Nirmatrelvir/ritonavir (Paxlovid^®) is the current first-line treatment to prevent hospitalization and death related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, also known as coronavirus infectious disease 19 (COVID-19) [1]. In the phase III trial EPIC-HR, the drug has been shown to decrease hospitalization and death from severe COVID-19 by 89% for high-risk patients [2]. However, due to the high potency of drug metabolism inhibition of ritonavir, the combination of nirmatrelvir/ritonavir with calcineurin inhibitors (tacrolimus and cyclosporine) and m-TOR inhibitors (everolimus and sirolimus) can lead to their accumulation and subsequent adverse drug reactions, the most worrisome being acute renal failure [3–5]. Despite this potential safety issue, and because the immunosuppressed patients are a high-risk group for severe COVID-19, nirmatrelvir/ritonavir has been prescribed to patients under immunosuppressive treatment with various risk mitigation approaches [6, 7]. In this context, the French societies of Transplantation (Société Francophone de Transplantation—SFT) and Pharmacology (Société Française de Pharmacologie et Thérapeutique—SFPT) have published recommendations to manage immunosuppressants dose adjustment, with the aim of decreasing the risk of accumulation during the nirmatrelvir/ritonavir treatment course in solid organ transplant recipients. In short, these recommendations are: to discontinue tacrolimus 12 h before nirmatrelvir/ritonavir initiation; or to decrease the cyclosporine (CsA) dose to 20% of the initial daily dose and administer it once a day; or to decrease everolimus and sirolimus dose to 12.5% of the initial dose and administer it every other day. For tacrolimus, everolimus, and sirolimus, reintroduction of the dose prior to the course of nirmatrelvir/ritonavir can be considered on day 7, while CsA can be resumed at full dose on day 8 [8]. Specific therapeutic drug monitoring (TDM) of immunosuppressive drugs (ISD) has also been suggested.

The aims of the PAXLOV-IS study were: 1) to evaluate the application of the French recommendations and their impact on exposure to tacrolimus and on clinical outcomes in solid organ transplant patients, and ) to present the results of simulations aimed at proposing an optimized tacrolimus dosage adjustment algorithm when combined with nirmatrelvir/ritonavir.

This two-step retrospective study was conducted in France and Belgium on behalf of the SFT. Between January and August 2022, data on solid organ transplant patients treated with nirmatrelvir/ritonavir from seven French and two Belgian transplantation centers (Bordeaux, Brest, Brussels, Lyon, Montpellier, Rennes, and Toulouse) were collected. Paxlovid^® was prescribed to prevent severe complications of SARS-CoV-2 infection in accordance with its summary of product characteristics. The initiation of nirmatrelvir/ritonavir occurred within 5 days after the first symptoms of SARS-CoV-2 infection, for a duration of 5 days, and the dose was adapted to renal function: 150 mg nirmatrelvir + 100 mg ritonavir twice a day if the estimated glomerular filtration rate (eGFR) was below 60 mL/min/1.73 m², or 300 mg nirmatrelvir + 100 mg ritonavir for an eGFR above 60 mL/min/1.73 m².

The following characteristics were collected from medical records and anonymized: sex, weight, age, COVID-19 vaccine status and COVID-19 symptoms, type of transplantation, post-transplantation time, plasma or serum creatinine, glomerular filtration rate estimated using the CKD-EPI formula, liver enzymes, immunosuppressive treatment (type, dose, trough concentrations from baseline to the first measurement after the end of the nirmatrelvir/ritonavir course), and adverse events. The study was authorized by the institutional review board and ethics committee of Limoges Hospital and was registered under #15-2023-03.

We present a collaborative French and Belgian experience, focusing on adherence to the French national recommendations for managing drug-drug interactions between ISD and nirmatrelvir/ritonavir, along with their PK and clinical impact in 138 solid organ transplant patients. Notably, our findings highlight a high adherence rate to the guidelines (96.5% for tacrolimus and 100% for cyclosporine A), revealing sustained tacrolimus exposure but also indicating potential accumulation after early ISD reintroduction.

Nirmatrelvir/ritonavir is a valuable treatment for solid organ transplant recipients with COVID-19 who display a high risk of morbidity and mortality due to SARS-CoV-2 infection. Oral therapy is particularly interesting in outpatient settings. Nevertheless, drug-drug interactions between the antiviral and the immunosuppressive therapy remain a source of concern. The interaction between ritonavir and CYP3A4-dependent drugs can lead to significant increases in drug exposure, up to 50-fold for tacrolimus [10]. Because CNI are highly dependent on CYP3A metabolism, their blood concentration will increase substantially and rapidly when combined with ritonavir. This effect has been previously reported in transplant patients on ritonavir as a single agent or in association [11–13]. High concentrations of tacrolimus can lead to serious side effects such as kidney injury, seizures, posterior reversible encephalopathy, and even death [11]. Several ISD adjustment strategies have recently been reviewed by Tang et al., but no consensus has yet been reached [14]. When CNI are held during nirmatrelvir/ritonavir treatment, studies differ in terms of both timing of ISD suspension and dose resumption. In general, tacrolimus is discontinued from the initiation of nirmatrelvir/ritonavir and resumed at partial or full dose on days 6–13 after treatment completion. Moreover, a close TDM should be considered to guide the resumption of ISD [5, 6, 15–20]. In our study, tacrolimus was discontinued 12 h before nirmatrelvir/ritonavir initiation and restarted at full dose on day 7, while CsA was decreased to 20% of the initial daily dose and resumed at full dose on day 8, according to the SFPT and SFT recommendations [8]. Tacrolimus or CsA trough concentrations were measured during and after nirmatrelvir/ritonavir treatment. This strategy was efficient in the majority of patients. Regarding safety, dysgeusia was the main reported adverse drug reaction, as expected with ritonavir. The second most frequent adverse drug reaction was diarrhea, which was probably of mixed origin (COVID-19 infection, nirmatrelvir/ritonavir, and ISD overexposure). In the whole cohort, four cases of acute renal failure (three in tacrolimus patients and one in CsA patient), two neurologic toxicities, and three gastrointestinal toxicities were reported. These events were consistent with the high exposure reported upon ISD reintroduction. Notably, a deviation from the ISD dosage adjustment was identified in one of these four cases. This is consistent with a recent pharmacovigilance study reporting that 11 out of 14 tacrolimus overexposures were linked to a lack of compliance with the French national guidelines. In two other cases, no information was reported, and only one out of 14 patients seemed to present an overexposure episode while following the guidelines [21]. Fortunately, in our study, all episodes were reversible within a few days with dose adjustments. Furthermore, none of the patients were hospitalized because of severe COVID-19.

