Drug Interaction between Paxlovid and Tacrolimus in an Adolescent with Inflammatory Bowel Disease

The coronavirus disease of 2019 (COVID-19) caused by SARS-CoV-2 virus led to a worldwide pandemic. Emergency use of an investigational medication, Paxlovid, was approved for patient 12 and older who tested positive for COVID-19 and at high risk for severe infection. Inflammatory Bowel Disease (IBD) is a chronic condition causing inflammation in the gastrointestinal tract. Ulcerative Colitis (UC) is a type of IBD centralized in colon and commonly treated with Immunosuppressive drugs. We present an adolescent with UC treated with paxlovid due to being on tacrolimus who developed with suspected tacrolimus toxicity. CASE REPORT: A 13-year-old female with UC presented to the ED with vomiting and fatigue after paxlovid ttreatment for COVID. The patient's UC treatment included tacrolimus along with ustekinumab. She had been diagnosed with SARS-CoV-2 and prescribed Paxlovid bid x 5 days due to immunosuppressive status. Tacrolimus was held during treatment. Once paxlovid completed, tacrolimus was restarted. Two days later, patient presented to ER for vomiting, fatigue, headaches and myalgia. Labs revealed a tacrolimus level of >60 ng/ml. Electrolytes and Creatinine were normal. Toxicology felt this was due to interaction between paxlovid and tacrolimus. Patient advised to hold tacrolimus for 48 hours and repeat levels were 15.8 ng/mL. Symptoms resolved and level repeated three days later and was 2.9 ng/mL. DISCUSSION: Tacrolimus is an immunosuppressant, commonly used for management of organ transplants but also been found effective in treatment of IBD. Tacrolimus requires close monitoring as toxicity may lead to acute or chronic kidney disease. The normal concentration is between 5-15 ng/mL. Due to rapid escalation of the COVID-19 pandemic, Paxlovid was approved for emergency use for treatment of high-risk patients. It is administered as a 5-day oral course consisting of nirmatrelvir and ritonavir. Our patient was prescribed Paxlovid due to risk secondary to immunosuppression. She was appropriately instructed to stop tacrolimus. Ritonavir is a cytochrome P450 3A inhibitor and can increase plasma concentration of tacrolimus. She restarted tacrolimus treatment 12 hours after her last dose of Paxlovid and presented with symptoms and a level consistent with toxicity. This level was concluded to be due to drug interaction between tacrolimus and Paxlovid. After further withholding of tacrolimus, symptoms improved, and levels normalized. Previous reports in transplant population stress importance of decreasing the dose of tacrolimus or withholding during the course of paxlovid treatment. This case demonstrates the importance of not only ceasing tacrolimus when administering paxlovid, but continuing discontinuation for longer period post completion of therapy to minimize interactions.Copyright © 2023

Drug Interaction between Paxlovid and Tacrolimus in an Adolescent with Inflammatory Bowel Disease

