RESUMO
Although ALK tyrosine kinase inhibitors (ALK-TKIs) have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy, the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers. In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. Based on the patient-derived models and clinical responses of the patient, we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib. In addition, NSCLC patients harboring the G1269A mutation, which was identified in alectinib, lorlatinib and crizotinib-resistant NSCLC, showed responsiveness to brigatinib and ceritinib. Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways, potentially contributing to its anti-tumor activity. Moreover, we constructed a prognostic model based on the expression of IL6, CXCL1, and CXCL5, providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.
Assuntos
Adenocarcinoma de Pulmão , Antineoplásicos , Neoplasias Pulmonares , Proteínas de Fusão Oncogênica , Compostos Organofosforados , Inibidores de Proteínas Quinases , Pirimidinas , Humanos , Compostos Organofosforados/uso terapêutico , Compostos Organofosforados/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Animais , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Prognóstico , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Lactamas/uso terapêutico , Carbazóis/uso terapêutico , Carbazóis/farmacologia , Sulfonas/uso terapêutico , Sulfonas/farmacologia , Crizotinibe/uso terapêutico , Crizotinibe/farmacologia , Linhagem Celular Tumoral , Piperidinas/uso terapêutico , Piperidinas/farmacologia , Feminino , Camundongos , Inflamação/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Masculino , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/metabolismo , Proliferação de Células/efeitos dos fármacos , Mutação , Aminopiridinas/uso terapêutico , Aminopiridinas/farmacologiaRESUMO
Anaplastic lymphoma kinase (ALK) is implicated in the genesis of multiple malignant tumors. Lorlatinib stands out as the most advanced and effective inhibitor currently used in the clinic for the treatment of ALK-positive non-small cell lung cancer. However, resistance to lorlatinib has inevitably manifested over time, with double/triple mutations of G1202, L1196, L1198, C1156 and I1171 frequently observed in clinical practice, and tumors regrow within a short time after treatment with lorlatinib. Therefore, elucidating the mechanism of resistance to lorlatinib is paramount in paving the way for innovative therapeutic strategies and the development of next-generation drugs. In this study, we leveraged multiple computational methodologies to delve into the resistance mechanisms of three specific double mutations of ALKG1202R/L1196M, ALKG1202R/L1198F and ALKI1171N/L1198F to lorlatinib. We analyzed these mechanisms through qualitative (PCA, DCCM) and quantitative (MM/GBSA, US) kinetic analyses. The qualitative analysis shows that these mutations exert minimal perturbations on the conformational dynamics of the structural domains of ALK. The energetic and structural assessments show that the van der Waals interactions, formed by the conserved residue Leu1256 within the ATP-binding site and the residues Glu1197 and Met1199 in the hinge domain with lorlatinib, play integral roles in the occurrence of drug resistance. Furthermore, the US simulation results elucidate that the pathways through which lorlatinib dissociates vary across mutant systems, and the distinct environments during the dissociation process culminate in diverse resistance mechanisms. Collectively, these insights provide important clues for the design of novel inhibitors to combat resistance.
