key: cord-0843133-dhc36q9o
authors: Corcione, Silvia; De Nicolò, Amedeo; Montrucchio, Giorgia; Scabini, Silvia; Avataneo, Valeria; Bonetto, Chiara; Mornese Pinna, Simone; Cusato, Jessica; Canta, Francesca; Urbino, Rosario; Di Perri, Giovanni; Brazzi, Luca; De Rosa, Francesco Giuseppe; D'Avolio, Antonio
title: Real life Study on the Pharmacokinetic of Remdesivir in ICU patients admitted for Severe COVID‐19 Pneumonia
date: 2021-05-14
journal: Br J Clin Pharmacol
DOI: 10.1111/bcp.14895
sha: e8a4ab1caefe94c50fc344bb442b7b35bcbdf651
doc_id: 843133
cord_uid: dhc36q9o

Remdesivir is one of the most encouraging treatments against SARS‐CoV‐2 infection. After intravenous infusion, RDV is rapidly metabolized (T(1/2) 1h) within the cells to its active adenosine triphosphate analogue form (GS‐443902) and, then, it can be found in plasma in its nucleoside analogue form (GS‐441524). In this real life study we describe the Remdesivir and GS‐441524 concentrations at 3 time points in nine ICU patients, through a validated UHPLC‐MS/MS method. The observed data confirmed the very rapid conversion of RDV to its metabolite and the quite long half‐life of GS‐441524. The mean C (min), C (max), AUC(0–24), were < 0.24 ng/mL and 122.3 ng/ml, 2637,3 ng/mL and 157,8 ng/ml, 5171.2 ng*h/mL and 3676.5 ng*h/ml respectively for RDV and GS‐441524. Three out of nine patients achieved a C (max)> 2610 ng/mL and 140 ng/mL and AUC(0–24) > 1560 ng*h/mL and 2230 ng*h/mL for RDV and GS‐441524, respectively. The mean T1/2 value for GS‐441524 was 26.3 h. Although the low number of patients, these data can represent an interesting preliminary report of the variability of RDV and GS‐441524 concentrations in real‐life ICU setting.

In this real life study we describe the Remdesivir and GS-441524 concentrations at 3 time points in nine ICU patients, through a validated UHPLC-MS/MS method.

The observed data confirmed the very rapid conversion of RDV to its metabolite and the quite long half-life of GS-441524. The mean Cmin, Cmax, AUC0-24, were < 0.24 ng/mL and 122.3 ng/ml, 2637,3 ng/mL and 157,8 ng/ml, 5171.2 ng*h/mL and 3676.5 ng*h/ml respectively for RDV and GS-441524.

Three out of nine patients achieved a Cmax> 2610 ng/mL and 140 ng/mL and AUC0-24 > 1560 ng*h/mL and 2230 ng*h/mL for RDV and GS-441524, respectively. The mean T1/2 value for GS-441524 was 26.3 h. Although the low number of patients, these data can represent an interesting preliminary report of the variability of RDV and GS-441524 concentrations in reallife ICU setting.

Since the first cases were reported in December 2019, infection with the severe acute respiratory coronavirus 2 (SARS-CoV-2) has become a worldwide pandemic 1 . The symptoms of SARS-CoV-2 infection vary widely, from asymptomatic disease to pneumonia and lifethreatening complications, including acute respiratory distress syndrome and, in some cases, veno-venous extra corporeal membrane oxygenation (V-V-ECMO) 2-3 . In the absence of a proven effective therapy, current management consists of supportive care, and many patients have received off-label or compassionate-use therapies, including antivirals such as remdesivir (RDV), steroids or tocilizumab with debating results 4-6 .

RDV is a prodrug of a nucleotide analogue (GS-441524) that is metabolized within the cells to an analogue of adenosine triphosphate (GS-443902), that inhibits viral RNA polymerases.

RDV has broad-spectrum activity against members of several virus families, including filoviruses (e.g., Ebola) and coronaviruses (e.g., SARS-CoV and Middle East respiratory syndrome coronavirus [MERS-CoV]) and has shown prophylactic and therapeutic efficacy in nonclinical models of these coronaviruses [7] [8] . In vitro testing has also shown that RDV has activity against SARS-CoV-2 and data from literature described the possible benefits of early initiation of RDV, especially within 10 days from clinical symptom onset, in term of shorter time to recovery, along with low risk of side effects or adverse events compared to placebo or However, information about RDV pharmacokinetics (PK) in clinical practice is inadequate so far and no therapeutic or toxic ranges have been reported. In this report, we describe the pharmacokinetic of RDV and GS-441524 in a cohort of ICU patients hospitalized for severe Covid-19 pneumonia.

We included all ICU patients with acute respiratory distress syndrome (ARDS) due to SARS-CoV-2 and treated with RDV as compassionate use protocol, admitted to 'Città della Salute e della Scienza' Hospital in Turin (Italy), in charge of the management of severe respiratory failure in the Piedmont Region (Italy) and ECMO referral regional center. All patients were tested positive for SARS-COV-2 by real-time PCR on respiratory samples and transferred from peripheral hospital to our referral ICU center.

