Phenytoin enzyme induction for management of supratherapeutic tacrolimus levels due to drug-drug interaction with nirmatrelvir/ritonavir: Case series and discussion

Abstract

Purpose

Nirmatrelvir/ritonavir is one of few options for outpatient treatment of COVID-19, but its use has been limited in transplant recipients due to significant drug interactions with immunosuppressants. Tacrolimus toxicity is possible when the drug is coadministered with nirmatrelvir/ritonavir and may require urgent reduction of tacrolimus levels. This case series describes the use of phenytoin for enzyme induction in 5 adult solid organ transplant recipients with supratherapeutic tacrolimus levels resulting from coadministration with nirmatrelvir/ritonavir.

Summary

Solid organ transplant recipients are at high risk for complications related to COVID-19. Outpatient treatment options are limited, and therapeutic drug monitoring is complex in patients requiring quarantine. The 5 solid organ transplant recipients described herein were initiated on nirmatrelvir/ritonavir in the outpatient setting and subsequently presented with supratherapeutic tacrolimus concentrations greater than 59 ng/mL and developed signs and symptoms of tacrolimus toxicity. In all patients, nirmatrelvir/ritonavir and tacrolimus were discontinued, and oral phenytoin (200-400 mg/day) was given for 2 to 4 days. Tacrolimus was resumed once tacrolimus levels decreased to appropriate levels.

Conclusion

These observations demonstrate that metabolism induction using phenytoin may be a useful strategy in the setting of supratherapeutic tacrolimus levels resulting from concomitant administration with nirmatrelvir/ritonavir.

Nirmatrelvir/ritonavir is approved for use by the Food and Drug Administration (FDA) for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adults who are at high risk for progression to severe COVID-19.¹ Prior to its FDA approval in May 2023, nirmatrelvir/ritonavir was available under an emergency use authorization (EUA).² Solid organ transplant and immunocompromised states are two of the underlying conditions associated with a high risk of severe COVID-19. In addition, transplant recipients often have comorbidities that put them at further increased risk for severe COVID-19 infection. Given the high risk of severe disease and limited treatment options, some providers have turned to nirmatrelvir/ritonavir for this population. Furthermore, with the withdrawal of monoclonal antibodies for both the treatment and prevention of COVID-19, it is likely that the use of nirmatrelvir/ritonavir in solid organ transplant recipients will continue to increase.

Standard dosing includes 300 mg of nirmatrelvir, a peptidomimetic inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease, with 100 mg of ritonavir, used in this combination to inhibit cytochrome P450 (CYP) isozyme 3A–mediated metabolism of nirmatrelvir, taken together twice daily for 5 days.¹ While there is a dose adjustment for nirmatrelvir to 150 mg per dose in the setting of moderately reduced kidney function (an estimated glomerular filtration rate of ≥30 to less than <60 mL/min), ritonavir 100 mg dosing is used in both regimens. The EUA fact sheet noted the possibility of significant drug interactions if nirmatrelvir/ritonavir is coadministered with medications highly dependent on CYP3A4 for clearance and for which elevated concentrations are associated with serious reactions. The FDA-approved package insert also includes a warning regarding CYP3A inhibition and advises review of medications to determine if adjustments, interruption, or monitoring is required.

Many transplant recipients are maintained on immunosuppression regimens containing tacrolimus, a calcineurin inhibitor and substrate of CYP3A isozymes with a narrow therapeutic index.³ Both the nirmatrelvir/ritonavir fact sheet and package insert warn of the risk of severe adverse reactions due to increased tacrolimus concentrations and recommend to avoid use if monitoring concentrations is not feasible and to obtain expert consultation for dose adjustments and monitoring. Elevated tacrolimus concentrations can cause a multitude of severe adverse effects, most notably nephrotoxicity, neurotoxicity, and profound electrolyte disturbances such as hyperkalemia and hypomagnesemia. While minor signs of neurotoxicity include insomnia, tremor, and headache, severe symptoms such as seizures, aphasia, coma, and delirium can occur, particularly at higher concentrations.³

Previous case reports have identified transplant recipients with supratherapeutic tacrolimus concentrations after nirmatrelvir/ritonavir administration,^4-8 but there is still limited literature describing the utilization of CYP3A4 induction for treatment related to toxicities from this specific drug-drug interaction. Phenytoin is a potent CYP3A4 inducer, and case reports have demonstrated successful use of oral phenytoin to manage acute tacrolimus toxicity in adult patients.^8-12 In comparison with other CYP3A4 inducers, phenytoin may provide the added benefit of seizure prophylaxis in cases of neurotoxicity.