Assuntos
Aminopiridinas , Carcinoma Pulmonar de Células não Pequenas , Lactamas , Neoplasias Pulmonares , Pirazóis , Humanos , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Resistencia a Medicamentos Antineoplásicos , Lactamas/farmacologia , Lactamas/uso terapêutico , Lactamas Macrocíclicas/farmacologia , Lactamas Macrocíclicas/uso terapêutico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêuticoRESUMO
Six ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, ensartinib) have received first-line treatment indication of advanced ALK+ NSCLC in various countries. In Ba/F3 cells, lorlatinib achieved lowest IC50 among these 6 ALK TKIs against EML4-ALK variant 1 or 3. In 2022, 7 abstracts reported updated efficacy and safety data from CROWN. With a median follow-up time of 36.7 months, the 3-year progression-free survival (PFS) rate was 63.5% for lorlatinib-treated patients and the median PFS of lorlatinib still has not been reached. Importantly, post-lorlatinib treatment median PFS2 was 74.0% at 3-years. Lorlatinib-treated Asian patients achieved similar 3-year PFS rate as overall lorlatinib-treated patients. Median PFS was 33.3 months among lorlatinib-treated EML4-ALK v3 patients. CNS AE occurred fewer than 1 event per patient over the median follow-up time of 36.7 months and most resolved without intervention. Altogether these data affirm our belief that lorlatinib should be the treatment of choice of advanced ALK+ NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/induzido quimicamente , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Lactamas/uso terapêutico , Lactamas Macrocíclicas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Carbapenem-resistant Acinetobacter baumannii (CRAB) is a difficult-to-treat nosocomial pathogen responsible for significant morbidity and mortality. Sulbactam-durlobactam (SUL-DUR), formerly ETX2514SUL, is a novel ß-lactam-ß-lactamase inhibitor designed specifically for the treatment of CRAB infections. The United States Food and Drug Administration (FDA) fast-track approval of SUL-DUR for the treatment of CRAB infections is currently pending after completion of the phase III ATTACK trial, which compared SUL-DUR to colistin, both in combination with imipenem-cilastatin (IMI) for patients with CRAB-associated hospital-acquired bacterial pneumonia, ventilator-associated pneumonia, and bacteremia. The results of this trial demonstrated that SUL-DUR was non-inferior to colistin for CRAB while also possessing a much more favorable safety profile. SUL-DUR was well-tolerated with the most common side effects being headache, nausea, and injection-site phlebitis. With the current landscape of limited effective treatment options for CRAB infections, SUL-DUR represents a promising therapeutic option for the treatment of these severe infections. This review will discuss the pharmacology, spectrum of activity, pharmacokinetics/pharmacodynamics, in vitro and clinical studies, safety, dosing, administration, as well as the potential role in therapy for SUL-DUR.
Assuntos
Infecções por Acinetobacter , Acinetobacter baumannii , Estados Unidos , Humanos , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/uso terapêutico , Antibacterianos/efeitos adversos , Colistina/farmacologia , Lactamas/farmacologia , Lactamas/uso terapêutico , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Infecções por Acinetobacter/tratamento farmacológicoRESUMO
OBJECTIVES: Bloodstream infections (BSIs) caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) have become a worldwide public health threat, and beta-lactam/beta-lactamase inhibitor combinations (BLBLIs) are considered as one reliable carbapenem-sparing antibiotic. However, it is still controversial whether BLBLIs are truly noninferior to carbapenems. Therefore, we conducted this meta-analysis to compare the efficacy of BLBLIs with carbapenems for ESBL-PE BSIs. METHODS: A systematic search of PubMed, Cochrane Library, and Embase was conducted until December 2021 to enroll studies comparing BLBLIs with carbapenems for ESBL-PE BSIs. A subgroup analysis was performed based on the choice of therapy (empirical, definitive, and mixed therapy). The protocol was registered in the International Prospective Register of Systematic Reviews (#CRD42022316011). RESULTS: A total of 2786 patients from one randomized clinical trial and 25 cohorts were included. There was no statistically significant difference between BLBLIs and carbapenems groups in therapeutical response (odds ratio [OR] = 1.19, P = 0.45) and mortality (OR = 1.06, P = 0.68). Furthermore, although the statistical difference was also not found in the subgroup analysis, BLBLIs performed better in definitive therapy than empirical therapy than carbapenems, with a numerically higher therapeutical response (OR = 1.42 vs 0.89) and a mildly lower mortality (OR = 0.85 vs 1.14). CONCLUSION: BLBLIs were noninferior to carbapenems for ESBL-PE BSIs, especially in definitive therapy. BLBLIs may be a valid alternative to spare the use of carbapenems.