Patients were eligible to receive compassionate RDV administration if they were a male or non-pregnant female aged >18 years, had SARS-CoV-2 infection confirmed by a positive reverse-transcriptase polymerase chain reaction (RT-PCR) test of a respiratory tract sample and pneumonia confirmed by a chest X-ray or computed tomography (CT) scan, and were mechanically ventilated (i.e. intubated or tracheostomy). Patients were excluded if their alanine or aspartate aminotransferase level was >5 times the upper limit of the normal range and creatinine clearance was <30 mL/min.

Gilead together with the patient's clinical history. Written informed consent was obtained from all of the patients except those who were undergoing invasive mechanical ventilation, for whom the principle of urgency was applied. This study was approved by the Local Ethical In approved cases, the planned treatment was a 10-day course of RDV, consisting of a loading dose of 200 mg intravenously on day 1, plus 100 mg daily for the following 9 days. Supportive therapy was to be provided at the discretion of the clinicians, according to clinical and routine laboratory tests. Sequential Organ Failure Assessment (SOFA), Simplified Acute Physiology Score (SAPS) and Acute Physiologic Assessment and Chronic Health Evaluation (APACHE II) mean score at ICU admission were calculated for all patients.

Information regarding demographic and clinical characteristics were collected for each patient, including days of hospitalization, length of stay in the unit and ICU mortality.

Plasma RDV and GS-441524 concentrations were determined at steady-state 4 days after the beginning of therapy. The eligible time-points for blood sampling were at the end of infusion, after 15h and before the next infusion (24h). The Cmin corresponds to concentration before administration (T24h) and the Cmax was considered as the concentration at the end of the infusion. Pharmacokinetic parameters were calculated by Phoenix WinNonlin (ver. 8.1, Certara, NJ, USA) software. Due to the impossibility to perform intensive PK sampling on critical patients, the estimation of elimination t1/2 for GS-441524 was based on two points (period between 15-24 h), assuming a constant t1/2 at this late elimination timings, as reported in previous works [13] [14] [15] . The method was validated following FDA and EMA guidelines, showing contained bias and coefficients of variation (all <15% for both RDV and GS-441524) and good linearity (linear R 2 >0.996) [13] [14] [15] .

Nine patients were enrolled in the study. The main clinical characteristics were described in Table 1 . The majority of patients were male (6; 67%) with a median age of 56 years old (SD +7.3). Patients had few comorbidities, mostly obesity, with a mean BMI of 30 (SD +5) and hypertension. SOFA, SAPS and APACHE II mean score at ICU admission were respectively: 8, 56 and 22, while mean MuLBSTA score was 9. All patients were admitted to ICU due to ARDS caused by COVID-19 and were mechanical ventilated, five out of nine patients were treated with V-V ECMO support.

RDV was administered after a mean of 25 days from the onset of COVID-19 symptoms and after a mean of 15 days from ICU admission. All patients were previously treated with combination therapy of hydroxychloroquine, steroids, antivirals (mostly darunavir/cobicistat) or tocilizumab. ICU mortality rate was 66% (6). Among those patients, only one died within 28 days (28 days ICU mortality 11%; 1). No side effects have been reported during RDV administration.

The main RDV and GS-441524 PK parameters were reported in Table 2 . The mean Cmin, Cmax, AUC0-24, were 0 ng/mL and 122.3 ng/ml, 2637,3 ng/mL and 157,8 ng/ml, 5171.2 ng*h/mL and 3676.5 ng*h/ml respectively. GS-441524 exhibited a quite flat PK profile, suggesting a delayed tmax.

Three out of nine patients achieved a Cmax> 2610 ng/mL and 140 ng/mL and AUC0-24 > 1560 ng*h/mL and 2230 ng*h/mL for RDV and GS-441524, respectively. The mean T1/2 value for GS-441524 was 26.3 h, in strict concordance with previous preclinical PK studies [13] [14] [15] .

RDV is a prodrug of the C-adenosine nucleoside analogue GS-441524. showing clinical improvement, shortening time to recovery and a generally acceptable toxicity profile. These data generated a great deal of controversy, due to many limitations including the small sample size, the short duration of follow-up, missing data and the absence of a control group 17-19. In our real-life study, patients have few comorbidities, but BMI was high for the majority of them, supporting the association between obesity and severity of the disease and death among COVID-19 patients. Moreover, obesity may have affected PK parameters of RDV and GS-441524, leading to suboptimal concentration and distribution of the antiviral during treatment 19 . Further dedicated studies including intensive PK sampling on obese volunteers could be beneficial to better describe the specific impact of obesity on RDV PK. RDV was administered after a mean of 25 days from clinical symptoms and 15 days after ICU admission, since the majority of patients were transferred to our referral hospital from other peripheral centers. The delayed time of RDV administration, compared to those reported in other studies, was mainly due to the time needed to receive the drug in compassionate setting as well as to the arrival of the patients from peripheral hospital to the regional ECMO ICU, and may have had a negative impact on the survival rate. In fact, preclinical studies suggest that RDV has little benefit when administered after the peak in viral replication and, although the precise timing of peak viral loads was not available for our patients, it may be unfair to attribute any outcome when RDV was given beyond 10-12 days by the initial symptoms 20 .

