A Case Report of Safe Coadministration of Amiodarone with Short‐Term Treatment Nirmatrelvir‐Ritonavir

In their recent article, Marzolini et al. recommend against the use of nirmatrelvir/ritonavir in amiodaronetreated patients, due to a risk of toxicity. They argue that its very long halflife makes it useless to stop amiodarone to mitigate the drug– drug interaction (DDI). The report of our experience illustrates that this DDI could be managed safely provided careful monitoring. A 72yearold patient presented with protracted COVID19. He suffered from follicular lymphoma treated by rituximabc y c l o p h o s p h a m i d e d o x o r u b i c i n vincristineprednisone, and persistent atrial fibrillation treated by amiodarone and anticoagulated by apixaban for 4 months. COVID19 had been diagnosed 3 months earlier, and despite treatment with remdesivir, persistent high viralload shedding and pneumonia were demonstrated, delaying the next chemotherapy course. Considering the risk– benefit balance, we started nirmatrelvir/ritonavir during hospitalization under clinical surveillance and therapeutic drug monitoring (TDM). Apixaban was transiently relayed by nadroparin. Amiodarone was halted 48 hours before nirmatrelvir/ritonavir initiation and restarted 96 hours after completion of the 5day antiviral course. Clinical tolerance was good and TDM of amiodarone and metabolite showed no accumulation (Table 1). The patient improved gradually and his viral load was undetectable on Days 7 and 14 after treatment initiation. Amiodarone is known for its potent class III antiarrhythmic activity. Its lipophilic nature results in broad accumulation in the peripheral adipose and muscular tissues, leading to a large distribution volume and a very long terminal halflife (55 days). The drug is mainly eliminated by cytochrome P450 3A4 (CYP3A4) into desethylamiodarone, a metabolite with pharmacodynamic effect close to the parent drug. Knowing that DDI between amiodarone and nirmatrelvir/ritonavir is mainly mediated through irreversible CYP3A4 inhibition by ritonavir, acute toxic accumulation seems highly improbable if amiodarone is discontinued before nirmatrelvir/ritonavir initiation. Moreover, the existence of an active CYP3A4produced metabolite— namely desethylamiodarone— makes clinical relevance of the shortterm DDI further questionable. As a matter of precaution, knowing the relatively slow and variable absorption as well as the extensive enterohepatic recirculation of amiodarone, we decided to apply a 2day washout period after the last amiodarone dose before nirmatrelvir/ritonavir start. Our findings suggest that there might not be an irrevocable contraindication for the use of nirmatrelvir/ritonavir in amiodaronetreated patients. Our approach deserves a formal DDI study before being accepted as standard. Meanwhile it should be restricted to selected cases, after careful weighing of risks and benefits, and provided that close supervision, notably TDM, is applied.