Coronavirus disease 2019 (COVID-19) is an infectious respiratory illness caused by SARS-CoV-2, and was first identified in Wuhan, China in December 2019 before being declared a global pandemic by the World Health Organization (WHO) in March 2020 [1, 2]. In April of 2020, the cumulative case fatality rate of COVID-19 was 8% worldwide, and reached 6% in the US in May of 2020 [3]. The spread of COVID-19 globally required the rapid development of both vaccines and therapeutic agents. In December 2021, nirmatrelvir/ritonavir (Paxlovid™) received emergency use authorization (EUA) in the United States for the treatment of adults and pediatric patients (12 years of age and older weighing at least 40 kg) with mild-to-moderate COVID-19 and who are at high risk for progression to severe COVID-19, including hospitalization or death [4].

Paxlovid consists of nirmatrelvir tablets co-packaged with ritonavir tablets [5]. Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease, which prevents viral replication [5]. Ritonavir does not directly inhibit SARS-CoV-2, it instead acts to inhibit the cytochrome P450 (CYP) 3 A-mediated metabolism of nirmatrelvir, which leads to increased plasma concentration of nirmatrelvir [5]. Due to its potent inhibition of CYP3A, ritonavir is typically prescribed as a booster for drugs that are rapidly metabolized by CYP3A to enhance their bioavailability, as seen in many HIV regimens [6]. The safety and efficacy of nirmatrelvir/ritonavir was initially evaluated in the EPIC-HR study, an international, phase 2/3, double-blind, randomized, controlled trial [7]. The trial reported an 86% relative risk reduction in hospitalization or death in patients treated with nirmatrelvir/ritonavir compared with placebo, with no serious safety concerns [5, 7].

Drug-drug interactions (DDIs) were known to be a potential safety concern for nirmatrelvir/ritonavir due to the inclusion of ritonavir, which has a well-established DDI profile following its initial approval in March 1996 [8]. Indeed, the DDI profile of nirmatrelvir/ritonavir was initially ascertained based on ritonavir labels and supplemented by Pfizer-sponsored DDI studies [9, 10]. Because knowledge of ritonavir-associated DDIs has generally been confined to the HIV healthcare provider (HCP) community, whereas the potential patients and HCPs who would use or prescribe nirmatrelvir/ritonavir were broad and heterogeneous, steps were taken to proactively inform and educate HCPs and patients/caregivers about DDIs.

The EUA for nirmatrelvir/ritonavir was granted in record time; from first synthesis to EUA was approximately 18 months and from first-in-human study to EUA was approximately 10 months [7, 11,12,13]. This compressed development timeline was followed by the rapid uptake of nirmatrelvir/ritonavir during the early days after EUA, since oral outpatient treatment options were urgently needed to prevent hospitalization and death from COVID-19. It was therefore necessary to expeditiously develop a rapid, widespread, and comprehensive strategy to educate HCPs and patients about potential DDIs and the safe use of nirmatrelvir/ritonavir. This unique case study may help to guide best practices for future therapeutics that require timely and comprehensive dissemination of medical information.