So far, few data are available about the PK parameters of RDV in the clinical setting, and especially in ICU patients, in which pathophysiological changes and invasive procedures (e.g. ECMO, CVVH) affected the PK profile of drugs, leading to a suboptimal plasma concentration [21] [22] [23] [24] . Despite the low number and heterogeneity of patients, our data suggested a high interpatient variability in PK parameters of RDV and GS, which lead to obtain for 33% of patients Cmax and AUC values comparable to those reported in healthy volunteers 13 Moreover, in patients 7-9, very low RDV Cmax could be related to, other than the capillary leak syndrome, to the degradation of RDV by plasma esterases: this process could be increased by a delayed processing (eg. delayed transport from the ICU to the laboratory).

Our study has several limitations: first of all, the sample size, as well as the timing of treatment, deferred compared to the values of previous studies. From a PK perspective, we probably overestimated the AUC of RDV (its Cmin could be reached as soon as 2-3 hours) and probably underestimated the AUC of GS-441524 (delayed Tmax would be expected, due to metabolism of RDV), due to the lack of intermediate time points between T1 and T15. On the other hand, the description of Cmin for GS-441524, as well as its observed halflife, despite the poor number of data for its calculation (15h -24h), can be considered reliable: considering the fast conversion of the prodrug and the quite long halflife, GS-441524 could be the most practical and reliable marker of exposure and antiviral effect retrievable in plasma, also considering experience from other prodrugs of antiviral nucleosides (eg. anti-HCV Sofosbuvir) [26] [27] .

Moreover, since the plasma PK characteristics for a intracellular metabolized prodrug as RDV could have a limited correlation with its activity (eg. anti-HIV Tenofovir-alafenamide) 28 In conclusion, this is the first real-life report describing some preliminary PK data of RDV in ICU setting, showing a high interpatient variability with slow attainment of PK parameters reported in healthy volunteers, supporting the possible future relevance of therapeutic drug monitoring (TDM) in this setting.

These data may provide useful information to better define the best strategy to care for these challenging patients and may also provide a framework for much-needed future research about the management of these patients. Our experience seems to suggest, in fact, the need for strict TDM at least in the first days of RDV therapy for critically ill COVID-19 patients.

Funding: none to declare Conflict of interests: none to declare Table 2 . Main PK/PD characteristics of RDV and GS in ICU patients. RDV: remdesivir; GS: nucleotide analogue GS-441524. Undetectable results for RDV were reported as lower than the limit of detection (0.24 ng/mL for RDV).

novel coronavirus (2019-nCo) outbreak: A new challenge

Veno-venous Extracorporeal Membrane Oxygenation for Respiratory Failure in COVID-19 Patients: Early Experience From a Major Academic Medical Center in North America

Extracorporeal Life Support Organization. Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry

COVID-19) Treatment Guidelines. National Institutes of Health

Repurposed Antiviral Drugs for Covid-19 -Interim WHO Solidarity Trial Results

Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection

Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses

A randomized, controlled trial of Ebola virus disease therapeutics

Summary on compassionate use: Remdesivir Gilead

Effectiveness of remdesivir for the treatment of hospitalized COVID-19 persons: A network meta-analysis

Clinical efficacy and safety of remdesivir in patients with COVID-19: a systematic review and network metaanalysis of randomized controlled trials

Remdesivir: Review of Pharmacology, Preclinical Data, and Emerging Clinical Experience for COVID-19

Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

Pharmacodynamic, and Drug-Interaction Profile of Remdesivir, a SARS-CoV-2 Replication Inhibitor

Development and validation of a UHPLC-MS/MS method for quantification of the prodrug remdesivir and its metabolite GS-441524: a tool for clinical pharmacokinetics of SARS-CoV-2/COVID-19 and Ebola virus disease

ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19

Compassionate remdesivir treatment of severe Covid-19 pneumonia in intensive care unit (ICU) and Non-ICU patients: Clinical outcome and differences in post_treatment hospitalisation status

Compassionate Use of Remdesivir for Patients with Severe Covid-19

Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19

30-day mortality in patients hospitalized with COVID-19 during the first wave of the Italian epidemic: a prospective cohort study

Removal of Remdesivir's Metabolite GS-441524 by Hemodialysis in a Double Lung Transplant Recipient with COVID-19

Pharmacokinetics of linezolid in critically ill patients: impact of continuous venovenous haemofiltration

Pharmacokinetics of linezolid during extracorporeal membrane oxygenation

Endothelial cell infection and endotheliitis in COVID-19

Pharmacogenetics of the anti-HCV drug sofosbuvir: a preliminar study

UPLC-MS/MS method for the simultaneous quantification of sofosbuvir, sofosbuvir metabolite (GS-331007) and daclatasvir in plasma of HIV/HCV co-infected patients

Plasma and intracellular pharmacokinetics of tenofovir in patients switched from tenofovir disoproxil fumarate to tenofovir alafenamide

P. RDV