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• W4311457585 abstract "The Precision Interventions for Severe and/or Exacerbation-Prone Asthma clinical trials network is actively assessing novel treatments for severe asthma during the coronavirus disease (COVID-19) pandemic and has needed to adapt to various clinical dilemmas posed by the COVID-19 pandemic. Pharmacologic interactions between established asthma therapies and novel drug interventions for COVID-19 infection, including antivirals, biologics, and vaccines, have emerged as a critical and unanticipated issue in the clinical care of asthma. In particular, impaired metabolism of some long-acting beta-2 agonists by the cytochrome P4503A4 enzyme in the setting of antiviral treatment using ritonavir-boosted nirmatrelvir (NVM/r, brand name Paxlovid) may increase risk for adverse cardiovascular events. Although available data have documented the potential for such interactions, these issues are largely unappreciated by clinicians who treat asthma, or those dispensing COVID-19 interventions in patients who happen to have asthma. Because these drug-drug interactions have not previously been relevant to patient care, clinicians have had no guidance on management strategies to reduce potentially serious interactions between treatments for asthma and COVID-19. The Precision Interventions for Severe and/or Exacerbation-Prone Asthma network considered the available literature and product information, and herein share our considerations and plans for treating asthma within the context of these novel COVID-19–related therapies. The Precision Interventions for Severe and/or Exacerbation-Prone Asthma clinical trials network is actively assessing novel treatments for severe asthma during the coronavirus disease (COVID-19) pandemic and has needed to adapt to various clinical dilemmas posed by the COVID-19 pandemic. Pharmacologic interactions between established asthma therapies and novel drug interventions for COVID-19 infection, including antivirals, biologics, and vaccines, have emerged as a critical and unanticipated issue in the clinical care of asthma. In particular, impaired metabolism of some long-acting beta-2 agonists by the cytochrome P4503A4 enzyme in the setting of antiviral treatment using ritonavir-boosted nirmatrelvir (NVM/r, brand name Paxlovid) may increase risk for adverse cardiovascular events. Although available data have documented the potential for such interactions, these issues are largely unappreciated by clinicians who treat asthma, or those dispensing COVID-19 interventions in patients who happen to have asthma. Because these drug-drug interactions have not previously been relevant to patient care, clinicians have had no guidance on management strategies to reduce potentially serious interactions between treatments for asthma and COVID-19. The Precision Interventions for Severe and/or Exacerbation-Prone Asthma network considered the available literature and product information, and herein share our considerations and plans for treating asthma within the context of these novel COVID-19–related therapies. The Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE Asthma) network, sponsored by the National Heart, Lung, and Blood Institute, is actively conducting phase II/proof-of-concept clinical trials of precision interventions in patients with severe and exacerbation-prone asthma.1Georas S.N. Wright R.J. Ivanova A. Israel E. LaVange L.M. Akuthota P. et al.The Precision Interventions for Severe and/or Exacerbation-Prone (PrecISE) Asthma Network: an overview of network organization, procedures, and interventions.J Allergy Clin Immunol. 2022; 149: 488-516.e9Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar In this protocol, participants in the study cohort use, as part of their baseline controller therapy for asthma, combination inhalers that contain both an inhaled corticosteroid (ICS) and a long-acting selective beta (2)-adrenoceptor agonist (LABA). This controller therapy is provided without charge to participants in the form of fluticasone, 500 μg per inhalation, and salmeterol, 50 μg per inhalation (Advair, donated by GlaxoSmithKline), to be used twice daily. Interventions proposed within the trial include medications with potential for immunomodulation or immunosuppression, such as imatinib, an inhibitor of c-kit, and clazakizumab, an mAb directed against IL-6. