Austin, TX—With nirmatrelvir/ritonavir (NIM-RTV), marketed as Paxlovid, recently granted emergency use authorization for mild-to-moderate COVID-19, a new study warns that drug-drug interactions between ritonavir and tacrolimus are underappreciated by nontransplant providers.

An article in Open Forum Infectious Diseases describes two solid organ–transplant recipients who were prescribed NIM-RTV for outpatient use subsequently developed tacrolimus toxicity. The patients required hospitalization and were managed with rifampin for toxicity reversal, according to researchers from The University of Texas Department of Pharmacy and colleagues.

"Immunocompromised solid organ transplant recipients (SOTRs) are at risk of severe COVID-19 8 disease, making them ideal candidates for NIM-RTV," according to the authors. "Ritonavir, a strong cytochrome P450 3A 9 (CYP3A) inhibitor, 'boosts' concentrations of nirmatrelvir targeting SARS-CoV-2, while also raising concentrations of other CYP3A-metabolized medications."

The problem is that coadministration of NIM-RTV with tacrolimus can cause complications. "Clarity regarding the magnitude of this interaction is important to guide decision-making for SOTRs diagnosed with COVID-19," according to researchers.

One patient was a 40-year-old male with a history of pancreas-kidney transplant 7 years earlier, and the other was a 58-year-old bilateral lung–transplant recipient who presented for emergency care with 1 day of fever (38.1°C) and epigastric pain.

Tacrolimus was lowered and temporarily discontinued in the patients when they had adverse effects, but the study warns that "even more conservative management (i.e., holding tacrolimus for 1-2 days pre-NIM-RTV) may be necessary for high-risk recipients."

The authors added that the approach could reduce efficacy by delaying NIM-RTV therapy.

"This group recognizes that there may be significant barriers to safe NTM-RTV use in SOTRs on tacrolimus and recommend a greater focus on local strategies that allow coordinated access to remdesivir and monoclonal antibodies as first-line therapy in this patient population. Increased NIM-RTV prescriptions by outpatient providers unfamiliar with immunosuppression could result in serious toxicities."

The report noted, "These DDIs extend beyond CNIs, including common therapeutic classes like anticoagulants, antiarrhythmics, antifungals, and antiepileptics. It becomes imperative to urgently educate non-transplant professionals and patients through national and state resources. We believe that a 'Boxed Warning' added directly to medication packaging, provider fact sheets, and drug-interaction software in inpatient and outpatient pharmacies prior to EUA (emergency use authorization) approval and nationwide distribution would mitigate the dire consequences of these drug interactions for SOTRs and other patient populations on medications with narrow therapeutic indices."

The article also cautioned that the "decision to initiate rifampin for reversal should be carefully balanced with these risks against severe or worsening symptomatology (e.g., neuro, cardiac, renal toxicity) of tacrolimus toxicity."

Calling outpatient therapy for COVID-19 "an exciting development," the authors urged that, "the complexities with NIM-RTV coadministration must be cautiously comanaged by a multi-disciplinary partnership between community providers, transplant centers, and specialty pharmacists (e.g., transplant, infectious disease)."

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