CASE REPORT
A 60-year-old Caucasian male, weighing 59 kg, liver transplanted 2 months ago. In the outpatient clinic he was asymptomatic, had normal biochemistry, and tacrolimus trough concentrations within the therapeutic range (7.2 ng/mL and an estimated area under the curve is steady state (eAUC) of 245 ng·h/ml) (Table 1). He was on prophylactic treatment with tacrolimus (extended-released capsules) 8 mg qd, mycophenolate mofetil 1000 mg bid and prednisone 5 mg qd. His oral medication at home included: magnesium 53 mg tid, hydropherol 0.266 mg, furosemide 40 mg bid, cotrimoxazole 400/80 mg qd, nystatin and pantoprazole 20 mg qd.
Fifteen days after the outpatient visit, he was admitted to hospital with signs of respiratory infection and was diagnosed of empyema secondary to Enterobacter cloacae infection. At admission, the patient presented with significant renal impairment (creatinine clearance (CrCl): 27.9 ml/min/1.72 m2) with a tacrolimus trough concentration of 20.5 ng/ml and an eAUC 524 ng·h/ml, consistent with the nephrotoxicity associated with supratherapeutic exposure to tacrolimus (Table 1). Correct veno sampling were ensured and no changes were made in the tacrolimus determination technique (enzyme-linked immunosorbent assay (DimensionⓇ)), or to the commercial presentation of the tacrolimus prescribed to the patient. No relevant changes in the prescribed treatment were identified that could affect the bioavailability or pharmacokinetics of tacrolimus.
After interviewing the patient, he reported a daily intake of an over-the-counter (OTC) herbal laxative for several days taken concomitant with tacrolimus first time in the morning. The OTC is composed of 80% senna leaves (Cassia angustifolia vahl ), hibiscus extract, liquorice (Glycyrrhiza glabra ) and peppermint (Mentha piperita ). The herbal preparation and tacrolimus treatment were discontinued until tacrolimus plasma concentrations normalized.
A trough of 5 ng/ml was reached three days after drug withdrawal. Tacrolimus treatment was then gradually reintroduced. The dose was increased using individual pharmacokinetic parameters calculated by Bayesian estimation (Graph 1). One week after tacrolimus intoxication and after discontinuation of herbal medicine, the patient recovered baseline renal function (ClCr 81.9 ml/min/1.72 m2) and achieved tacrolimus target levels at a dose similar to that before the episode (Table 1, Graph 1).