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease 2019 [COVID-19]) pandemic of early 2020 coincided with the beginning of active recruitment for PrecISE Asthma, which was subsequently halted. The investigators of PrecISE Asthma were tasked with identifying institutionally and regionally appropriate policies for testing, masking, and conducting in-person procedures, with a focus on participant and staff safety. The PrecISE Asthma Safety Committee was responsible for identifying potential interactions between the asthma interventions in PrecISE Asthma and varied exposures, including vaccination for COVID-19, which was prioritized for this high-risk population. As the COVID-19 pandemic continues and therapies for this infection have evolved, a new clinical situation has emerged. We and the asthma community at large are encountering patients who contract SARS-CoV-2 infection and are being considered for therapy with ritonavir-boosted nirmatrelvir (NVM/r, brand name Paxlovid) treatment. However, the NVM/r prescribing information warns of drug-drug interactions with any agent metabolized by cytochrome enzyme P4503A4 (CYP3A4).2Paxlovid [package insert]. Pfizer, Inc, New York, NY2022Google Scholar Popular COVID-19 advisory websites such as the Ontario Science Table3Science Table COVID-19 Advisory for Ontario.https://covid19-sciencetable.caDate accessed: September 29, 2022Google Scholar (https://covid19-sciencetable.ca) and the University of Liverpool COVID-19 Drug Interactions website4COVID-19 drug interactions: University of Liverpool.https://www.covid19-druginteractions.orgDate accessed: September 29, 2022Google Scholar (https://www.covid19-druginteractions.org) specifically warn to avoid the use of salmeterol when prescribing NVM/r for COVID-19 infection. The PrecISE Asthma Safety Committee has carefully reviewed this interaction and has considered available literature regarding other potential drug-drug interactions for the treatment of COVID-19 in patients with asthma and has created recommendations for managing these interactions for our research study participants. Herein, we share our findings and offer management recommendations for implementation by providers who treat patients with asthma. The cytochrome p450 family of super enzymes functions as monooxygenases, oxidizing a large number of compounds and xenobiotics including fatty acids, steroid hormones, naturally occurring chemical compounds, and pharmaceuticals.5Li A.P. Kaminski D.L. Rasmussen A. Substrates of human hepatic cytochrome P450 3A4.Toxicology. 1995; 104: 1-8Crossref PubMed Scopus (329) Google Scholar,6Guengerich F.P. Cytochrome P-450 3A4: regulation and role in drug metabolism.Annu Rev Pharmacol Toxicol. 1999; 39: 1-17Crossref PubMed Scopus (1070) Google Scholar These enzymes are responsible for a large amount of drug metabolism and clearance, along with some prodrug activation. A number of drugs and other compounds, such as chemicals found in grapefruit juice (furanocoumarins), can alter the activity of cytochrome P450 enzymes. Increasing or inhibiting enzyme activity can markedly affect the pharmacokinetics and risk profiles of medications metabolized by those enzymes. CYP3A4 is the most highly expressed isoform of the cytochrome p450 system in humans and is responsible for metabolism of a large proportion of common medications.7Zanger U.M. Klein K. Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance.Front Genet. 2013; 4: 24Crossref PubMed Scopus (230) Google Scholar The enzyme is highly expressed in the small intestine and in hepatocytes,5Li A.P. Kaminski D.L. Rasmussen A. Substrates of human hepatic cytochrome P450 3A4.Toxicology. 1995; 104: 1-8Crossref PubMed Scopus (329) Google Scholar,6Guengerich F.P. Cytochrome P-450 3A4: regulation and role in drug metabolism.Annu Rev Pharmacol Toxicol. 1999; 39: 1-17Crossref PubMed Scopus (1070) Google Scholar,8Leeder J.S. Gaedigk A. Lu X. Cook V.A. Epitope mapping studies with human anti-cytochrome P450 3A antibodies.Mol Pharmacol. 