Assuntos
Bacteriemia , Infecções por Enterobacteriaceae , Sepse , Humanos , Carbapenêmicos/uso terapêutico , Inibidores de beta-Lactamases , Lactamas/uso terapêutico , Infecções por Enterobacteriaceae/tratamento farmacológico , Bacteriemia/tratamento farmacológico , Antibacterianos/uso terapêutico , Enterobacteriaceae , beta-Lactamas/uso terapêutico , Sepse/tratamento farmacológico , beta-Lactamases , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
INTRODUCTION: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of ALK-rearranged non-small cell lung cancer (NSCLC), but these patients will eventually develop resistance and progression of disease after 10 months of first-generation and more than 30 months after second-generation TKIs. Lorlatinib is a third-generation highly selective ALK-TKI capable of inducing significant and durable CNS responses and overcoming known ALK resistance mutations. AREAS COVERED: This review summarizes the mechanism of action, efficacy, and safety of lorlatinib in ALK-positive NSCLC. The authors provide their expert opinions on the use of this drug, including its future prospects. EXPERT OPINION: Lorlatinib has shown good efficacy and safety in ALK-positive NSCLC patients progressing to first- and second-generation ALK-TKIs. The phase III trial CROWN evaluating lorlatinib as first-line therapy has provided promising results; however, the comparing arm was crizotinib, supplanted now by second-generation agents. Whether lorlatinib can replace them as upfront strategy is a relevant question that still remains open. In our opinion, longer follow-up and face-to-face studies are required to determine which is the best treatment sequence strategy. The advent of liquid biopsy will contribute to treatment tailoring according to the genomic profile at progression.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Quinase do Linfoma Anaplásico , Lactamas/uso terapêutico , Aminopiridinas/uso terapêutico , Lactamas Macrocíclicas/uso terapêutico , Proteínas Tirosina Quinases , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
BACKGROUND: There are limited treatment options for uncomplicated urinary tract infection (uUTI) caused by resistant pathogens. Sulopenem etzadroxil/probenecid (sulopenem) is an oral thiopenem antibiotic active against multidrug-resistant pathogens that cause uUTIs. METHODS: Patients with uUTI were randomized to 5 days of sulopenem or 3 days of ciprofloxacin. The primary endpoint was overall success, defined as both clinical and microbiologic response at day 12. In patients with ciprofloxacin-nonsusceptible baseline pathogens, sulopenem was compared for superiority over ciprofloxacin; in patients with ciprofloxacin-susceptible pathogens, the agents were compared for noninferiority. Using prespecified hierarchical statistical testing, the primary endpoint was tested in the combined population if either superiority or noninferiority was declared in the nonsusceptible or susceptible population, respectively. RESULTS: In the nonsusceptible population, sulopenem was superior to ciprofloxacin, 62.6% vs 36.0% (difference, 26.6%; 95% confidence interval [CI], 15.1 to 7.4; P <.001). In the susceptible population, sulopenem was not noninferior to ciprofloxacin, 66.8% vs 78.6% (difference, -11.8%; 95% CI, -18.0 to 5.6). The difference was driven by a higher rate of asymptomatic bacteriuria (ASB) post-treatment in patients on sulopenem. In the combined analysis, sulopenem was noninferior to ciprofloxacin, 65.6% vs 67.9% (difference, -2.3%; 95% CI, -7.9 to 3.3). Diarrhea occurred more frequently with sulopenem (12.4% vs 2.5%). CONCLUSIONS: Sulopenem was noninferior to ciprofloxacin in the treatment of uUTIs. Sulopenem was superior to ciprofloxacin in patients with uUTIs due to ciprofloxacin-nonsusceptible pathogens. Sulopenem was not noninferior in patients with ciprofloxacin-susceptible pathogens, driven largely by a lower rate of ASB in those who received ciprofloxacin. CLINICAL TRIAL REGISTRATION: NCT03354598.
Assuntos
Ciprofloxacina , Infecções Urinárias , Humanos , Feminino , Ciprofloxacina/uso terapêutico , Infecções Urinárias/microbiologia , Antibacterianos , Lactamas/uso terapêuticoRESUMO
Acute respiratory distress syndrome (ARDS) is a lethal clinical entity that has become an emergency event with the outbreak of COVID-19. However, to date, there are no well-proven pharmacotherapies except dexamethasone. This study is aimed to evaluate IRAK4 inhibitors as a potential treatment for ARDS-cytokine release syndrome (CRS). We applied two IRAK4 inhibitors, BAY-1834845 and PF-06650833 to an inhaled lipopolysaccharide (LPS)-induced ARDS mouse model with control of high dose dexamethasone (10 mg/kg). Unexpectedly, although both compounds had excellent IC50 on IRAK4 kinase activity, only BAY-1834845 but not PF-06650833 or high dose dexamethasone could significantly prevent lung injury according to a blinded pathology scoring. Further, only BAY-1834845 and BAY-1834845 combined with dexamethasone could effectively improve the injury score of pre-existed ARDS. Compared with PF-06650833 and high dose dexamethasone, BAY-1834845 remarkably decreased inflammatory cells infiltrating lung tissue and neutrophil count in BALF. BAY-1834845, DEX, and the combination of the two agents could decrease BALF total T cells, monocyte, and macrophages. In further cell type enrichment analysis based on lung tissue RNA-seq, both BAY-1834845 and dexamethasone decreased signatures of inflammatory cells and effector lymphocytes. Interestingly, unlike the dexamethasone group, BAY-1834845 largely preserved the signatures of naïve lymphocytes and stromal cells such as endothelial cells, chondrocytes, and smooth muscle cells. Differential gene enrichment suggested that BAY-1834845 downregulated genes more efficiently than dexamethasone, especially TNF, IL-17, interferon, and Toll-like receptor signaling.
