ABSTRACT Background In the UK, a regional vertical system for the delivery of COVID-19 medicines has been in place. This enabled centralization of expertise in risk stratification of patients, and in understanding and mitigating drug–drug interactions. Research design and methods We analyzed real-world drug–drug interactions in adult patients referred for nirmatrelvir/ritonavir therapy across one such geographic area covering 2.2 million London citizens. Results Among 208 who received NMV/r therapy, we identified 184 potential DDIs, 8% precluded nirmatrelvir/ritonavir use, 53% required management, but 56% of these did not have documented advice to hold therapy. Conclusions This highlights the need to maintain and develop pathways for clinical pharmacology expertise in COVID-19 management.