1996; 49: 234-243PubMed Google Scholar but the lung also has significant expression.9Anttila S. Hukkanen J. Hakkola J. Stjernvall T. Beaune P. Edwards R.J. et al.Expression and localization of CYP3A4 and CYP3A5 in human lung.Am J Respir Cell Mol Biol. 1997; 16: 242-249Crossref PubMed Scopus (139) Google Scholar CYP3A4 has a broad capacity for oxidative metabolism and can accommodate various structurally diverse substrates.10Sevrioukova I.F. Poulos T.L. Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir.Proc Natl Acad Sci U S A. 2010; 107: 18422-18427Crossref PubMed Scopus (201) Google Scholar Polymorphisms in CYP3A4 may contribute to interperson variability in enzyme activity.7Zanger U.M. Klein K. Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance.Front Genet. 2013; 4: 24Crossref PubMed Scopus (230) Google Scholar,11Krishna D.R. Shekar M.S. Cytochrome P450 3A: genetic polymorphisms and inter-ethnic differences.Methods Find Exp Clin Pharmacol. 2005; 27: 559-567Crossref PubMed Scopus (26) Google Scholar Ritonavir, a protease inhibitor originally developed as part of the highly active antiretroviral therapy for HIV treatment,12Danner S.A. Carr A. Leonard J.M. Lehman L.M. Gudiol F. Gonzales J. et al.A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. European-Australian Collaborative Ritonavir Study Group.N Engl J Med. 1995; 333: 1528-1533Crossref PubMed Scopus (527) Google Scholar,13Markowitz M. Saag M. Powderly W.G. Hurley A.M. Hsu A. Valdes J.M. et al.A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection.N Engl J Med. 1995; 333: 1534-1539Crossref PubMed Scopus (466) Google Scholar is perhaps the most potent known inhibitor of CYP3A4 developed to date. This molecule has been been shown to irreversibly bind to the heme portion of the enzyme, preventing reduction functions and inhibiting binding of other molecules to the active site (Fig 1).10Sevrioukova I.F. Poulos T.L. Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir.Proc Natl Acad Sci U S A. 2010; 107: 18422-18427Crossref PubMed Scopus (201) Google Scholar Because of this, ritonavir acts as a pharmacologic boost to other drugs metabolized by CYP3A4, such as in the case of highly active antiretroviral therapy, where ritonavir enhances the pharmacokinetics of antiviral agents and thereby improves clinical efficacy.14Xu L. Desai M.C. Pharmacokinetic enhancers for HIV drugs.Curr Opin Investig Drugs. 2009; 10: 775-786PubMed Google Scholar In a similar way, ritonavir added to nirmatrelvir, a protease inhibitor with activity against SARS-CoV-2 (NVM/r, Paxlovid), improves the clinical activity of the latter 5-fold through achieving higher sustained serum concentrations, and forms the basis of combination therapy in the treatment of early COVID-19 infection.15Hammond J. Leister-Tebbe H. Gardner A. Abreu P. Bao W. Wisemandle W. et al.Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19.N Engl J Med. 2022; 386: 1397-1408Crossref PubMed Scopus (599) Google Scholar Inhibition of CYP3A4 by ritonavir occurs within 48 hours of dosing. Because the molecule irreversibly binds to the enzyme, de novo enzyme synthesis is required to restore CYP3A4 function. Marzolini et al16Marzolini C. Kuritzkes D.R. Marra F. Boyle A. Gibbons S. Flexner C. et al.Recommendations for the management of drug-drug interactions between the COVID-19 antiviral nirmatrelvir/ritonavir (Paxlovid) and comedications.Clin Pharmacol Ther. 2022; 112: 1191-1200Crossref PubMed Scopus (34) Google Scholar recommend, on the basis of modeling data, that medications held during ritonavir therapy could be restarted 3 to 5 days after the last dose of ritonavir. These recommendations acknowledged that approximately 80% of enzyme function would return within 3 days, but that because of interpatient variability, a 5-day window would reduce the likelihood of interaction. Also, ritonavir is known to induce expression of non-CYP3A4 enzymes, thereby reducing levels of medications metabolized through those pathways. Maximal induction occurs after approximately 1 week of therapy, but the extent of impact is dependent on the pharmacologic parameters and dosing of those affected medications, and less well quantified.17Ramsden D. Fung C. Hariparsad N. Kenny J.R. Mohutsky M. Parrott N.J. et al.Perspectives from the Innovation and Quality Consortium Induction Working Group on factors impacting clinical drug-drug interactions resulting from induction: focus on cytochrome 3A substrates.Drug Metab Dispos. 