Case presentation
A 73-year-old man weighing 60 kg developed a fever of 38.3 °C, with no
other apparent symptoms, on 20th January 2020. He came
to the fever clinic at the Third People’s Hospital of Shenzhen.
He disclosed that he lived in Erzhou of Hubei and took the train from
Wuhan to Shenzhen on 19th January. He denied any
exposure to the Huanan seafood market or wild animals.
A nasal swab for testing COVID-19 was performed immediately, and the
result was positive. Given his travel history and nasal swab findings,
the patient was admitted to an airborne isolation unit as a suspected
case of COVID-19 on 23rd January 2020. On 24 January,
the Centers for Disease Control (CDC) confirmed that the patient’s
oropharyngeal swab test for SARS-CoV-2 by qualitative real-time
reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay was
positive.
On admission, he was administered symptomatic treatment and
antimicrobial therapy, including oseltamivir, lopinavir/ritonavir, and
azithromycin. On 3rd February, physicians added
voriconazole with a loading dose of 360 mg q12 h on day 1; the patient
also received a maintenance dose of 200 mg q12 h because of the
continuous fever and suspected fungal infection. Therapeutic drug
monitoring (TDM) of voriconazole was performed almost daily beginning on
7th February. Unexpectedly, the concentration of
voriconazole was almost twice as high as the normal therapeutic range
(figure 1)17. The dose of voriconazole was decreased
to 160 mg q 12 h on 8th February; TDM showed that the
trough concentration was still unexpectedly high. As a result, the dose
was adjusted to 130 mg q12h, but the though concentration was still
higher than 8 mg/L. The concentration decreased to 0.7 mg/l after two
days of voriconazole withdrawal, which led to our suspicion that
lopinavir/ritonavir decreased the concentration of voriconazole by
inducing CYP2C19 expression. Other concomitant medications are listed in
figure 2. Several studies have discovered that coadministration of
CYP3A4 inhibitors might induce a voriconazole plasma level increase
among CYP2C19 activity-reduced patients 8-9. We
supposed that CYP2C19 activity was impaired in this patient due to gene
polymorphisms, so the patient’s CYP450 genotype was detected; the CYP450
genotype result was CYP2C19 *1/*2; CYP3A4 *1/*1; CYP2C9*1/*1.
However, on 23rd March, voriconazole was administered
again with a load dose of 350 mg q 12 h and a maintenance dose 200 mg,
q12 h; the trough concentration on 24th March was
lower than 2 mg/l. Even after increasing the dose to 300 mg q 12 h for 5
days, the concentration still lower than 1.6 mg/L, which could not be
explained by impaired CYP2C19 activity. At the same time, ECMO was used,
and no circuits were changed. During the observation period, there were
no significant CYP450 enzyme inhibitors or inducers among the
concomitant medications and recently used medications.