Herein, we describe 5 patients who were treated with CYP3A4 induction using phenytoin for elevated tacrolimus levels after coadministration with nirmatrelvir/ritonavir, with additional patient details provided in Table 1 and Figure 1. The Drug Interaction Probability Scale (DIPS) score for all 5 cases was 7, indicating initiation of nirmatrelvir/ritonavir was the probable cause of supratherapeutic tacrolimus levels.¹³ Of note, all tacrolimus levels reported were measured using Abbott’s Architect tacrolimus assay. This report was approved by the University of South Florida institutional review board.

Case series

Case 1.

A 75-year-old Hispanic female (weight, 52 kg) with a history of heart transplant over 19 years ago, diabetes mellitus, hypertension, and cardiac allograft vasculopathy presented to her primary care provider’s office with diarrhea, malaise, appetite loss, and shortness of breath. She was diagnosed with COVID-19 and was prescribed standard-dose nirmatrelvir/ritonavir, which was appropriate for her baseline kidney function. She started taking nirmatrelvir/ritonavir (day 0), and the next day (day 1) called her transplant team and was given instructions to stop taking tacrolimus. On the evening of day 2, she presented to the hospital with headache, malaise, and acute kidney injury. Her tacrolimus level (an approximately 36-hour level) was greater than 60 ng/mL, serum creatinine concentration was 1.4 mg/dL (baseline, 0.6 mg/dL), and liver function tests were within normal limits. She had taken 5 doses of nirmatrelvir/ritonavir. Nirmatrelvir/ritonavir was discontinued, and she received remdesivir. Due to acute kidney injury, losartan and dapagliflozin were also withheld. On day 4, the patient’s tacrolimus level remained greater than 60 ng/mL and the decision was made to initiate phenytoin 200 mg by mouth twice daily for 5 doses. Tacrolimus was resumed on day 7, when the tacrolimus level was 8.4 ng/mL and the serum creatinine level was 0.7 mg/dL. Tacrolimus was resumed at a 40% dose reduction from baseline requirement, and tacrolimus trough levels on days 8, 9, and 10 were 7.6, 6.5, and 4.7 ng/mL, respectively.

Case 2.

A 43-year-old Black male (weight, 191 kg) with a history of deceased donor kidney transplant 5 years ago, hypertension, and obesity presented to a freestanding emergency department with malaise, fever, cough, and body aches. He tested positive for COVID-19 and was prescribed reduced-dose nirmatrelvir/ritonavir (day 0), which was appropriate for his baseline kidney function. He took 4 doses, then self-discontinued due to worsened fatigue, decreased urination, and nausea. On day 4, he notified the transplant team of his COVID-19 diagnosis and nirmatrelvir/ritonavir course. His symptoms had resolved, but due to the potential for tacrolimus toxicity, he was instructed to discontinue tacrolimus and present to the emergency department. His tacrolimus level was greater than 60 ng/mL (timing of the last dose was unknown), his serum creatinine level was 2.4 mg/dL (baseline, 1.9 mg/dL), and his alanine transaminase and aspartate transaminase (AST) levels were approximately twice the baseline values. Due to acute kidney injury, losartan and chlorthalidone were also withheld. On day 5, the patient’s tacrolimus level remained greater than 60 ng/mL, and the decision was made to initiate phenytoin 100 mg by mouth 3 times daily. Phenytoin was continued for 4 doses, then the patient was discharged home on day 6, when his tacrolimus level was 50.4 ng/mL and his serum creatinine level was 2.1 mg/dL. The patient remained under isolation, and blood sampling for repeat laboratory tests could not be performed until day 13. Once the laboratory results were reported to the transplant team, tacrolimus was resumed at the previous dose on day 18; at that time the patient’s tacrolimus level was less than 1.0 ng/mL and the serum creatinine level was 1.7 mg/dL. The tacrolimus level 1 week later (on day 25) was 9.6 ng/mL, and the patient’s tacrolimus dose was decreased.

Case 3.

