Sublingual Administration of Tacrolimus and Cases of Significant Nephrotic and Neurologic Toxicity

Abstract

<h3>Introduction</h3> This topic warrants consideration due to the popularity of sublingual administration of tacrolimus and the possibility of deleterious effects. There are significantly different characteristics of sublingual tacrolimus compared to oral administration. In bypassing enterohepatic circulation, a greater proportion of circulating tacrolimus may be available in a 'free' form, unbound to proteins and blood cells. This is similar to a rapid intravenous delivery of calcineurin inhibitor which has noted toxicities. <h3>Case Report</h3> (Case 1) A 49 year old male underwent heart transplant without induction, sublingual tacrolimus was started and after two days of trough levels of 5ng/mL or below, the dose was increased to 4mg SL bid, levels increased from to 17.8 ng/mL. While creatinine increased from 1.7 mcg/dL (POD#2) to a peak of 5.1 mcg/dL on POD#6. The patient was otherwise quite stable. Tacrolimus was held temporarily then converted to oral administration. The creatinine eventually recovered to a value of 1.5mg/dL. The average tacrolimus trough level (while receiving oral dosing) during this period of creatinine recovery was 5.9 ng/ML. (Case 2) 64 year old man with ICM received a heart transplant with uneventful operative course and no induction. He received tacrolimus 1mg orally pre-operatively. Then he received 2mg Of the drug sublingually twice daily until POD # 2. On POD#3 he experienced a generalized tonic-clonic seizure that terminated with anticonvulsant therapy. The tacrolimus trough levels rose quickly after the initial tacrolimus sublingual dosing postoperatively, measured at 11.4 ng/mL on POD#2. Neurology recommended a switch to cyclosporine (goal trough level 200-250ng/mL). The patient remained on levetiracetam for 14 days, no further epileptic activity was observed. Renal function during this episode from a creatinine of 1.4 mg/dL on POD#1 to 4.2 mg/dL on POD#3. <h3>Summary</h3> The molecular size of tacrolimus allows for passage into the glomerulus when in the free form. This may also facilitate blood/brain barrier transport. The presented cases provide cause for consideration of possible toxicity of tacrolimus given sublingually, particularly in patients whose levels rise rapidly. Through rapid absorption, the drug may not have sufficient time to bind to proteins and cells before it reaches end organs in which toxicity occurs.