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.