A 60-year-old white male (weight, 84 kg) with a history of bilateral lung transplant secondary to idiopathic pulmonary fibrosis presented to the emergency department with acute-on-chronic left-sided chest wall pain and nonproductive cough. He tested positive for COVID-19 and was discharged on standard-dose nirmatrelvir/ritonavir (day 0), which was appropriate for his kidney function. He took 2 doses before contacting the primary transplant team, at which time he reported sinus congestion, dysphonia, and oxygen desaturations to 88% with walking but with quick recovery. He was instructed to discontinue tacrolimus and nirmatrelvir/ritonavir and present to the hospital for monitoring. Upon his arrival laboratory tests revealed a serum creatinine of 1.4 mg/dL (baseline, 1.3 mg/dL) and liver function tests within normal limits, and he was given a dose of bebtelovimab. The next morning his tacrolimus level was greater than 60 ng/mL (the timing relative to the last dose was unknown). Tacrolimus levels remained greater than 60 ng/mL on day 3, and thus phenytoin was initiated at a dosage of 100 mg by mouth 3 times daily based on clinician decision to use the low end of the published dosing range as the patient did not initially present with any clinical signs of tacrolimus toxicity. Phenytoin was continued for 4 days before the patient was discharged from the hospital on day 6, when the tacrolimus level was 17.7 ng/mL and the serum creatinine level was 1.0 mg/dL (after peaking at 1.6 mg/dL on day 4), and instructed to take phenytoin for 1 more day. A blood sample for determination of the tacrolimus level was drawn by a mobile blood draw company on day 8, and the decision was made to resume tacrolimus on that day, before the laboratory result became available (the result, reported several days later, was 5.8 ng/mL). Of note, at the time of nirmatrelvir/ritonavir initiation the patient was also on itraconazole, which was discontinued during hospital admission and resumed simultaneously with tacrolimus. Itraconazole was given as a protocolized prophylactic antifungal; thus, the patient had been at steady-state concentrations of both tacrolimus and itraconazole at the time of discontinuation. Due to its long half-life of 34-42 hours,¹⁴ itraconazole likely still had residual effects, which may have contributed to a slightly longer time to normalization of the tacrolimus concentrations. After resumption of tacrolimus, goal trough concentrations were achieved in 7 days and concentrations remained stable until 20 days after tacrolimus resumption, when a supratherapeutic trough of 21.6 ng/mL was noted, followed by a 25% dose reduction and subsequent therapeutic trough concentrations.

Case 4.

A 53-year-old white male (weight, 73 kg) with a past medical history of hypertension, hyperlipidemia, immunoglobulin A nephropathy, and living-related kidney transplant 2.5 years ago presented with headache, nasal congestion, and cough to an urgent care facility, where he was diagnosed with COVID-19 and prescribed nirmatrelvir/ritonavir (day 0) at standard dosing, which was appropriate per kidney function. After taking 2 doses, the man presented to the hospital with intractable nausea and vomiting. He was instructed to discontinue tacrolimus extended release and nirmatrelvir/ritonavir and was given a dose of bebtelovimab. His tacrolimus level on admission (day 1) was greater than 60 ng/mL (approximately 12 hours after the morning dose) and remained so the following day, at which time the decision was made to initiate phenytoin 100 mg by mouth twice daily for 4 doses. While the patient’s liver function tests were within normal limits at baseline, at admission he had an isolated elevation in AST level, which normalized within 48 hours. Tacrolimus extended release was resumed at a lower dose on day 5, when the level was 9.2 ng/mL. His serum creatinine concentration peaked at 2.2 mg/dL (baseline, 1.4-1.9 mg/dL) on day 5 and returned to baseline on day 10.

Case 5.

A 57-year-old Hispanic male (weight, 93 kg) with a history of heart transplants 35 and 16 years ago, respectively, posttransplant lymphoproliferative disorder, hypertension, and hyperlipidemia presented to his primary care physician with symptoms of sinus congestion and headache. He was diagnosed with COVID-19 and prescribed nirmatrelvir/ritonavir (day 0). The outpatient dosing of nirmatrelvir/ritonavir was unknown, but full dosing was indicated based on the man’s baseline kidney function. After 3 days and 7 doses of nirmatrelvir/ritonavir, he presented to an outside hospital with severe headache and informed his transplant team of his infection and treatment. He was transferred to the transplant hospital, where he was found to have a tacrolimus level of 59.9 ng/mL (the time relative to the last dose was unknown). Liver function tests were within normal limits. Nirmatrelvir/ritonavir and tacrolimus were both discontinued (on day 4) and remdesivir initiated. His tacrolimus level remained elevated at 55 ng/mL on day 5, so phenytoin was initiated at a dosage of 200 mg by mouth twice daily for 3 doses, followed by 100 mg by mouth twice daily for 2 doses. The serum creatinine concentration remained stable. On day 8, the patient’s tacrolimus level was 11.5 ng/mL, so tacrolimus was resumed at the previous dose on day 10, resulting in a level of 5.6 ng/mL on day 18.