The coronavirus disease of 2019 (COVID-19) caused by SARS-CoV-2 virus led to a worldwide pandemic. Emergency use of an investigational medication, Paxlovid, was approved for patient 12 and older who tested positive for COVID-19 and at high risk for severe infection. Inflammatory Bowel Disease (IBD) is a chronic condition causing inflammation in the gastrointestinal tract. Ulcerative Colitis (UC) is a type of IBD centralized in colon and commonly treated with Immunosuppressive drugs. We present an adolescent with UC treated with paxlovid due to being on tacrolimus who developed with suspected tacrolimus toxicity. CASE REPORT: A 13-year-old female with UC presented to the ED with vomiting and fatigue after paxlovid ttreatment for COVID. The patient's UC treatment included tacrolimus along with ustekinumab. She had been diagnosed with SARS-CoV-2 and prescribed Paxlovid bid x 5 days due to immunosuppressive status. Tacrolimus was held during treatment. Once paxlovid completed, tacrolimus was restarted. Two days later, patient presented to ER for vomiting, fatigue, headaches and myalgia. Labs revealed a tacrolimus level of >60 ng/ml . Electrolytes and Creatinine were normal. Toxicology felt this was due to interaction between paxlovid and tacrolimus. Patient advised to hold tacrolimus for 48 hours and repeat levels were 15.8 ng/ mL. Symptoms resolved and level repeated three days later and was 2.9 ng/mL DISCUSSION: Tacrolimus is an immunosuppressant, commonly used for management of organ transplants but also been found effective in treatment of IBD. Tacrolimus requires close monitoring as toxicity may lead to acute or chronic kidney disease. The normal concentration is between 5-15 ng/mL. Due to rapid escalation of the COVID-19 pandemic, Paxlovid was approved for emergency use for treatment of high-risk patients. It is administered as a 5-day oral course consisting of nirmatrelvir and ritonavir. Our patient was prescribed Paxlovid due to risk secondary to immunosuppression. She was appropriately instructed to stop tacrolimus. Ritonavir is a cytochrome P450 3A inhibitor and can increase plasma concentration of tacrolimus. She restarted tacrolimus treatment 12 hours after her last dose of Paxlovid and presented with symptoms and a level consistent with toxicity. This level was concluded to be due to drug interaction between tacrolimus and Paxlovid. After further withholding of tacrolimus, symptoms improved, and levels normalized. Previous reports in transplant population stress importance of decreasing the dose of tacrolimus or withholding during the course of paxlovid treatment. This case demonstrates the importance of not only ceasing tacrolimus when administering paxlovid, but continuing discontinuation for longer period post completion of therapy to minimize interactions.

SARS-CoV-2 and pregnancy outcomes under universal and non-universal testing in Sweden: register-based nationwide cohort study.

OBJECTIVE: To assess associations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and pregnancy outcomes considering testing policy and test-positivity-to-delivery interval. DESIGN: Nationwide cohort study. SETTING: Sweden. POPULATION: From the Pregnancy-Register we identified 88 593 singleton births, 11 March 2020-31 January 2021, linked to data on SARS-CoV-2-positivity from the Public Health Agency, and information on neonatal care admission from the Neonatal Quality Register. Adjusted odds ratios (aORs) were estimated stratified by testing-policy and test-positivity-to-delivery interval. MAIN OUTCOME MEASURES: Five-minute Apgar score, neonatal care admission, stillbirth and preterm birth. RESULTS: During pregnancy, SARS-CoV-2 test-positivity was 5.4% (794/14 665) under universal testing and 1.9% (1402/73 928) under non-universal testing. There were generally lower risks associated with SARS-CoV-2 under universal than non-universal testing. In women testing positive >10 days from delivery, generally no significant differences in risk were observed under either testing policy. Neonatal care admission was more common (15.3% versus 8.0%; aOR 2.24, 95% CI 1.62-3.11) in women testing positive ≤10 days before delivery under universal testing. There was no significant association with 5-minute Apgar score below 7 (1.0% versus 1.7%; aOR 0.64, 95% CI 0.24-1.72) or stillbirth (0.3% versus 0.4%; aOR 0.72, 95% CI 0.10-5.20). Compared with term births (2.1%), test-positivity was higher in medically indicated preterm birth (5.7%; aOR 2.70, 95% CI 1.60-4.58) but not significantly increased in spontaneous preterm birth (2.3%; aOR 1.12, 95% CI 0.62-2.02). CONCLUSIONS: Testing policy and timing of test-positivity impact associations between SARS-CoV-2-positivity and pregnancy outcomes. Under non-universal testing, women with complications near delivery are more likely to be tested than women without complications, thereby inflating any association with adverse pregnancy outcomes compared with findings under universal testing. TWEETABLE ABSTRACT: Testing policy and time from SARS-CoV-2 infection to delivery influence the association with pregnancy outcomes.

