most studies reporting a 20-80% discontinuation rate due to gastrointestinal distress, pneumonitis, thrombocytopenia, etc., making the mTOR inhibitor class less appealing.\[19\] It is apparent that changes to immunosuppression management earlier in the post-transplant period are ideal to see a maximum benefit in preserved renal function.9 However, this is complicated by the concerns for acute cellular rejection, which has a peak incidence at 6 months post-lung transplantation.\[21,22\] Acute cellular rejection is a leading risk factor for the development of chronic lung allograft dysfunction (CLAD, chronic rejection).\[23\] Hence any dose reduction in CNI or the use of an agent associated with ACR (Belatacept) is less desirable within the first few months post-transplant. Given the preference to utilize a CNI-based regimen early-post transplant but still minimize nephrotoxic effects, the investigators seek to determine whether the early use of long acting tacrolimus, LCP-Tacrolimus (LCP-tacro, Envarsus XR, Veloxis Pharmaceuticals), results in improved renal function compared to intermediate release tacrolimus (IR-tacrolimus, IR-tacro). Anecdotally, LCP-tacro has been used in lung transplant recipients as an alternative agent for those with debilitating headache or tremor. Early use of LCP-tacro has not been widely adopted due to perceptions associated with ability to closely titrate trough levels and cost. However, early use of LCP-tacro may provide several benefits. As a long-acting formulation, LCP-tacro allows for daily dosing. Moreover, LCP-tacro has greater absorption and bioavailability, leading to decreased swings in peak and trough concentrations; frequent fluctuations in serum tacrolimus levels potentiates afferent arteriolar vasoconstriction.\[24\] A steady state of systemic tacrolimus trough levels is desirable, since tacrolimus metabolism is directly related to nephrotoxicity.\[25\] The use of LCP-Tacro has been studied in renal transplant recipients. Langone and colleagues identified that LCP-tacrolimus compared to IR-tacrolimus was associated with improved tremor incidence and quality of life.\[1\] Rostaing and colleagues demonstrated that the use of LCP-tacro compared to intermediate tacrolimus was non-inferior in terms of combined death, allograft failure, biopsy-proven acute rejection and loss to follow-up. However, the use of LCP-tacro was associated with a significant reduction in total daily dose, and a 30% reduction in peak dose, without an increase in biopsy proven acute rejection episodes. Although not a prospective end-point, there was no significant impact on renal function.\[26\] In other studies, though, higher concentration/ drug (C/D) ratios for tacrolimus are associated with an improved renal safety profile.\[27\] It is conceivable that a clinical benefit of LCP-tacro over IR-tacro may be better manifested in clinical arenas that require higher target tacrolimus trough levels, such as lung allograft recipients, where initial post-transplant targets can be as high as 12-15 ng/mL, compared to renal transplantation where target trough levels are a relatively conservative 4-8 ng/mL.\[2, 3\] The experience of LCP-tacrolimus in the realm of lung transplantation is limited. Murakoezy and colleagues studied 53 patients that were converted from short-acting Tacrolimus to long-acting Envarsus. Conversion was performed at an average 3.6 years post-transplant. Ten patients were switched back due to side-effects (unknown), though the remainder tolerated conversion without complication. Ahmed and colleagues demonstrated feasibility in using long-acting Tacrolimus in 8 patients that were unable to achieve sufficient therapeutic levels with a short-acting formulation due to suspected polymorphisms of CYP3A4/3A5.\[28\] McCurry and colleagues assessed safety and feasibility of LCP-tacrolimus in a retrospective analysis of 18 lung transplant recipients. They found that patients on LCP-tacro had a 27% reduction in total dose. No patients experienced any adverse effects. Moreover, 2/18 patients had an improvement in tremors and headache.\[29\] Given the limited experience with of LCP-tacrolimus in lung transplant populations, the investigators propose a prospective, randomized, controlled pilot study to assess the safety, tolerability, and side-effect profile of early use LCP-tacro within the first 9 months post-transplantation. It is hypothesized that the early use of LCP-tacro in lung transplant recipients is safe and tolerable, and associated with an improved side-effect profile compared to patients treated with standard IR-tacro.