Discussion

As solid organ transplant recipients are at high risk for morbidity and mortality from COVID-19, this population would benefit from early outpatient treatment to prevent progression to severe disease.¹⁵ Following the Food and Drug Administration’s EUA of nirmatrelvir/ritonavir in December 2021, concerns were immediately raised regarding use in the solid organ transplant population due to the potential for significant drug interaction between ritonavir and immunosuppressant medications. The American Society of Transplantation released a guidance document describing the drawbacks of nirmatrelvir/ritonavir use in the solid organ transplant population, with the primary recommendation being to preferably treat outpatients with appropriate anti-spike monoclonal antibody or remdesivir therapy.¹⁶ However, since the release of this guidance document and as of March 2023, there were no anti-spike monoclonal antibody therapies authorized for treatment of COVID-19 in the United States, given their diminished efficacy against newer COVID-19 variants. Despite the well-documented potential for tacrolimus toxicity in the setting of concomitant ritonavir use, the limited therapeutic options for COVID-19 leave little choice for providers in treating this vulnerable population.

A retrospective study reviewed outcomes of ambulatory solid organ transplant patients at one institution who received a prescription for nirmatrelvir/ritonavir, including 21 patients on tacrolimus.¹⁵ In this institution’s previously published protocol, tacrolimus was withheld at the time of nirmatrelvir/ritonavir initiation and then tacrolimus levels were to be checked 1 to 2 days after course completion, with resumption of tacrolimus at a reduced dose once levels were within or below the therapeutic target.¹⁷ None of the 19 patients for whom pre- and post- tacrolimus trough concentrations were available had elevated levels at the first check after completing the course of nirmatrelvir/ritonavir, and only 4 had supratherapeutic levels after resumption of tacrolimus. Another case series demonstrated supratherapeutic tacrolimus levels in patients who resumed tacrolimus within 24 hours of nirmatrelvir/ritonavir discontinuation, further supporting assessment of levels and potentially delayed resumption in the setting of prolonged CYP inhibition.¹⁸ The American Society of Transplantation also recommends either withholding or reducing doses of calcineurin inhibitors and mTOR inhibitors during treatment with nirmatrelvir/ritonavir.¹⁶

At our institution, each transplant team has a dedicated transplant pharmacotherapy specialist, who is involved in rounds, clinical decision-making, protocol review, and patient education in the inpatient and outpatient settings. Consultation with the pharmacist is recommended before initiation of any medication with a known drug-drug interaction with antirejection medications. Unfortunately, the prescribers and patients in this series did not confer with the transplant team prior to initiation of nirmatrelvir/ritonavir use, and the prescriptions were written in a variety of outpatient settings, precluding a proactive approach as previously described. This highlights the critical importance of adequate access to and assessment of patient health information before prescribing nirmatrelvir/ritonavir. In addition to providers, the EUA allows prescribing of nirmatrelvir/ritonavir by state-licensed pharmacists under certain conditions, including the presence of sufficiently informative documentation in health records and a comprehensive list of medications.² As the COVID-19 pandemic continues and use of nirmatrelvir/ritonavir expands, effort must be made to educate prescribers about appropriate recommendations for interacting medications and referral to specialists in cases such as these.

In addition to direct CYP enzyme inhibition via drug interactions, other variables have the potential to alter tacrolimus metabolism. As in other viral infections, the pro-inflammatory response in COVID-19 can reduce CYP3A4 metabolism.¹⁹ In the setting of elevated cytokines, including C-reactive protein, tumor necrosis factor, and others, inflammation may inhibit transcription of CYP3A4 and enzyme activity. In contrast, the use of corticosteroids to treat COVID-19 can induce CYP3A4 metabolism. Although it is unclear whether the altered CYP3A4 activity would warrant tacrolimus dose adjustment empirically, the addition of nirmatrelvir/ritonavir to narrow therapeutic index drugs presents an added and significant challenge. In patients with COVID-19–related diarrhea, as was identified in case 1, management of tacrolimus levels can be further complicated because trough elevations may be related to hemoconcentration, fasting, and increased intestinal permeability.³

