Most lung transplantation immunosuppression regimens include tacrolimus. Single nucleotide polymorphisms (SNPs) in genes important to tacrolimus bioavailability and clearance (ABCB1, CYP3A4, and CYP3A5) are associated with differences in tacrolimus pharmacokinetics. We hypothesized that polymorphisms in these genes would impact immunosuppression-related outcomes. We categorized ABCB1, CYP3A4, and CYP3A5 SNPs for 321 lung allograft recipients. Genotype effects on time to therapeutic tacrolimus level, interactions with antifungal medications, concentration to dose (C /D), acute kidney injury, and rejection were assessed using linear models adjusted for subject characteristics and repeat measures. Compared with CYP3A poor metabolizers (PM), time to therapeutic tacrolimus trough was increased by 5.1 ± 1.6 days for CYP3A extensive metabolizers (EM, P < 0.001). In the post-operative period, CYP3A intermediate metabolizers spent 1.2 ± 0.5 days less (P = 0.01) and EM spent 2.1 ± 0.5 days less (P < 0.001) in goal tacrolimus range than CYP3A PM. Azole antifungals interacted with CYP3A genotype in predicting C /D (P < 0.001). Increased acute kidney injury rates were observed in subjects with high ABCB1 function (OR 3.0, 95% CI 1.1-8.6, P = 0.01). Lower rates of acute cellular rejection were observed in subjects with low ABCB1 function (OR 0.36, 95% CI 0.07-0.94, P = 0.02). Recipient genotyping may help inform tacrolimus dosing decisions and risk of adverse clinical outcomes.

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Pirfenidone slows the progression of idiopathic pulmonary fibrosis, motivating a hypothesis of utility in restrictive chronic lung allograft dysfunction (RCLAD). We assessed the safety and tolerability of pirfenidone in lung recipients, who require stable immunosuppression and are at risk of adverse events (AE) from polypharmacy. METHODS: We performed preliminary analysis of Pirfenidone for Restrictive Chronic Lung Allograft Dysfunction (PIRCLAD) (NCT03359863), an ongoing trial designed to assess tacrolimus dose stability and AE of pirfenidone for 56 weeks, including a 4week titration. Participants had therapeutic steady-state tacrolimus blood concentration before pirfenidone, with two weekly trough levels on a stable dose. After pirfenidone start, tacrolimus trough levels were measured weekly for 6 weeks, at week 8, then monthly. The tacrolimus concentration/daily dose ratio (CDR) was calculated for all measures. Measures after initiation of antifungal therapy were excluded given the expected CDR change. We compared the average CDR before and after pirfenidone by paired T-test and calculated the conversion ratio before-to-after pirfenidone (CDR after/CDR before). For participants also taking everolimus or sirolimus at steady-state concentration, the CDR and conversion ratio before-to-after pirfenidone were calculated. Total bilirubin (TB), alkaline phosphatase (AP), aspartate (AST) and alanine (ALT) aminotransferases were measured monthly for 6 months, then every 3 months. AE were recorded before and repeatedly after pirfenidone; every two weeks for 6 weeks, then monthly. RESULTS: Eight participants (75% male, age 53AE17 years) received pirfenidone for a median of 44.5 weeks (interquartile range; 20-55). The CDR was similar before and after pirfenidone for tacrolimus (2.9AE1.8 vs 2.5AE1.6, p¼0.19), everolimus (2.4AE1.4 vs 2.2AE1.2, p¼0.49, N¼3 participants), and sirolimus (3.3AE1.8 vs 4.5AE1.5, p¼0.10, N¼1 participant). The conversion ratio beforeto-after pirfenidone was 0.9AE0.3 for tacrolimus, 1.0AE0.2 for everolimus, and 1.5AE0.4 for sirolimus. One participant had TB elevation (1.5 mg/dl) before, that normalized after pirfenidone. Otherwise, TB, AP, AST, and ALT were normal before and after. Two participants stopped pirfenidone due to progressive RCLAD; one after 2 weeks followed by retransplant and death, one after 47 weeks due to respiratory failure leading to insufficient oral intake to tolerate pirfenidone after week 43, followed by death. Two stopped due to intolerance of AE, after 12 and 20 weeks. Two continue taking it after 27 and 42 weeks. Two completed the study. Emesis, occurring in 63%, was the most common new AE. Nausea and diarrhea had non-statistically significant increases. CONCLUSIONS: Pirfenidone is safe and tolerable in most lung recipients. CLINICAL IMPLICATIONS: The safety and tolerability profile of pirfenidone in lung recipients can aid in the design of efficacy trials for RCLAD.