Aims: We aim to evaluate the clinical pharmacokinetics of a single dose interleukin-6 (IL-6) antibody tocilizumab (TCZ) in methylprednisolone (MP)-treated COVID-19 patients with cytokine storm... Show moreAims: We aim to evaluate the clinical pharmacokinetics of a single dose interleukin-6 (IL-6) antibody tocilizumab (TCZ) in methylprednisolone (MP)-treated COVID-19 patients with cytokine storm syndrome (CSS). Methods: MP pre-treated patients with COVID-19-associated CSS, defined as at least two elevations of C-reactive protein (CRP) >100 mg/L, ferritin >900 mu g/L or D-dimers >1500 mu g/L, received intravenous TCZ (8 mg/kg, max. 800 mg) upon clinical deterioration. A nonlinear-mixed effects model was developed based on TCZ serum concentrations and dosing information. Population pharmacokinetic parameters were estimated and concentration-time profiles were plotted against individual predicted values. Fixed dose simulations were subsequently performed based on the final model. Results:In total 40 patients (mean [SD] age: 62 [12] years, 20% female, body weight: 87 [17] kg) with COVID-19 induced CSS were evaluated on pharmacokinetics and laboratory parameters. A biphasic elimination of TCZ serum concentration was described by a homogeneous population pharmacokinetic model. Serum TCZ concentrations above the 1 mu g/L target saturation threshold were covered for 16 days in all evaluated patients treated with a single dose of 8 mg/kg. In a simulation with TCZ 400 mg fixed dose, this condition of full IL-6 receptor occupancy at minimum serum concentration was also met. Conclusions: A single dose (8 mg/kg, max. 800 mg) is sufficient to cover a period of 16 days of IL-6-mediated hyperinflammation in COVID-19-induced CSS in MP-treated patients. Based on body weight PK simulations, a fixed-dose tocilizumab of 400 mg should be considered to prevent overtreatment, future drug shortage and unnecessary drug expenditure. Show less
Background: We systematically reviewed the literature to answer the following research questions: (1) Does interleukin 6 (IL-6) (receptor) antagonist therapy reduce mortality in coronavirus disease... Show moreBackground: We systematically reviewed the literature to answer the following research questions: (1) Does interleukin 6 (IL-6) (receptor) antagonist therapy reduce mortality in coronavirus disease 2019 (COVID-19) patients compared to patients not treated with IL-6 (receptor) antagonists; and (2) is there an increased risk of side effects in COVID-19 patients treated with IL-6 (receptor) antagonists compared to patients not treated with IL-6 (receptor) antagonists?Methods: We systematically searched PubMed, PMC PubMed Central, Medline, World Health Organization COVID-19 Database, Embase, Web of Science, Cochrane Library, Emcare, and Academic Search Premier (through 30 June 2020). Random effects meta-analysis was used to pool the risk ratios and risk differences of individual studies. Risk of bias was appraised using the Methodological Index for Non-randomized Studies (MINORS) checklist.Results: The search strategy retrieved 743 unique titles, of which 10 studies (all on tocilizumab [TCZ]) comprising 1358 patients were included. Nine of 10 studies were considered to be of high quality. Meta-analysis showed that the TCZ group had lower mortality than the control group. The risk ratio was 0.27 (95% confidence interval [CI], .12-.59) and the risk difference was 12% (95% CI, 4.6%-20%) in favor of the TCZ group. With only a few studies available, there were no differences observed regarding side effects.Conclusions: Our results showed that mortality was 12% lower for COVID-19 patients treated with TCZ compared with those not treated with TCZ. The number needed to treat was 11, suggesting that for every 11 (severe) COVID-19 patients treated with TCZ, 1 death is prevented. These results require confirmation by randomized controlled trials. Show less
Elens, L.; Langman, L.J.; Hesselink, D.A.; Bergan, S.; Moes, D.J.A.R.; Molinaro, M.; ... ; Lemaitre, F. 2020
Background: COVID-19 is a novel infectious disease caused by the severe acute respiratory distress (SARS)-coronavirus-2 (SARS-CoV-2). Several therapeutic options are currently emerging but none... Show moreBackground: COVID-19 is a novel infectious disease caused by the severe acute respiratory distress (SARS)-coronavirus-2 (SARS-CoV-2). Several therapeutic options are currently emerging but none with universal consensus or proven efficacy. Solid organ transplant recipients are perceived to be at increased risk of severe COVID-19 because of their immunosuppressed conditions due to chronic use of immunosuppressive drugs (ISDs). It is therefore likely that solid organ transplant recipients will be treated with these experimental antivirals. Methods: This article is not intended to provide a systematic literature review on investigational treatments tested against COVID-19; rather, the authors aim to provide recommendations for therapeutic drug monitoring of ISDs in transplant recipients infected with SARS-CoV-2 based on a review of existing data in the literature. Results: Management of drug-drug interactions between investigational anti-SARS-CoV-2 drugs and immunosuppressants is a complex task for the clinician. Adequate immunosuppression is necessary to prevent graft rejection while, if critically ill, the patient may benefit from pharmacotherapeutic interventions directed at limiting SARS-CoV-2 viral replication. Maintaining ISD concentrations within the desired therapeutic range requires a highly individualized approach that is complicated by the pandemic context and lack of hindsight. Conclusions: With this article, the authors inform the clinician about the potential interactions of experimental COVID-19 treatments with ISDs used in transplantation. Recommendations regarding therapeutic drug monitoring and dose adjustments in the context of COVID-19 are provided. Show less
