A. Feist

Increased incidence of cutaneous squamous cell carcinoma in lung transplant recipients taking long-term voriconazole

BACKGROUND Voriconazole has been used for prevention and treatment of fungal infections in patients after lung transplantation. We postulate that long-term use of voriconazole may increase the risk of squamous cell carcinoma of the skin in these patients. METHODS The study included 120 patients who received lung transplantation at UC San Diego Health System between July 2000 and June 2006. All patients received a similar initial immunosuppression regimen, and 43 (35.8%) received voriconazole for treatment or prophylaxis for fungal diseases. In this retrospective study, we compared the incidence of squamous cell carcinoma in lung transplant recipients with or without voriconazole use. RESULTS Squamous cell carcinomas developed in 39.5% of patients (17 of 43) who received voriconazole for prophylaxis or treatment of fungal disease, compared with 19.5% (15 of 77) who did not receive voriconazole (p = 0.03). Four patients died of metastatic squamous cell carcinoma, all in the voriconazole group. Multiple logistic regression analysis showed older age at the time of transplant (odds ratio [OR], OR (95% CI) 2.8 (1.5-5.5)), skin cancer pre-transplant (OR, 11.0 (1.76-68.4), and longer voriconazole therapy (OR, 1.8 (1.3-2.6)) were independent risk factors for development of skin cancer after transplant. CONCLUSIONS Our results suggest that long-term use of voriconazole may be associated with development of cutaneous squamous cell carcinoma in patients after lung transplant. Greater clinical aggressiveness of skin cancer was also noted in these patients.

The “generic” effect of food on tacrolimus pharmacokinetics

A recent commentary entitled ‘‘Can generics be trusted?’’ questioned a standard of bioequivalence that would allow a 20% increase or decrease in the blood levels produced by ‘‘equivalent’’ doses of generic tacrolimus (TAC) and branded product (Prograf) (1). Understandable concern was voiced over possible increased rejection risks and need for further study of possible dangers of generic TAC (1). However, it is not as well recognized that concomitant food ingestion may reduce exposure of both branded TAC and branded cyclosporine (CSA) more than would simply substituting an FDA approved generic alternative. The bioequivalence data submitted to the FDA for approval of generic TAC highlight the marked difference in drug exposure between the fed and fasting state. Fig. 1 displays the differences in absorption in the same subjects when either the branded or the generic TAC preparation is taken with food or taken in the fasting state on an empty stomach (2). Under the same conditions, the time vs. concentration curves for the generic and branded preparation are very similar. Average values for peak levels (Cmax) and for time averaged exposure (AUC 0-infinity) for Prograf and generic TAC are within 10% of each other. However, for both branded and generic product, ingestion with food decreased Cmax from over 30 ng/mL to about 7 ng/mL and similarly reduced the AUC. The data in Fig. 1 should not be surprising; the package insert for Prograf reports a 28–37% decrease in AUC and a 65–77% decrease in Cmax when Prograf is taken with meals. The effect was substantially the same even when Prograf was taken 1.5 h after eating. All of the above data are from normal volunteers, as the FDA does not require generic immunosuppressive drugs to be studied in transplant recipients (1). However, concomitant food administration has the same effect decreasing TAC and CSA AUC by 30–40% (3, 4). The FDA requires that generics be within 80–125% of branded agents with respect to Cmax and AUC, as these are the standard measures of bioequivalence (1). The concept that AUC determines efficacy for calcineurin inhibitors is widely accepted and has been supported by several clinical studies in CNI s as summarized by Curtis (4). Contrary to a popular misconception, the reduction in TAC AUC caused by food is not Fig. 1. By randomized two-way crossover study, AUC comparisons by least squares means ratios for orally administered generic (test) vs. branded (reference) were 111% (CI 101–122%) for fasting and 96% (CI 92–100%) for the fed state. Note the different scale for the lower panel, which illustrates the profound effect of concomitant food ingestion on exposure. (adapted from reference 2.) Clin Transplant 2011: 25: 334–335 DOI: 10.1111/j.1399-0012.2010.01387.x a 2010 John Wiley & Sons A/S.

Low dose posaconazole delayed release tablets for fungal prophylaxis in lung transplant recipients

In November 2013, posaconazole delayed release (DR) tablets were approved by the FDA with the labeled dose of 300 mg daily for fungal prophylaxis. There are no studies demonstrating the appropriate dose in lung transplant recipients (LTR). We performed a 2‐center retrospective cohort study of LTR taking posaconazole DR tablets for prophylaxis between January 2014 and January 2017. Mean serum trough concentrations and percentage of measurements ≥0.7 mcg/mL were compared by daily dose. Forty‐nine subjects with 156 steady state serum posaconazole concentrations were included. There was a significant difference in percentage of first measured concentration ≥0.7 mcg/mL by initial daily dose (P = .04). The mean serum posaconazole concentration by dose was 0.9 (±0.42) mcg/mL for 100 mg daily, 1.66 (±0.91) mcg/mL for 200 mg daily, 2.39 (±1.49) mcg/mL for 300 mg daily, and 1.75 (±0.21) mcg/mL for 400 mg daily (P < .001). Mean concentrations were at goal in 63.3%, 96.9%, 94.9%, and 100% of subjects taking 100 mg, 200 mg, 300 mg, and 400 mg daily respectively (P = .04). Our results suggest that doses less than 300 mg daily of posaconazole DR tablets may be adequate to achieve target serum concentrations in LTR. Larger studies are needed to confirm these findings.