2019; 47: 1206-1221Crossref PubMed Scopus (14) Google Scholar Although the clinical significance of this induction is not well understood, it is thought to be of minimal impact given the short duration of NVM/r therapy for COVID-19. Several other drugs are known to inhibit CYP3A4 and thus have the same considerations regarding drug dosing as does ritonavir. Indeed, antifungal agents such as ketoconazole, an imidazole drug, has been used as a standard agent to test the involvement of CYP3A4 in drug metabolism in preclinical pharmacokinetic investigations, and on binding to CYP3A4 has a structure similar to that of ritonavir-bound CYP3A4.10Sevrioukova I.F. Poulos T.L. Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir.Proc Natl Acad Sci U S A. 2010; 107: 18422-18427Crossref PubMed Scopus (201) Google Scholar Other common clinical agents with known activity against CYP3A4 that may be encountered in the treatment of patients with asthma include macrolide antibiotics such as erythromycin, clarithromycin, and azithromycin.18Rowland Yeo K. Walsky R.L. Jamei M. Rostami-Hodjegan A. Tucker G.T. Prediction of time-dependent CYP3A4 drug-drug interactions by physiologically based pharmacokinetic modelling: impact of inactivation parameters and enzyme turnover.Eur J Pharm Sci. 2011; 43: 160-173Crossref PubMed Scopus (86) Google Scholar, 19Westphal J.F. Macrolide-induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin.Br J Clin Pharmacol. 2000; 50: 285-295Crossref PubMed Scopus (173) Google Scholar, 20Zhou S.F. Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4.Curr Drug Metab. 2008; 9: 310-322Crossref PubMed Scopus (520) Google Scholar The inhibitory effect of azithromycin on CYP3A4 may be less than that of other macrolides,21Polasek T.M. Miners J.O. Quantitative prediction of macrolide drug-drug interaction potential from in vitro studies using testosterone as the human cytochrome P4503A substrate.Eur J Clin Pharmacol. 2006; 62: 203-208Crossref PubMed Scopus (75) Google Scholar and may be context specific, depending on the substrate. In summary, clinicians may encounter CYP3A4 inhibition with drugs other than ritonavir when treating patients with asthma. The potential risks of CYP3A4 inhibition on a CYP3A4-metabolized comedication relates to that drug’s mechanism of action and the range of its therapeutic window. The side effects of asthma medications will increase proportionally in the setting of higher sustained drug levels. For asthma medications, considerations regarding side effects will also rely on the duration of ritonavir therapy. In chronic antiretroviral treatment with ritonavir (eg, for the treatment of HIV infection), long-term asthma controller therapy should be carefully selected to minimize interactions and side effects. Table I summarizes the risk of CYP3A4 inhibitors on commonly used asthma medications.Table IRisk of CYP3A4 inhibitors with asthma medicationRepresentative CYP3A4 inhibitorsDrug class of asthma medicationAsthma medicationsLikely to be affected by CYP3A4 inhibitionPossibly affected by CYP3A4 inhibition∗Monitoring for side effects during use of strong CYP3A4 inhibitor is suggested.Unlikely to be affected by CYP3A4 inhibitionRitonavir, and other protease inhibitorsLABASalmeterol VilanterolOlodaterolFormoterolKetoconazole, and other imidazole antifungalsShort-acting beta2-adrenergic agonistAlbuterolClarithromycin, and other macrolide antibioticsCorticosteroidFluticasoneMethylprednisoloneBudesonideMometasoneTriamcinoloneBeclomethasonePrednisoneCimetidine, RanitidineLong-acting muscarinic antagonistTiotropiumUmeclidiniumAclidiniumDiltiazemMacrolide antibioticClarithromycinAzithromycinCyclosporineOtherMontelukastTheophylline†Theophylline serum levels may decrease due to ritonavir induction of CYP1A2.FluoxetineGrapefruit JuiceAsthma biologicsOmalizumabMepolizumabReslizumabBenralizumabDupilumabTezepelumab∗ Monitoring for side effects during use of strong CYP3A4 inhibitor is suggested.