Case description
An 83-year-old female patient, transplanted in October 2010 for polycystic renal disease, whose immunosuppressive treatment consisted in 5 mg daily of extended reléase tacrolimus (Advagraf ®), mycophenolate mofetil 500mg every 12 hours and prednisone 5mg daily. The patient started with mild symptoms (cough, odynophagia and dyspnea), and after a positive result in the COVID-19 antigen test, she contacted the nephrology service of our hospital. Being a patient at high risk of progression to severe disease, she was prescribed nirmatrelvir/ritonavir, two tablets every 12 hours (dose adjusted to renal function) for 5 days. After consultation with the pharmacy service, immunosuppressive treatment was adjusted, maintaining prednisone and mycophenolate. As for tacrolimus, the patient was informed that she should interrupt its administration during antiviral treatment, and reintroduce it progressively according to the blood concentrations once treatment was completed, in order to avoid possible adverse effects. Before starting treatment, an analytical control was performed, presenting a minimum tacrolimus blood concentration of 7.9ng/ml and a serum creatinine of 1.31mg/dl.
The patient, mistakenly, continued taking tacrolimus at the same dose (Figure 1) while being treated with nirmatrelvir/ritonavir for three days. At the next medical review, on day +6 relative to the initiation of nirmatrelvir/ritonavir treatment, a tacrolimus blood concentration of 112ng/mL was determined, more than ten times above the reference range, 5-10ng/mL, that leads to an inmediate suspension of the immunosuppressant administration. The following day (day +7), the patient went to the emergency room due to the development of neurological manifestations such as impaired level of consciousness, amnesia, tremors, decrease of intake and mucocutaneous dryness; so se was therefore admitted to hospital for the control of the neurological symptoms and close monitoring of tacrolimus concentrations. Analytically, a progressive worsening of renal function was observed, reaching a serum creatinine concentration peak of 1.95mg/dl (Figure 2), although diuresis did not decrease at any time.
During admission, tacrolimus remained suspended and the patient was treated with serum therapy, experiencing a rapid improvement of the neurological symptons and a decrease in serum creatinine values to baseline values without the need for other drugs. Tacrolimus blood concentration decrease was slower, due to the persistence over time of CYP3A4 inhibition by ritonavir, even after treatment had been terminated (3). Tacrolimus intake was reintroduced on day +11 at reduced doses (1mg), when blood concentrations were back in range (8.2ng/ml); and was progressively increased: it grew to 2mg the following day and to 2.5mg on day +14. After ten days of hospital admission, the patient was discharged on day +17 due to the resolution of her clinical picture, with a daily tacrolimus dose of 3mg daily. She did not present dyspnea or other symptoms associated with COVID-19.