Clinical Scorecard: Development and Use of a Digital Drug-Drug Interaction Screening Tool for the STRIVE Trial of Ensitrelvir in COVID-19 Treatment
At a Glance
Category
Detail
Condition
COVID-19 with lower respiratory tract involvement
Key Mechanisms
Ensitrelvir is a CYP3A substrate and inhibitor of CYP3A, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporter-3 (OAT-3), leading to significant drug–drug interaction potential
Target Population
Hospitalized adults with COVID-19 and evidence of lower respiratory tract involvement
Care Setting
Hospital inpatient clinical trial settings across multiple international sites
Key Highlights
Ensitrelvir exhibits a longer elimination half-life (~48 hours) than nirmatrelvir/ritonavir (~6 hours), extending DDI risk up to 10 days post-treatment.
A multidisciplinary team developed an online DDI screener for the STRIVE trial to categorize concomitant medications as permitted, prohibited, or conditionally permitted with washout and restart guidance.
The DDI screener was widely used (117,192 searches) across 150 sites in 13 countries, aiding safe trial conduct by managing complex DDIs, especially with anticoagulants, immunosuppressants, and emergency medications.
Guideline-Based Recommendations
Diagnosis
Identify hospitalized adults with COVID-19 and lower respiratory tract involvement eligible for ensitrelvir treatment within the STRIVE trial.
Management
Use the STRIVE trial-specific online DDI screener to assess concomitant medications for interactions with ensitrelvir.
Classify medications as permitted, prohibited, or conditionally permitted with dosage adjustments and washout periods as per screener guidance.
Provide alternative medication suggestions when prohibited drugs are identified.
Incorporate multidisciplinary input and real-time feedback from trial sites to update DDI guidance.
Monitoring & Follow-up
Monitor for potential DDIs during and up to 10 days after ensitrelvir treatment due to its prolonged half-life.
Regularly update DDI resources and screener content based on emerging data and site feedback.
Risks
Potential for serious DDIs due to ensitrelvir's inhibition of multiple metabolic pathways (CYP3A, P-gp, BCRP, OAT-3).
Challenges in managing DDIs with anticoagulants, immunosuppressants, and emergency use medications in a blinded trial setting.
Patient & Prescribing Data
Hospitalized adults with COVID-19 enrolled in the STRIVE ensitrelvir trial across 150 sites in 13 countries.
Ensitrelvir demonstrated antiviral efficacy against SARS-CoV-2 including Omicron variants with rapid viral load decline and no viral rebound; DDI management via the digital screener was critical for safe concomitant medication use.
Clinical Best Practices
Assemble a multidisciplinary team including pharmacists, pharmacologists, physicians, and statisticians for DDI management in clinical trials.
Develop and maintain an accessible, regularly updated online DDI screening tool tailored to the investigational drug's interaction profile.
Provide clear categorization of concomitant medications with guidance on washout periods, dosage adjustments, and alternative therapies.
Incorporate real-time feedback from trial sites to iteratively improve DDI resources.
Educate trial sites on the importance of DDI screening during patient screening and enrollment phases.
by Joshua P Havens, Nayon Kang, Lucy Chung, Courtney V Fletcher, Page Crew, Jacqueline Nordwall, Lianne Siegel, Katrina Harper, Birgit Grund, Marcelo Losso, Shikha Vasudeva, Kyle C Molina, Adit A Ginde, Ryosuke Shimizu, Ahmad Mourad, Alpha Diallo, Mina Pak, Anne Davis-Karim, Phiona Nabaggala, Alfredo J Mena Lora, Derek W Russell, Sho Saito, Jason V Baker, for the STRIVE Ensitrelvir Trial Study Group and the STRIVE Network
A retrospective cohort study of more than 520,000 hospitalized patients found no clinically meaningful improvement in deterioration or mortality with early treatment targeting community-acquired pneumonia.