Utilization of an inflammatory bowel disease (IBD) dashboard to improve process and patient outcome measures

Pre-Visit Planning (PVP) is a time intensive, manual process comprised of chart review and data gathering for each upcoming clinic patient but is integral in IBD management. The goal is to provide a comprehensive view of a patient's health status and review intercurrent issues as well as recent results. The review of the data for each patient helps direct the primary provider in adjusting or maintaining the plan for the clinic visit. These data points are based on Improve Care Now (ICN) guidelines. In order to improve the PVP process and IBD patient care, our group created a dashboard which hosts the necessary data in a common area in an easy to interpret manner. The goals of creating the dashboard were to: (1) Identify and validate the IBD patient population. (2) Improve efficiency by automating the data gathering process from the electronic medical record (EMR). (3) Create a visual representation of division and patient level data. (4) Identify areas of process improvement that will impact patient outcomes. Creation of the dashboard highlighted areas of improvement opportunity in IBD patient care. Specifically, the dashboard provides visibility of provider documentation compliance and identifies patients not seen within the 200-day ICN goal. It allows the team to identify newly diagnosed patients and sets a standard to have them seen a minimum of three visits within 180 days. Data for the dashboard is sourced directly from the Allscripts EMR. Data retrieval is contingent upon quality documentation. Following input in the EMR, Phoenix Children's Hospital (PCH) has a data warehouse of orders, results, (Admission-Discharge-Transfer) ADT, documentation, and flowsheets from the EMR and external data sources. Microsoft tools (SQL, SSAS, and Power BI) are utilized to harvest and display the data for the IBD staff to review at weekly PVP meetings. The process of developing the dashboard helped detect gaps in data input. Preliminary analysis of existing data identified actionable targets of improving percent of documentation of physician global assessment (PGA), patients needing follow-up appointments scheduled, and patients being seen within 200 days. The dashboard launch date was May 2019, though not all the current data metrics were added to the dashboard until January 2021. This process was confounded by the COVID-19 pandemic, which produced an initial decline in percent of patients seen within 200 days from 93% in July 2020 to 80% in January 2021. However, we have seen reversal of this trend with 88% seen within 200 days in April 2021. In addition, we have improved our PGA documentation significantly with 98% complete in March 2021 compared to 77% in January 2020. Utilization of the dashboard during the PVP process has resulted in an improvement in our remission rate, defined by PGA, from 79% in January 2020 to 84% in April 2021. Though it is in its early stages, the IBD Dashboard has proven to be a powerful tool in improving outcomes in IBD patient care. With the currently existing data, opportunities for improvement in patient practice have been identified. We have shown significant improvement in provider documentation and time to perform PVP. In addition, by focusing on patients lacking follow-up appointments and patients who have not been seen in 200 days, we are improving the trend in completion of patient follow up. With this tool, we can focus on newly diagnosed patients to achieve earlier remission. We predict this will continue to improve our clinical remission rate, patients off steroids, and sustained remission rates. More importantly, the principles of this novel tool can be adopted by other centers to help improve IBD patient care globally.

Direct oral anticoagulant use and risk of severe COVID-19.

BACKGROUND: Hypercoagulability and thromboembolism are prominent features of severe COVID-19, and ongoing anticoagulant use might be protective. METHODS: We conducted a nationwide register-based cohort study in Sweden, February through May, 2020, to assess whether ongoing direct oral anticoagulant (DOAC) use was associated with reduced risk of hospital admission for laboratory-confirmed COVID-19, or a composite of intensive care unit (ICU) admission or death due to laboratory-confirmed COVID-19. RESULTS: DOAC use (n = 103 703) was not associated with reduced risk of hospital admission for COVID-19 (adjusted hazard ratio [aHR] [95% confidence interval] 1.00 [0.75-1.33] vs. nonuse atrial fibrillation comparator [n = 36 875]; and aHR 0.94 [0.80-1.10] vs. nonuse cardiovascular disease comparator [n = 355 699]), or ICU admission or death due to COVID-19 (aHRs 0.76 [0.51-1.12], and 0.90 [0.71-1.15], respectively). CONCLUSION: Ongoing DOAC use was not associated with reduced risk of severe COVID-19, indicating that prognosis would not be modified by early outpatient DOAC initiation.