In the second phase of the study, PK modelling was performed in a subset of patients for whom adequate data were available. We showed a sustained tacrolimus drug exposure due to metabolism inhibition during nirmatrelvir/ritonavir treatment, even after tacrolimus discontinuation. Four patients experienced a more pronounced decrease (between 47% and 82%) without any clinical signs of acute graft rejection. However, a considerable number of patients had predicted supratherapeutic levels of tacrolimus after the cessation of nirmatrelvir/ritonavir (C₀ > 20 ng/mL during days 9–12 in approximately 20% of the patients). Other studies have reported supratherapeutic levels despite tacrolimus interruption during nirmatrelvir/ritonavir treatment [5, 6, 17, 19, 20]. In addition, a few case reports have illustrated the importance of tacrolimus discontinuation to avoid supratherapeutic concentrations and potentially severe adverse reactions [13, 17, 22], sometimes with rifampin [23] or phenytoin [24] treatment for toxicity reversal. Our results suggest a longer inhibition of CYP3A in some patients. Katzenmaier et al. previously reported that it may take at least 3 days after ritonavir discontinuation to restore CYP3A activity [25]. This has led us to re-evaluate the SFPT and SFT recommendations, considering patients’ metabolism recovery. PK modelling of 22 patients allowed us to define two extreme (low and rapid) metabolism recovery profiles. These profiles were used to simulate different strategies for resuming tacrolimus therapy after nirmatrelvir/ritonavir treatment. The best scenario was to stop tacrolimus during nirmatrelvir/ritonavir treatment and restart tacrolimus at 50% of the initial dose from day 8 and then 100% from day 9 (Figure 4). Simulations using extensive data collected from 22 patients showed that this strategy limits the risk of tacrolimus accumulation in patients with a slow recovery metabolism while limiting the risk of low exposure in patients with a rapid metabolism recovery. This one-size-fits-all strategy provides simple and convenient management of this at-risk period following antiviral treatment and is now included in the French national recommendations. Nonetheless, TDM is essential during resumption of immunosuppressive therapy, particularly tacrolimus. This is critical for the early detection of patients who may accumulate immunosuppressants after treatment with nirmatrelvir/ritonavir (days 8–12). Tacrolimus TDM based on trough concentrations measured on days 2 and 3, or even better measurement of its area under the curve, can be proposed to individualize the treatment strategy. Moreover, TDM should be performed early when ISD is restarted to rapidly detect patients with high or low ISD exposure. Volumetric absorptive microsampling (VAMS) could facilitate this process for outpatients infected with COVD-19.

This work has some limitations, including the retrospective design of the study and a limited sample size, especially for the PK modelling phase, where only 22 patients were included. The immunosuppressive treatment in the cohort predominantly consisted in tacrolimus (82%). The observations made on the 13 patients receiving cyclosporine A need confirmation in a larger population, and a similar evaluation should be considered for everolimus and sirolimus. Additionally, it would be interesting to assess the impact of CYP3A genotype on ISD exposure and potential accumulation during nirmatrelvir/ritonavir treatment and after ISD reintroduction.

This study reports the implementation of the French national recommendations for ISD drug adjustments during nirmatrelvir/ritonavir treatment in 138 solid organ recipients. These data demonstrate that discontinuing tacrolimus 12 h before the introduction of nirmatrelvir/ritonavir enables the maintenance of tacrolimus concentrations within the therapeutic range. It also ensures a tacrolimus exposure during the 5 days of treatment with nirmatrelvir/ritonavir close to the pre-treatment exposure. However, real-life data showed that some patients receiving a combination of tacrolimus-nirmatrelvir/ritonavir experienced tacrolimus accumulation when the treatment was resumed. Simulations performed on patients with repeated TDM showed that a strategy with 50% of the dose initially prescribed from day 8 (60 h after the last nirmatrelvir/ritonavir dose) and then 100% from day 9 (84 h after the last nirmatrelvir/ritonavir dose) should improve drug safety. TDM is an invaluable tool in such combination cases, allowing real-time ISD drug dosage adjustment, and should therefore be used systematically in patients receiving nirmatrelvir/ritonavir.