Based on available data, nirmatrelvir/ritonavir appeared to be clinically indicated in each of our cases, in which patients had mild to moderate COVID-19 and were at high risk for progression to severe disease. The supratherapeutic tacrolimus levels were deemed to be a probable effect of the drug-drug interaction between nirmaltrelvir/ritonavir and tacrolimus (the DIPS score was 7 in all cases). As the DIPS assesses the probability of a causal relationship between a drug interaction and an event,¹³ it was selected over the Naranjo adverse drug reaction probability scale, which evaluates single drug–induced adverse reactions. In addition, the acute kidney injury seen in cases 1 through 4 were attributed to the supratherapeutic tacrolimus levels, but other risk factors in the setting of COVID-19 infection must be acknowledged, such as dehydration, poor oral intake, and hemodynamic changes. While additional nephrotoxic medications are noted in Table 1, these were used chronically and not newly initiated. Similarly, the patient in case 3 was taking itraconazole, but with its chronic use had tacrolimus levels within the target range; thus, itraconazole was unlikely to have contributed to the elevated tacrolimus levels at the time of hospital presentation.

Soon after nirmatrelvir/ritonavir was available for COVID-19 patients, case reports demonstrated supratherapeutic tacrolimus levels that resolved after withholding of the medication.^4,5 In the first published case, the patient was initially maintained on his normal tacrolimus dosing and was found to have a level greater than 30 ng/mL on day 2 of therapy. Tacrolimus was withheld upon receipt of the level, and the level was reduced to 8.8 ng/mL by day 10.⁵ In the second published case, the patient’s tacrolimus dose was reduced and ultimately withheld in the setting of supratherapeutic levels, which reached a maximum of 92.4 ng/mL on the fourth day after nirmatrelvir/ritonavir initiation. The last reported tacrolimus concentration in this case was 14.9 ng/mL 4 days later.⁴ In the latter case, the patient had no clinical manifestation of a tacrolimus overdose, and in the former the elevated tacrolimus level was much lower than our patients’ levels. In contrast, a majority of the patients in our case series presented with tacrolimus toxicity, with acute kidney injury being the most predominant. Additionally, the inability to discern actual tacrolimus concentrations above the upper limit of detection of 60 ng/mL, as well as failure of levels to drop below this threshold after withholding of tacrolimus, provided further clinical inclination toward phenytoin induction.

CYP induction starts with the process of ligand-activated CYP gene transcription and ultimately ends with increased synthesis of CYP protein.²⁰ While the CYP3A4 enzyme turnover half-life is approximately 3 days, the onset of induction can occur quickly. Induction may persist for weeks following discontinuation of phenytoin during chronic use. This was shown by Wada and colleagues,²¹ who demonstrated that 2- to 3-fold higher doses of tacrolimus were required in the setting of concomitant phenytoin use, but those investigators also observed the normalization of levels after just 11 days following a shorter 21-day course of phenytoin. Though the potential for variable tacrolimus levels post phenytoin exposure is notable, this could not be fully elucidated in this case series given the lack of serial levels post tacrolimus re-initiation in conjunction with lower tacrolimus dosing upon reinitiation in some patients. Given the limited doses that were administered in our patients, the duration of induction was expected to be shorter than in the setting of chronic use.

Sindelar and colleagues⁸ reported successful use of phenytoin to manage acute tacrolimus toxicities, including acute kidney injury and encephalopathy, following nirmatrelvir/ritonavir therapy in an orthotopic heart transplant recipient. Similar to our patients, in this case the patient had not been provided instructions to reduce or stop taking tacrolimus and limited data was available after reinitiation post discharge. Kwon and colleagues⁷ also reported use of phenytoin in a kidney transplant recipient with tacrolimus-related neurotoxicity and nephrotoxicity. Again, there was a delay in communication to the transplant team regarding how to adjust tacrolimus after starting nirmatrelvir/ritonavir, but this case included follow-up data demonstrating the patient achieved therapeutic tacrolimus levels when reinitiated on tacrolimus at 90% of his previous dose.