† Theophylline serum levels may decrease due to ritonavir induction of CYP1A2. Open table in a new tab Salmeterol, vilanterol, olodaterol, and formoterol are inhaled LABAs commonly prescribed in combination inhalers to treat patients with asthma and chronic obstructive pulmonary disease. Although previous Global INitiative for Asthma guidelines considered the use of different ICS-LABA combinations as equivalent, the most recent Global INitiative for Asthma guidelines recommend the use of ICS-formoterol combinations as “initial track” therapy for asthma and other LABAs combined with ICS as “alternative track” therapy.22Global INitiative for Asthma. Global strategy for asthma management and prevention. Available at: www.ginasthma.org. Accessed October 14, 2022.Google Scholar Yet, many patients with asthma receive ICS-LABA combinations that contain salmeterol or vilanterol as the LABA agent. Systemic absorption of LABAs occurs from oropharyngeal membranes, the airway mucosa, and the gastrointestinal tract. Major potential side effects of systemic LABA exposure include cardiovascular toxicity such as tachycardia, palpitations, and prolonged QT interval. Ritonavir will not affect the plasma concentrations of either formoterol or olodaterol because these drugs are not metabolized by CYP3A4 (non–CYP3A4-metabolized LABAs). Similarly, albuterol, a short-acting beta agonist, is not metabolized by CYP3A4 and has no known interaction with ritonavir. In contrast, both salmeterol and vilanterol are metabolized by CYP3A4; thus, concentrations may be increased by CYP3A4 inhibition.23Cazzola M. Testi R. Matera M.G. Clinical pharmacokinetics of salmeterol.Clin Pharmacokinet. 2002; 41: 19-30Crossref PubMed Scopus (84) Google Scholar,24Kempsford R. Allen A. Bal J. Rubin D. Tombs L. The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of inhaled fluticasone furoate and vilanterol trifenatate in healthy subjects.Br J Clin Pharmacol. 2013; 75: 1478-1487Crossref PubMed Scopus (29) Google Scholar Kempsford et al24Kempsford R. Allen A. Bal J. Rubin D. Tombs L. The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of inhaled fluticasone furoate and vilanterol trifenatate in healthy subjects.Br J Clin Pharmacol. 2013; 75: 1478-1487Crossref PubMed Scopus (29) Google Scholar published the pharmacodynamic study of fluticasone furoate and vilanterol trifenatate with ketoconazole. In healthy participants, vilanterol plasma concentrations were increased by 65% with ketoconazole coadministration, with no change in heart rate but slight increase in mean QT interval. No participants had QT prolongation to intervals of concern. Salmeterol prescribing information describes a placebo-controlled, crossover study of 20 healthy subjects receiving salmeterol with or without ketoconazole.25Advair [package insert]. GlaxoSmithKline, Research Triangle Park, NC2008Google Scholar In this study, plasma exposure to salmeterol was increased 16-fold with ketoconazole administration. Three subjects had to discontinue coadministration because of adverse effects of QT prolongation or sinus tachycardia. Although mean heart rate and QT interval were not different between the placebo and ketoconazole groups, some individuals had outlier events. These data suggest that there will be individuals susceptible to potentially harmful cardiovascular effects of increased systemic salmeterol concentrations seen following CYP3A4 inhibition. The PrecISE Asthma Steering Committee recognizes that the risk for adverse cardiac side effects from salmeterol or vilanterol during therapy with a CYP3A4 inhibitor such as ritonavir may vary with individual susceptibility factors. Clinicians are not able to predict which patients will develop an adverse therapeutic response, however, and there is an approximately 15% rate of significant adverse cardiovascular outcomes. Therefore, the PrecISE Asthma Safety Committee decided that the risk of continuing salmeterol or vilanterol therapy during treatment with ritonavir is unacceptable. Therefore, participants receiving ritonavir therapy as part of NVM/r for COVID-19 in the PrecISE Asthma protocol will discontinue the use of salmeterol- and vilanterol-containing inhalers as soon as possible after