Tocilizumab in COVID-19: finding the optimal route and dose – Authors' reply
Authors: Giovanni Guaraldi, Jovana Milic, Alessandro Cozzi-Lepri, Federico Pea, Cristina Mussini
Journal: The Lancet Rheumatology (2020)

We thank Siddharth Jain and colleagues for their interest in our Article;1Guaraldi G Meschiari M Cozzi-Lepri A et al.Tocilizumab in patients with severe COVID-19: a retrospective cohort study.Lancet Rheumatol. 2020; 2: e474-e484Summary Full Text Full Text PDF PubMed Scopus (717) Google Scholar they underline that in the Tocilizumab in Patients with Severe COVID-19 Pneumonia (TESEO) cohort, there was no difference in efficacy of the subcutaneous tocilizumab formulation compared with the intravenous route, and they advocate for use of the subcutaneous formulation due to an approximately six-times cost reduction. However, we argue that intravenous administration has other advantages—eg, a pharmacokinetic profile that is more linear and predictable compared with the subcutaneous formulation, for which proteolytic degradation can be variable. Additionally, elevated levels of interleukin (IL)-6 might downregulate hepatic cytochromes,2Morgan ET Impact of infectious and inflammatory disease on cytochrome P450-mediated drug metabolism and pharmacokinetics.Clin Pharmacol Ther. 2009; 85: 434-438Crossref PubMed Scopus (373) Google Scholar which could promote enhanced drug exposure, as has been recently postulated for darunavir.3Cojutti PG Londero A Della Siega P et al.Comparative population pharmacokinetics of darunavir in SARS-CoV-2 patients vs HIV patients: the role of interleukin-6.Clin Pharmacokinet. 2020; (published online Aug 27.)https://doi.org/10.1007/s40262-020-00933-8Crossref PubMed Scopus (24) Google Scholar Consistently, we believe that prospective pharmacokinetic studies comparing different administration routes are needed to address both appropriate dose finding and safety. A formal cost-effectiveness analysis should also be considered. We agree that determining the optimal time for tocilizumab administration in patients with COVID-19 is crucial. While a beneficial effect of tocilizumab on mortality has been shown in observational studies, a recent randomised trial (NCT04320615) did not confirm these results. Besides unmeasured confounding, the case mix of the target population, number of doses, and the timing of the intervention are other possible reasons for the conflicting results between observational and randomised studies. Assuming that a causal link could be established, the question of when it is best to start tocilizumab treatment should be addressed in a randomised study. Emulation of such a trial in an observational setting would require sophisticated methodology beyond that used in our study,1Guaraldi G Meschiari M Cozzi-Lepri A et al.Tocilizumab in patients with severe COVID-19: a retrospective cohort study.Lancet Rheumatol. 2020; 2: e474-e484Summary Full Text Full Text PDF PubMed Scopus (717) Google Scholar as well as a collaborative setting with a much larger sample size. A simple correlation analysis is unlikely to produce the answer that we need. Regarding the need for monitoring patients with severe renal impairment, in the TESEO cohort, chronic kidney disease was found in 14 participants at hospital admission, seven (50%) of whom received tocilizumab.1Guaraldi G Meschiari M Cozzi-Lepri A et al.Tocilizumab in patients with severe COVID-19: a retrospective cohort study.Lancet Rheumatol. 2020; 2: e474-e484Summary Full Text Full Text PDF PubMed Scopus (717) Google Scholar The primary endpoint of invasive ventilation or death was observed in four (57%) of seven patients in the tocilizumab plus standard care group and in three (43%) of seven patients in the standard care group (p=1·0). Of the seven patients who experienced the endpoint, all but one (who was treated with tocilizumab) have died. Therefore, our data, although limited to few patients, suggest that tocilizumab use was not harmful in this subgroup. To conclude, the challenge of appropriate tocilizumab use rests on the prediction of progression of respiratory failure in people who develop a cytokine storm. This is typically accompanied by so-called respiratory crush, which is unlikely to be captured by chest radiology. Indeed, a recent study showed little benefit with this regard.4Colombi D Bodini FC Petrini M et al.Well-aerated lung on admitting chest CT to predict adverse outcome in COVID-19 pneumonia.Radiology. 2020; 296: e86-e96Crossref PubMed Scopus (345) Google Scholar To identify these patients, it might be possible to rely on a machine learning algorithm that we recently developed, which provides a trustworthy 48-h prediction of severe respiratory failure, with satisfactory accuracy.5Ferrari D Milic J Tonelli R et al.Machine learning in predicting respiratory failure in patients with COVID-19 pneumonia—challenges, strengths, and opportunities in a global health emergency.medRxiv. 2020; (published online June 3.) (preprint)https://doi.org/10.1101/2020.05.30.20107888PubMed Google Scholar We declare no competing interests. Tocilizumab in patients with severe COVID-19: a retrospective cohort studyTreatment with tocilizumab, whether administered intravenously or subcutaneously, might reduce the risk of invasive mechanical ventilation or death in patients with severe COVID-19 pneumonia. Full-Text PDF Tocilizumab in COVID-19: finding the optimal route and doseThe Tocilizumab in Patients with Severe COVID-19 Pneumonia (TESEO) study by Giovanni Guaraldi and colleagues1 provides vital information regarding the benefits of tocilizumab in severe pneumonia due to COVID-19. However, certain aspects of the study warrant deliberation in greater detail. Full-Text PDF