Treatment of Acute Tacrolimus Toxicity with Phenytoin in Solid Organ Transplant Recipients

Abstract

The pharmacokinetics of tacrolimus are influenced by many factors, including genetic variability, acute infections, liver dysfunction, and interacting medications, which can result in elevated concentrations. The most appropriate management of acute tacrolimus toxicity has not been defined though case reports exist describing the therapeutic use of enzyme inducers to increase tacrolimus metabolism and decrease concentrations. We are reporting on the utilization of phenytoin to assist in decreasing tacrolimus concentrations in a case series of four solid organ transplant recipients with acute, symptomatic tacrolimus toxicity presenting with elevated serum creatinine, potassium, and tacrolimus trough concentrations greater than 30 ng/mL. All four patients had the potential causative agents stopped or temporarily held and were given 300 to 400 mg/day of phenytoin for two to three days. Within three days of beginning phenytoin, all four patients had a decrease in tacrolimus concentration to less than 15 ng/mL, a return to or near baseline creatinine concentration, and lack of phenytoin-related side effects. Therefore, phenytoin appears to be a safe and potentially beneficial treatment option in patients with symptomatic tacrolimus toxicity.

Treatment of prolonged tacrolimus toxicity using phenytoin in a haemodialysis patient

“…However, tacrolimus concentrations began to decline within 16 hours of initiating phenytoin in this case and were undetectable within 4 days. This rapid reduction in tacrolimus concentration is consistent with other reports of phenytoin induction that have shown tacrolimus concentrations decrease by 6‐fold in 24 hours and greater than 2‐fold in 3 days . It is possible that the tacrolimus concentration was declining prior to initiating phenytoin but we were unable to detect this because the concentration exceeded the upper limit of the assay.…”

“…Our patient presented with progressively severe symptoms of tacrolimus neurotoxicity, beginning with calcineurin‐inhibitor pain syndrome characterized by symmetrical pain in the lower extremities, followed by tremors, worsening encephalopathy and psychosis . In the presence of severe symptoms (as reported by others) or persistently elevated tacrolimus concentrations with symptoms (as in this case), use of pharmacologic induction of tacrolimus metabolism is a viable therapeutic option . Phenytoin appears to be the agent of choice for inducing metabolism as it is a strong CYP3A4/5 inducer and has the additional benefit of anti‐seizure activity which is a possible manifestation of tacrolimus neurotoxicity.…”

Using known drug interactions to manage supratherapeutic calcineurin inhibitor concentrations

“…In total, 10 publications were identified that utilized pharmacoenhancement with CYP450 enzyme inducing agents for the management of CNI toxicity; 7 reported use of phenytoin and 3 reported use of phenobarbital. No articles using carbamazepine or rifampin were identified (Figure and Table ) …”

Combination Drug Products for HIV–A Word of Caution for the Transplant Clinician

“…In the current report, we expand on our experience of using phenytoin therapeutically to induce CNI metabolism as a treatment for intoxication (17). Enzyme induction depends on both the half-life of the inducing agent as well as the enzyme being induced (18).…”