Table 2 includes a comparison of dosing strategies used for CYP3A induction by oral phenytoin in the setting of supratherapeutic tacrolimus levels.^8-12 These cases have involved multiple transplanted organ types and toxicity from a variety of interacting medications, including protease inhibitors (atazanavir, darunavir, and ritonavir), cobicistat, azole antifungals, clarithromycin, and vitamin/herbal products. Phenytoin dosing strategies have varied, with most ranging from total daily doses of 300 to 600 mg for durations between 2 and 4 days. Dosing strategies in the patients in our cases also varied and depended on ordering provider, transplanted organ type, and presence of tacrolimus-related toxicities. Pharmacists were involved in the clinical decision-making in most but not all of these patient cases, which may have impacted the dosing chosen as well. Most of the patients described in this case series had similar timelines to resolution of toxic tacrolimus levels after initiation of phenytoin, which appears to have been a favorable strategy compared with the watch-and-wait approach that may be considered in lower-risk patients. One of our patients received a lower dose than those previously reported: 100 mg by mouth twice daily for 4 doses. This patient’s tacrolimus levels fell to less than 10 ng/mL 3 days after phenytoin administration, so it is possible lower daily doses may be efficacious for this purpose. Interestingly, this patient was also the only patient who was maintained on the extended-release formulation of tacrolimus (Envarsus XR). A potential enhanced interaction between tacrolimus extended release and phenytoin has been previously described and is thought to be due to the absorption of tacrolimus extended release throughout the gastrointestinal tract in areas with varying levels of CYP activity.²²

No adverse effects from phenytoin were identified in our patients, and though 2 patients had phenytoin levels checked, it was determined these levels were not clinically useful and thus they were not obtained in other patients. It is worth mentioning that the presented cases were compared to available literature on use of oral phenytoin in adult solid organ transplant recipients, but other phenytoin administration strategies and target patient populations, such as intravenous phenytoin and pediatric patients, have been reported. Together with previously reported evidence on oral phenytoin regimens, these cases support use of a total daily phenytoin dose of 300 to 400 mg. To determine appropriate phenytoin dosing and duration for an individual patient, considerations may include presenting tacrolimus level, severity or risk of developing toxicity or rejection, and feasibility of future monitoring once therapy is safe to resume.

Since there is no clinical trial data supporting this practice, prescribers must be thoughtful in weighing which patients may benefit from it with minimal risks. Special consideration must be paid to the anticipated duration of CYP3A induction after administration of phenytoin, as subsequent subtherapeutic tacrolimus levels may place patients at risk for rejection. Additionally, phenytoin is also an inducer of CYP isozymes 1A2, 2B6, 2C9, and 3A5.²⁰ This puts patients at risk for additional unwanted or unintended drug interactions with variable timelines for waning induction. While this case series documents use of phenytoin to address supratherapeutic tacrolimus concentrations due to drug-drug interaction with nirmatrelvir/ritonavir in a variety of solid organ transplant recipients, it should be made clear that this induction strategy is not routine.

An important limitation to note was use of the Abbott tacrolimus immunoassay, as the company’s laboratory reports concentrations only up to the upper limit of detection (60 ng/mL) and immunoassays are not specific for the parent compound and may be impacted by metabolite accumulation. While tacrolimus levels decreased after oral phenytoin use, it remains unclear if CYP3A4 enzyme induction directly reduced tacrolimus-related adverse effects in comparison with a watch-and-wait approach. If considering phenytoin for CYP3A4 induction, clinicians must evaluate other prescribed medications and potential metabolic consequences as well as the possibility of prolonged induction and difficulty achieving therapeutic levels after reinitiating tacrolimus, which was not elucidated in our study due to limited patient follow-up.

Conclusion

Concomitant use of nirmatrelvir/ritonavir and tacrolimus poses a high risk for supratherapeutic tacrolimus levels and associated toxicities in transplant recipients. As COVID-19 treatment options have dwindled with new data and evolving resistance patterns, prescribers must consider the risks and benefits of nirmatrelvir/ritonavir use. Prescribers should ensure they have access to and have considered patients’ medical history and active medications. These cases demonstrate that phenytoin induction may be a useful strategy in managing supratherapeutic tacrolimus levels in patients who are inadvertently initiated on nirmatrelvir/ritonavir without preemptive calcineurin inhibitor discontinuation or dose adjustments.

Data availability

The data underlying this article are available in the article.

Disclosures

Dr. Bowman serves on the speakers’ bureau for Veloxis Pharmaceuticals. The other authors have declared no potential conflicts of interest.

References