initiation of ritonavir. For patients with severe asthma who require the use of ICS/LABA for asthma control, we recommend alternate therapy using either budesonide-formoterol or mometasone-formoterol. For patients with less severe disease, ICSs with or without long-acting muscarinic antagonists could be used as alternatives to ICS/LABA therapy in the setting of NVM/r dosing, as discussed below. On the basis of aforementioned pharmacokinetics, patients should use this alternative therapy for at least 5 days after completing NVM/r dosing. Because NVM/r can be prescribed by physicians and pharmacists and is likely to be prescribed by a practitioner outside our research network, we provide anticipatory education to all participants about this interaction. We also acknowledge that payers impose prescribing limitations that may variably affect access to alternative inhalers; patient advocacy (eg, the use of “prior authorization” mechanisms) may be necessary to ensure that patients receive appropriate alternative medication in a timely manner. National and international guidelines recommend the benefit of ICS therapy for prevention and control of asthma at all severity levels.22Global INitiative for Asthma. Global strategy for asthma management and prevention. Available at: www.ginasthma.org. Accessed October 14, 2022.Google Scholar,26Cloutier M.M. Baptist A.P. et al.Expert Panel Working Group of the National Heart, Lung, and Blood Institute, coordinated National Asthma Education and Prevention Program Coordinating Committee2020 Focused Updates to the Asthma Management Guidelines: a report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group.J Allergy Clin Immunol. 2020; 146: 1217-1270Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar Ideally, long-term use of locally acting, minimally absorbed ICSs with extensive first-pass metabolism and clearance by CYP3A4 is preferable to intermittent systemic steroid dosing both for the morbidity related to exacerbations and for the long-term risk of cumulative steroid systemic side effects. Indeed, maintenance and reliever therapy with ICS-formoterol preparation was shown to be safe, even at higher daily doses.27Reddel H.K. Bateman E.D. Schatz M. Krishnan J.A. Cloutier M.M. A practical guide to implementing SMART in asthma management.J Allergy Clin Immunol Pract. 2022; 10: S31-S38Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar With such evidence, the current 2022 Global INitiative for Asthma guidelines recommend the use of ICSs, in combination with formoterol when possible, as a primary controller medication to be initiated as soon as possible after asthma diagnosis. It has been well established that ICSs can be absorbed into the bloodstream; as with LABA, this occurs via the oropharyngeal membranes and by transfer from the airway mucosa, peripheral airways, and the gastrointestinal tract.28Selroos O. Halme M. Effect of a volumatic spacer and mouth rinsing on systemic absorption of inhaled corticosteroids from a metered dose inhaler and dry powder inhaler.Thorax. 1991; 46: 891-894Crossref PubMed Scopus (114) Google Scholar Generally, the amount of ICS in plasma leads to minimal side effects, but even with ordinary use, adrenal suppression can occur with side effects that include thinning skin, cataracts, and weight gain.29Broersen L.H. Pereira A.M. Jorgensen J.O. Dekkers O.M. Adrenal insufficiency in corticosteroids use: systematic review and meta-analysis.J Clin Endocrinol Metab. 2015; 100: 2171-2180Crossref PubMed Scopus (250) Google Scholar, 30Allen D.B. Effects of inhaled steroids on growth, bone metabolism, and adrenal function.Adv Pediatr. 2006; 53: 101-110Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 31Dluhy R.G. Clinical relevance of inhaled corticosteroids and HPA axis suppression.J Allergy Clin Immunol. 