RÉSUMÉ
PURPOSE: While nirmatrelvir/ritonavir (NMV-r) has been positioned as a first-line treatment for mild to moderate COVID-19, it has multiple and significant drug-drug interactions (DDIs). The use of NMV-r in Japan has been limited compared to the United States. This study aimed to describe the distribution of DDIs with NMV-r and their management in patients with COVID-19 under the control of a management system for the appropriate use of NMV-r. METHODS: A retrospective observational study was conducted at a Japanese university hospital. The management system included a flowchart for selecting antivirals and a list for reviewing DDI management, based on the National Institutes of Health guidelines and the guidance of the Japanese Society of Pharmaceutical Health Care and Sciences. Patients with mild to moderate COVID-19 and prescribed NMV-r or molnupiravir (MOV) were included. The primary outcome was DDI management practices, including the selected COVID-19 medications. The secondary outcome included the distribution of DDI classification and the 30-day all-cause mortality. RESULTS: This study included 241 patients (median age of 60 years, 112 [46.5%] females), of whom 126 and 115 received NMV-r and MOV, respectively. Of the 241 patients, 145 (60.2%) received concomitant medications that have DDIs with NMV-r. All 30 patients with severe renal impairment or insufficient details on concomitant medications received MOV. Forty-nine patients with concomitant medications required alternative COVID-19 therapy consideration due to DDIs, of whom 42 (85.7%) patients received MOV. Eighty-one patients had concomitant medications requiring temporary adjustment, of whom 44 (54.3%) patients received NMV-r, and 42 of these patients temporarily adjusted these concomitant medications. Five patients with concomitant medications that can continued by monitoring the effects/adverse effects, of whom 4 (80.0%) patients received NMV-r. Seventy-six patients without concomitant medications requiring DDI management, of whom 71 (93.4%) patients received NMV-r. The 30-day all-cause mortality for eligible patients was 0.9% [95% confidence interval, 0.1-3.1]. CONCLUSIONS: Most patients received appropriate antivirals according to the classification of DDIs, and most patients with concomitant medications requiring temporary adjustment received the recommended DDI management. Our management system is effective in promoting the use of NMV-r in the appropriate patients and managing problematic DDIs.
RÉSUMÉ
We experienced a patient with a remarkable and prolonged increase in tacrolimus blood concentrations when nirmatrelvir/ritonavir was concomitantly used. The inhibitory intensity and duration of nirmatrelvir/ritonavir on tacrolimus pharmacokinetics were examined using a model-based analysis. A renal transplant patient taking oral tacrolimus continuously was treated with nirmatrelvir/ritonavir for 5 days. The baseline tacrolimus trough blood concentration was 4.2 ng/mL. Tacrolimus was discontinued on Day 6 after the concomitant administration of nirmatrelvir/ritonavir, and the trough concentration increased to 96.4 ng/mL on Day 7. The model-based analysis showed that tacrolimus clearance decreased to 35% and bioavailability increased by 18.7-fold after the coadministration of nirmatrelvir/ritonavir, compared with before the coadministration. Therefore, nirmatrelvir/ritonavir drastically decreased both the apparent clearance and apparent volume of distribution. Simulated tacrolimus concentrations could be best fitted to the observed concentrations when the inhibitory effects of nirmatrelvir/ritonavir were modeled to disappear over about 10 days by first-order elimination. In conclusion, nirmatrelvir/ritonavir greatly increases tacrolimus concentrations by not only reducing clearance, but also increasing bioavailability. Interactions between nirmatrelvir/ritonavir and low-bioavailability drugs which are substrates for CYP3A and P-glycoprotein, such as tacrolimus, are harmful, and concomitant use of these medicines should be avoided.