Assuntos
Tratamento Farmacológico da COVID-19 , Quinases Associadas a Receptores de Interleucina-1 , Inibidores de Proteínas Quinases , Síndrome do Desconforto Respiratório , Animais , Camundongos , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Células Endoteliais , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Lactamas/farmacologia , Lactamas/uso terapêutico , Lipopolissacarídeos/farmacologia , Pulmão/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/prevenção & controleAssuntos
Antivirais , Tratamento Farmacológico da COVID-19 , Lactamas , Leucina , Nitrilas , Prolina , Ritonavir , Carga Viral , Antivirais/efeitos adversos , Antivirais/farmacologia , Antivirais/uso terapêutico , Combinação de Medicamentos , Humanos , Lactamas/efeitos adversos , Lactamas/farmacologia , Lactamas/uso terapêutico , Leucina/efeitos adversos , Leucina/farmacologia , Leucina/uso terapêutico , Nitrilas/efeitos adversos , Nitrilas/farmacologia , Nitrilas/uso terapêutico , Prolina/efeitos adversos , Prolina/farmacologia , Prolina/uso terapêutico , Recidiva , Ritonavir/efeitos adversos , Ritonavir/farmacologia , Ritonavir/uso terapêutico , Carga Viral/efeitos dos fármacosAssuntos
Antivirais , Tratamento Farmacológico da COVID-19 , Lactamas , Leucina , Nitrilas , Prolina , Ritonavir , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Combinação de Medicamentos , Humanos , Lactamas/efeitos adversos , Lactamas/uso terapêutico , Leucina/efeitos adversos , Leucina/uso terapêutico , Nitrilas/efeitos adversos , Nitrilas/uso terapêutico , Prolina/efeitos adversos , Prolina/uso terapêutico , Recidiva , Ritonavir/efeitos adversos , Ritonavir/uso terapêutico , SARS-CoV-2RESUMO
BACKGROUND: The oral protease inhibitor nirmatrelvir has shown substantial efficacy in high-risk, unvaccinated patients infected with the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Data regarding the effectiveness of nirmatrelvir in preventing severe coronavirus disease 2019 (Covid-19) outcomes from the B.1.1.529 (omicron) variant are limited. METHODS: We obtained data for all members of Clalit Health Services who were 40 years of age or older at the start of the study period and were assessed as being eligible to receive nirmatrelvir therapy during the omicron surge. A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association of nirmatrelvir treatment with hospitalization and death due to Covid-19, with adjustment for sociodemographic factors, coexisting conditions, and previous SARS-CoV-2 immunity status. RESULTS: A total of 109,254 patients met the eligibility criteria, of whom 3902 (4%) received nirmatrelvir during the study period. Among patients 65 years of age or older, the rate of hospitalization due to Covid-19 was 14.7 cases per 100,000 person-days among treated patients as compared with 58.9 cases per 100,000 person-days among untreated patients (adjusted hazard ratio, 0.27; 95% confidence interval [CI], 0.15 to 0.49). The adjusted hazard ratio for death due to Covid-19 was 0.21 (95% CI, 0.05 to 0.82). Among patients 40 to 64 years of age, the rate of hospitalization due to Covid-19 was 15.2 cases per 100,000 person-days among treated patients and 15.8 cases per 100,000 person-days among untreated patients (adjusted hazard ratio, 0.74; 95% CI, 0.35 to 1.58). The adjusted hazard ratio for death due to Covid-19 was 1.32 (95% CI, 0.16 to 10.75). CONCLUSIONS: Among patients 65 years of age or older, the rates of hospitalization and death due to Covid-19 were significantly lower among those who received nirmatrelvir than among those who did not. No evidence of benefit was found in younger adults.
Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , Lactamas , Leucina , Nitrilas , Prolina , Adulto , Idoso , Antivirais/uso terapêutico , COVID-19/virologia , Hospitalização , Humanos , Lactamas/uso terapêutico , Leucina/uso terapêutico , Pessoa de Meia-Idade , Nitrilas/uso terapêutico , Prolina/uso terapêutico , SARS-CoV-2 , Resultado do TratamentoAssuntos
Antivirais , Serviço Hospitalar de Emergência , Lactamas , Leucina , Nitrilas , Readmissão do Paciente , Prolina , Ritonavir , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Combinação de Medicamentos , Serviço Hospitalar de Emergência/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Humanos , Lactamas/administração & dosagem , Lactamas/efeitos adversos , Lactamas/uso terapêutico , Leucina/administração & dosagem , Leucina/efeitos adversos , Leucina/uso terapêutico , Nitrilas/administração & dosagem , Nitrilas/efeitos adversos , Nitrilas/uso terapêutico , Readmissão do Paciente/estatística & dados numéricos , Prolina/administração & dosagem , Prolina/efeitos adversos , Prolina/uso terapêutico , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Ritonavir/uso terapêuticoRESUMO
In lab studies, SARS-CoV-2 finds ways to evade key drug. Some of the viral mutations are already found in people.
Assuntos
Tratamento Farmacológico da COVID-19 , Proteases 3C de Coronavírus , Farmacorresistência Viral , Lactamas , Leucina , Nitrilas , Prolina , Ritonavir , SARS-CoV-2 , Inibidores de Protease Viral , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/genética , Combinação de Medicamentos , Farmacorresistência Viral/genética , Humanos , Lactamas/farmacologia , Lactamas/uso terapêutico , Leucina/farmacologia , Leucina/uso terapêutico , Mutação , Nitrilas/farmacologia , Nitrilas/uso terapêutico , Prolina/farmacologia , Prolina/uso terapêutico , Ritonavir/farmacologia , Ritonavir/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética , Inibidores de Protease Viral/farmacologia , Inibidores de Protease Viral/uso terapêuticoAssuntos
Tratamento Farmacológico da COVID-19 , Teste para COVID-19 , COVID-19 , Inibidores de Protease Viral , Antivirais/efeitos adversos , Antivirais/uso terapêutico , COVID-19/complicações , COVID-19/diagnóstico , Combinação de Medicamentos , Humanos , Lactamas/efeitos adversos , Lactamas/uso terapêutico , Leucina/efeitos adversos , Leucina/uso terapêutico , Nitrilas/efeitos adversos , Nitrilas/uso terapêutico , Prolina/efeitos adversos , Prolina/uso terapêutico , Recidiva , Ritonavir/efeitos adversos , Ritonavir/uso terapêutico , Inibidores de Protease Viral/efeitos adversos , Inibidores de Protease Viral/uso terapêuticoRESUMO
Nirmatrelvir/ritonavir (NR) use has not yet been described in solid organ transplant recipients (SOTRs) with mild COVID-19. The objective was to evaluate outcomes among SOTR and describe the drug-drug interaction of NR. This is an IRB-approved, retrospective study of all adult SOTR on a calcineurin inhibitor (CNI) or mammalian target of rapamycin inhibitor who were prescribed NR between December 28, 2021 and January 6, 2022. A total of 25 adult SOTR were included (n = 21 tacrolimus, n = 4 cyclosporine, n = 3 everolimus, n = 1 sirolimus). All patients were instructed to follow the following standardized protocol during treatment with 5 days of NR: hold tacrolimus or mTOR inhibitor or reduce cyclosporine dose to 20% of baseline daily dose. Four patients (16%) were hospitalized by day 30; one for infectious diarrhea and three for symptoms related to COVID-19. No patients died within 30 days of receipt of NR. Median tacrolimus level pre- and post-NR were 7.4 ng/ml (IQR, 6.6-8.6) and 5.2 (IQR, 3.6-8.7), respectively. Four patients experienced a supratherapeutic tacrolimus concentration after restarting tacrolimus post-NR. Our results show the clinically significant interaction between NR and immunosuppressive agents can be reasonably managed with a standardized dosing protocol. Prescribers should carefully re-introduce CNI after the NR course is complete.