1998; 101: S447-S450Abstract Full Text Full Text PDF PubMed Google Scholar These side effects may be dramatically increased by inhibition of drug metabolism, such as in the case of CYP3A4 inhibition by ritonavir. In 2008, Foisy et al32Foisy M.M. Yakiwchuk E.M. Chiu I. Singh A.E. Adrenal suppression and Cushing’s syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature.HIV Med. 2008; 9: 389-396Crossref PubMed Scopus (139) Google Scholar published a literature review of adrenal suppression or Cushing’s syndrome from fluticasone therapy in the setting of chronic ritonavir use for highly active antiretroviral therapy. In this review, 25 published cases detailed characteristics of this interaction. Both intranasal and inhaled fluticasone preparations were implicated, and 10 cases were found in the pediatric age group. Onset of symptoms for patients taking inhaled fluticasone was as early as within the first month, but usually required 2 to 5 months after comedication. Most patients had biochemical evidence of adrenal suppression. Since that time, case reports continue to be published,33Tiruneh F. Awan A. Didana A. Doshi S. Preventing Cushing: iatrogenic Cushing syndrome due to ritonavir-fluticasone interaction.Cureus. 2017; 9: e1484PubMed Google Scholar reinforcing that this interaction may still be underappreciated by clinicians.34Brennan V. Martin-Grace J. Greene G. Heverin K. Mulvey C. McCartan T. et al.The contribution of oral and inhaled glucocorticoids to adrenal insufficiency in asthma.J Allergy Clin Immunol Pract. 2022; 10: 2614-2623Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Package inserts for fluticasone furoate– and fluticasone proprionate–containing inhalers warn of the potential for increased systemic exposure, generally expressed as the area under the curve of drug levels over time, during coadministration with ketoconazole, which strongly inhibits CYP3A4.25Advair [package insert]. GlaxoSmithKline, Research Triangle Park, NC2008Google Scholar,35Breo [package insert]. GlaxoSmithKline, Research Triangle Park, NC2019Google Scholar In the aforementioned study by Kempsford et al,24Kempsford R. Allen A. Bal J. Rubin D. Tombs L. The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of inhaled fluticasone furoate and vilanterol trifenatate in healthy subjects.Br J Clin Pharmacol. 2013; 75: 1478-1487Crossref PubMed Scopus (29) Google Scholar the authors found a 36% increase in steroid exposure with coadministration of ketoconazole, and an associated 27% reduction in mean serum cortisol, concluding the possibility for an increased risk of adverse reactions. Prescribing information for fluticasone propionate states that coadministration with ketoconazole increases plasma fluticasone propionate exposure and reduces plasma cortisol exposure; however, this had no effect on urinary excretion of cortisol.25Advair [package insert]. GlaxoSmithKline, Research Triangle Park, NC2008Google Scholar Similarly, fluticasone propionate nasal spray coadministered with ritonavir showed a marked increase in serum levels that approached 1 to 2 orders of magnitude and an 86% reduction in serum cortisol concentrations, suggesting clinically significant adrenal- suppressive effects.36Flonase [package insert]. GlaxoSmithKline, Research Triangle Park, NC2003Google Scholar Seymour et al37Seymour N. Robinson M. Richardson D. Mohammed H. Williams D. McGilligan J.A. Prescribing intranasal steroids in HIV-positive patients: systematic review of the literature.J Laryngol Otol. 2021; 135: 755-758Crossref PubMed Scopus (3) Google Scholar reviewed case reports of Cushing’s syndrome related to intranasal steroids in patients taking ritonavir. Most reported cases were seen with fluticasone intranasal preparations and were reported months after the onset of comedication.37Seymour N. Robinson M. Richardson D. Mohammed H. Williams D. McGilligan J.A. Prescribing intranasal steroids in HIV-positive patients: systematic review of the literature.J Laryngol Otol. 2021; 135: 755-758Crossref PubMed Scopus (3) Google Scholar One study showed that exposure to orally administered budesonide was increased 6-fold with ketoconazole comedication.38Seidegard J. Reduction of the inhibitory effect of ketoconazole on budesonide pharmacokinetics by separation of their time of" @default.
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• W4311457585 title "Treating asthma in the time of COVID" @default.
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• W4311457585 doi "https://doi.org/10.1016/j.jaci.2022.12.800" @default.
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