Use of phenytoin for treatment of tacrolimus toxicity with superimposed sepsis

Abstract

A 40-year-old woman with a history of chronic graft-versus-host-disease on immunosuppression with tacrolimus presented to the hospital with somnolence, confusion and muscle cramps over a few days. She was found to have hypertension, hyperglycaemia and acute kidney injury with an elevated blood tacrolimus level of greater than 120 ng/mL (reference range 5–15 ng/mL). Discontinuation of tacrolimus with concomitant administration of intravenous phenytoin led to the successful reduction of elevated tacrolimus concentrations and the resolution of her symptoms. Tacrolimus is metabolised by the cytochrome P (CYP) 450 3A enzyme system, and utilisation of CYP 3A inducers to accelerate its clearance may be used as a successful therapy to treat tacrolimus toxicity.

Background

Tacrolimus is a macrolide antibiotic discovered in 1984 from the fermentation broth of Streptomyces tsukubaensis. It has emerged as the mainstay of most immunosuppressive regimens in solid organ and haematopoietic stem cell transplantations.^{1 2} Tacrolimus exerts its effects through the downregulation of interleukin-2 expression and has potent inhibitory effects on T-cell activation.³ Due to its narrow therapeutic index, tacrolimus requires close therapeutic drug monitoring, which is achieved by measuring whole blood trough concentrations.⁴ Tacrolimus is metabolised by the cytochrome P (CYP) 450 3A enzyme system in the liver and, to some extent, in the intestine. In addition to that, being a substrate for the P-glycoprotein efflux pump, tacrolimus is also absorbed in the intestinal mucosa through active transport.^{4 5} As a result, coadministration of CYP 3A inducing agents may accelerate the metabolism of tacrolimus, ultimately reducing plasma concentrations, leading to therapeutic failure. In turn, CYP 3A inhibitors like the azole antifungals and certain antiretrovirals reduce metabolism, elevate tacrolimus levels and increase the risk of toxicity.⁵ Apart from CYP 3A inhibitors, sepsis and graft failure are well-known causes for the acute elevation of tacrolimus levels. Despite the known mechanisms leading to tacrolimus toxicity, little evidence exists on how to manage it.⁶

There are a few published reports that take advantage of the inadvertent CYP 3A enzyme-inducing effects of phenytoin, rifampin and phenobarbital to decrease tacrolimus serum concentrations.^6–9 We, hereby, report a case of acute tacrolimus toxicity successfully treated with intravenous phenytoin without adverse effects from the phenytoin.

Case presentation

A 40-year-old woman presented to the hospital with progressively worsening somnolence and confusion over 4–5 days. She was difficult to arouse and was found mumbling to herself by family members a night before admission. The patient also reported leg cramps, nausea and weakness. She denied fevers, chills, cough, shortness of breath, increase in respiratory secretions, abdominal pain or diarrhoea.

The patient had a medical history of chronic myelomonocytic leukaemia with acute myeloid leukaemia transformation status post allogeneic haematopoietic cell transplant twelve years ago. The transplantation was complicated by graft-versus-host-disease, which manifested as bronchiolitis obliterans, leading to chronic severe hypoxic and hypercapnic respiratory failure requiring tracheostomy and percutaneous endoscopic gastrostomy tube placement ten months ago. During that previous prolonged hospitalisation, she developed severe protein-calorie malnutrition with a resulting body mass index of 13.

The patient was recently sent home from a long-term acute care hospital 1 week before the presentation. Her home medications included tacrolimus 1 mg two times per day and methylprednisolone 4 mg two times per day for chronic immunosuppression, clarithromycin 500 mg two times per day for Mycobacterium abscessus lung infection, prophylactic acyclovir 400 mg two times per day and single strength trimethoprim-sulfamethoxazole once daily along with atenolol 12.5 mg daily for inappropriate sinus tachycardia. She was taking all her medications as prescribed. There was no recent change in her tube feeding formulation or rate.

On examination, the patient had a blood pressure of 142/93 mm Hg, heart rate of 114 beats/minute, a temperature of 37.3°C, respiratory rate of 24/min with an oxygen saturation of 100% on 3 L oxygen per minute through tracheostomy mask. She appeared cachectic, drowsy and had dry oral mucosa.

Investigations

Lab-work revealed sodium 130 mmol/L, potassium 6.5 mmol/L, chloride 91 mmol/L, bicarbonate 38 mmol/L, blood urea nitrogen 81 mg/dL, creatinine 1.5 mg/dL (baseline 0.4 mg/dL), glucose 780 mg/dL, white cell count 19.8×10⁹/L with neutrophilic predominance and haemoglobin 105 g/L (baseline 70–80 g/L) with mean corpuscular volume of 95.7 fL. The patient had chronic leukocytosis secondary to steroid use with a baseline count of approximately 15×10⁹/L. There was a mild elevation in the serum beta-hydroxybutyrate at 3 mg/dL, with urine test being negative for ketones. Lipase, lactic acid, creatine kinase, liver function tests and arterial blood gas were within normal limits. Her blood tacrolimus level was found to be greater than 120 ng/mL (reference range 5–15 ng/mL). Respiratory cultures grew Pseudomonas aeruginosa and Pseudomonas luteola consistent with previous cultures from prior hospitalisations. Blood cultures were negative, and a chest X-ray was unrevealing for new consolidation.

