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.