First experience of optimization of tacrolimus therapeutic drug monitoring in a patient co-treated with nirmatrelvir/ritonavir: How microsampling approach changes everything

Nirmatrelvir/ritonavir is approved for patients with high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Few experiences are reported with nirmatrelvir/ritonavir in solid organ recipients1 and prescribing it in these patients can be challenging for clinicians because of expected drug–drug interactions between immunosuppressive drugs and the antiviral. Indeed, ritonavir is a potent irreversible cytochrome P450 3A and P-glycoprotein inhibitor, which leads to overexposure to substrates of immunosuppressive drugs and complicates the handling of commonly used immunosuppressants notably calcineurin inhibitors. The ideal situation would be to conduct a complete outpatient treatment as a shielding measure of social distancing and nirmatrelvir/ritonavir being an oral formulation allows us to do so. Thus, the 2 goals, that is, outpatient treatment to avoid secondary contamination and strict monitoring of tacrolimus concentrations, seem irreconcilable. A 32-y-old unvaccinated woman benefited from a kidney transplant in November 2007. Her graft rejection prevention was ensured by extended-release tacrolimus Advagraf (8 mg once daily) and azathioprine (50 mg once daily). She tested positive for SARS-CoV-2 and displayed asthenia, fever, headaches, nausea, vomiting, and dyspnea. Ambulatory medical evaluation was acceptable, particularly oxygen saturation and pulmonary auscultation. As a high-risk patient for severe disease, she was prescribed nirmatrelvir/ritonavir 300 mg/100 mg twice a day. The patient was referred to a pharmacologist for specialized advice for the evaluation of drug–drug interaction, drug dosage adjustment, and therapeutic drug monitoring (TDM) program. For tacrolimus TDM, the patient was provided second-generation dried blood spots for self-collection of blood at home (Neoteryx, Torrance, CA) and the required material for postal shipment of the samples. Tacrolimus concentrations in dried blood spots were measured at the Pharmacology Department of the Rennes University Hospital with a published chromatographic tandem mass spectrometry method.2 All samples taken on days 3, 5, 7, 8, 9, and 10 were received on the day after each sample collection, and results were available within 48 h from collection. Because the patient was at low immunological risk, tacrolimus treatment was discontinued 12 h before nirmatrelvir/ritonavir initiation according to guidelines,3 and azathioprine was continued unchanged. Results of close tacrolimus monitoring are shown in Figure 1. Pharmacokinetic parameters were estimated using the MWPHARM++ software (Mediware, Prague, Czech Republic) with a 5-d area under the curve (AUC) of tacrolimus blood concentrations (AUC0–120 h) of 1382 ng·h/mL during nirmatrelvir/ritonavir compared with the 1607 ng·h/mL AUC0–120 h estimated before the antiviral treatment.4 Tacrolimus exposure was then decreased by 14% during the nirmatrelvir/ritonavir 5-d treatment. During the ritonavir inhibition phase of tacrolimus metabolism, the half-life was estimated to be 161 h and the elimination constant was 0.00432 h–1, which are values close to what is reported in the literature.5 Evolution of SARS-CoV-2 infection was favorable without significant graft dysfunction.FIGURE 1.: Evolution of the patient’s tacrolimus blood concentrations before and during nirmatrelvir/ritonavir and at the end of the antiviral treatment during the tacrolimus restart phase. Triangles are tacrolimus concentration measured in VAMS, and circles are tacrolimus concentrations measured from a venipuncture. Bid, twice a day; die, once a day; TAC, tacrolimus; VAMS, volumetric absorptive microsampling strategy.Here, we provide the first report of a kidney transplant recipient whose tacrolimus treatment has been adjusted during and after the antiviral treatment by nirmatrelvir/ritonavir thanks to an innovative microsampling method of TDM performed at home by the patient herself. The microsampling approach seems as a potent tool for widespread optimized immunosuppressive drug treatment and to globally reshape TDM.