Differential diagnosis

The principal differential diagnosis was unintentional tacrolimus toxicity inducing hyperglycaemia, acute kidney injury, encephalopathy, hypertension and severe muscle cramps. Prior to the tacrolimus level, severe sepsis with associated electrolyte derangements was suspected, and empiric antimicrobials were initiated. Furthermore, the patient was started intravenous fluids and insulin for the suspicion of new-onset diabetic ketoacidosis. Although these could have contributed to the acute kidney injury and electrolyte abnormalities, the overall constellation of findings with elevated blood tacrolimus concentration points towards tacrolimus toxicity as the principal cause. The rapid improvement in the signs and symptoms with the initiation of phenytoin further support the diagnosis of tacrolimus toxicity.

Treatment

Tacrolimus was held, and intravenous phenytoin was administered at a dose of 200 mg wo times per day. Within 3 days of initiating phenytoin, tacrolimus levels dropped to 7.6 ng/mL with rapid improvement of symptoms, after which phenytoin was discontinued (figure 1). During her stay, she was also treated with a 7-day course of ceftolozane-tazobactam for bronchitis given positive respiratory cultures in an immunocompromised state with a history of colonisation with multidrug-resistant organisms.

Figure 1.

Blood tacrolimus level during hospital stay.

Outcome and follow-up

Her encephalopathy, hyperglycaemia, hyperkalaemia, hypertension and acute kidney injury improved with the return of serum creatinine to her baseline within 3 days of phenytoin administration (figure 2). Her confusion and muscle cramps also resolved. The patient did not encounter side effects from the phenytoin. After blood levels of tacrolimus decreased to less than 10 ng/mL, tacrolimus was restarted at a dose of 0.5 mg two times per day with close monitoring of trough levels.

Figure 2.

Serum creatinine level during hospital stay.

Discussion

Tacrolimus, a calcineurin inhibitor, is a widely used immunosuppressant whose pharmacokinetics have been well analysed. Significant variability in absorption, metabolism and clearance of tacrolimus exists due to multiple factors such as hepatic dysfunction, time after transplantation, patient age, race, concomitant medications and genetic polymorphism in the CYP 3A enzyme among others.² Sepsis can downregulate CYP 450 enzyme and consequently lead to rapid elevation to toxic trough concentration.⁶ That might have been one potential explanation of the elevated tacrolimus levels in our patient. Additionally, the patient’s condition of severe protein-calorie malnutrition may have led to low levels of tacrolimus-binding high-density lipoprotein, which in turn resulted in the increased serum bioavailability of active unbound tacrolimus.¹⁰

The signs and symptoms of tacrolimus toxicity have been well described in published literature. It commonly manifests as nephrotoxicity, neurotoxicity, glucose intolerance, malignant hypertension, gastrointestinal disturbances, electrolyte abnormalities and infection. These side effects tend to be frequent and severe when tacrolimus trough levels are significantly elevated.^{2 11} There are no definitive management guidelines for tacrolimus toxicity. Due to lipophilicity, a relatively large molecular weight of tacrolimus (822 daltons), and extensive partitioning of tacrolimus into red blood cells, haemodialysis and plasma exchange are ineffective. Other modalities such as gastric lavage and activated charcoal may also be ineffective unless employed early in acute overdose situations as tacrolimus is highly protein-bound and minimally excreted in the bile.^{6 7}

There are reports using CYP 3A enzyme inducers or simply close monitoring with temporary discontinuation of tacrolimus for the treatment of elevated tacrolimus levels.^{7 11 12} Since our patient had supratherapeutic trough levels of tacrolimus along with encephalopathy, electrolyte disturbances and acute kidney injury, we used phenytoin to facilitate the clearance of tacrolimus. Rapid reduction in trough levels would also have been desirable in our patient due to the potential downregulation of the CYP 3A enzyme system from active infection.⁶ The use of an antiepileptic drug for clearance of tacrolimus came with an additional benefit in countering the neurological toxicity of tacrolimus. Although there are other CYP 3A enzyme inducers with anti-epileptic properties, viz., carbamazepine and phenobarbital, phenytoin was selected for various reasons. The availability of intravenous formulation and therapeutic drug monitoring of the serum levels, along with minimal sedation, made phenytoin the most suitable choice for our patient.^13–16

Phenytoin is a widely prescribed and well-tolerated anticonvulsant agent with a narrow therapeutic range. Adverse events have been shown to affect the cardiovascular system and the central nervous system. The common manifestations include hypotension, arrhythmias, nystagmus, ataxia, confusion and seizures. ‘Purple glove syndrome,’ rash and dermatitis have also been reported with its use. A recent observational study found an association between intermediate/poor metaboliser phenotype for CYP2C9 enzyme and adverse events affecting the vestibulocerebellar system, such as ataxia, dysarthria and dizziness.¹⁷ Discontinuation of phenytoin and management with supportive care is indicated when serious side effects are encountered.^{15 16 18} Our patient did not experience any side effects from phenytoin and responded well to the treatment leading to rapid improvement in her mentation, muscle cramps and reversal of her serum creatinine back to the baseline within 3 days.

Learning points.

• Common manifestations of tacrolimus toxicity include nephrotoxicity, neurotoxicity, glucose intolerance, malignant hypertension, gastrointestinal disturbances, electrolyte abnormalities and infection.

• Careful monitoring of tacrolimus level is essential given the drug’s narrow therapeutic window, high toxicity risk and highly variable pharmacokinetics with multiple drug interactions.

• Cytochrome P 3A enzyme inducers such as phenytoin can decrease toxic tacrolimus levels and resolve the clinical effects by taking advantage of the drug’s pharmacokinetics.