pharmacotherapy of covid-19

PHARMACOTHERAPY OF COVID-19

2021-6-12亞東紀念醫院內科加護病房

張厚台

大綱

Case Sharing , Pathology process of SARS Cov 2, clinical spectrum Pharmacologic intervention in COVID Monoclonal antibody: SARS-CoV-2 Neutralizing Antibody Antiviral agents : Remdesivir ,baricitinib Anti-inflammation agents : corticosteroid , IL-6 antagonist Anticoagulants

Potential pharmacologic strategy for COVID-19 treatment

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Dexamethasone 6mg/d

Remdesivir 200mg, st and 100 mg, qd* 5d

O2NC O2

SM O2NRM

O2 SM

35 y/o female, husband :萬華果菜市場Nasal Swab (5/22) : SARS-Cov-2 RNA (+) Lym: 738 -> 1225 D D dimer: 407CRP: 0.584, PCT:0.05LDH: 228

Risk Factors: Age >65 y/o (-) , BMI>35 (-) , immunocompromise(-), HTN (-) , DM (-)

Clinical spectrum of SARS-Cov-2 infection

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Classification Asympto-matic

Mild Moderate Severe Critical

Definition NAAT(+) S/S of COVID fever, smell(-)CXR(-)

SpO2>94% ,at RAS/S of LRI,

SpO2 <94% , at RAPaO2/FiO2 <300 mm Hg,RR >30/min, or lung infiltrates >50%.

respiratory failure, septic shock, and/or multiple organ dysfunction.

% 81% 14% 5%

Treatment (I) SARS-Cov neutralizing antibody *bamlanivimab plus etesevimabor *casirivimab plus imdevimab

DexDex +RDV (Incr. O2)RDV

DexDex +TCZ

Treatment (2) Baricitinib +RDV LMWH

NIH guideline 新型冠狀病毒（SARS-CoV-2）感染臨床處置暫行指引

Pathology process of SARS-CoV-2

ZHOU ET AL. J Med Virol. 2021; 1–11.Eur Respir J 2021; in press

Initial stage: fever , cough…highest viral load in 7 days 2nd stage: dysfunctional host inflammatoryresponse => lung inflammation and lung injury follows

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Risk of progressive to severe COVID• Older age ( ≥65 years of age) • Obesity ( BMI >25 kg/m2, or 12-17y/o: BMI ≥85th )• Pregnancy , Chronic kidney disease , Diabetes ,Immunosuppressive

disease or immunosuppressive treatment , Sickle cell disease Cardiovascular disease (including congenital heart disease) or

hypertension Chronic lung diseases (ex: COPD, asthma [moderate-to-severe],

interstitial lung disease, cystic fibrosis, and pulmonary hypertension) Neurodevelopmental disorders (for example, cerebral palsy) Having a medical-related technological dependence (ex, tracheostomy,

gastrostomy, or positive pressure ventilation [not related to COVID 19]) Defined by EUA2021/6/12 6

簡報者

簡報註解

Emergency use authorization

ZHOU ET AL. J Med Virol. 2021;1–11..2021/6/12 7

Hajjar et al. Ann. Intensive Care (2021) 11:36

Viral cycle

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簡報者

簡報註解

PAR protease-activated receptorThe pathophysiology of SARS-CoV-2 infection. SARS-CoV-2, via its surface spike protein, binds to the human ACE2 receptor after spike protein activation by TMPRSS2. This results in down-regulation of ACE2 and increased angiotensin II levels and consequently increased plasminogen activator inhibitor C-1 expression and reduced fibrinolysis. The disease it causes is associated with an increase in inflammatory cytokines and coagulation disorders, with predisposition to thrombus formation. Mononuclear cells interact with activated platelets and the coagulation cascade, which activate 1 inflammatory cells by binding thrombin and tissue factor with specific protease activated receptors and by binding fibrin to Toll-like receptor 4. The activation of inflammatory cells results in the release of pro-inflammatory cytokines, leading to impairment of the natural coagulation pathways and shut down of fibrinolysis. This state of hyper inflammation and hypercoagulability leads to multiple organ dysfunction, most commonly affecting the lungs, heart and kidneys. ACE2 angiotensin-converting enzyme-2, aPTT activated partial thromboplastin time, ARDS acute respiratory distress syndrome, COVID-19 coronavirus disease 2019, HFpEF heart failure preserved ejection fraction, HFrEF, heart failure reduced ejection fraction, IL interleukin, PAR protease-activated receptor, PT prothrombin time, SARS-COV-2severe acute respiratory syndrome coronavirus 2, TMPRSS2 transmembrane protease serine, TLR4 Toll-like receptor 4, TNFα tumor necrosis factor-α

SARS-COV-2 NEUTRALIZING ANTIBODY

SARS-CoV-2 neutralzing antibody

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Antibody Therapeutics, 2020, Vol. 3, No. 4 246–256Viruses 2021, 13, 628.

* Targeting spike protein* Neutralize SARS Cov 2• Cocktail strategy - Two nAb

cocktails (casirivimab1200mg/ imdevimab 1200mg and bamlanivimab700mg/etesevimab 1200 mg )

• Mild to moderate , risk (+)• Within 10 days of symptoms

onset, not hospitalized

簡報者

簡報註解

Casi regimen 較不受resistance 影響 Monotherapy 不被推薦 RBD: recepter binding domain receptor binding motif.

台灣專家會議決議

Casirivimab/ imdevimab and bamlanivimab /etesevimab 具以下任一風險因子: 未使用氧氣, 且發病七天內之成人病患

風險因子: (1). 年齡> 65 y/o * 註: 因最近進量限制, 先訂75歲以上且具以下共病者

(2). 年齡> 55 y/o, 且具以下任一情形: 糖尿病、慢性腎病、心血管疾病( 含高血壓) 、慢性肺疾、BMI >30, 或其他影響免疫功能疾病

(3), 懷孕

劑量: 600mg casirivimab +600mg imdevimab ;

700mg Bamlanivimab+1400mg etesevimab2021/6/12 11

ANTIVIRAL AGENTS Remdesivir

JAMA. 2020;323(18):1824-1836

virus-induced host immune system response and viral processing within target cells

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簡報者

簡報註解

ACE2, angiotensin-converting enzyme 2; S protein, spike protein; and TMPRSS2, type 2 transmembrane serine protease.

Remdesivir

GS-5734, Remdesivir inhibits viral RNA-dependent RNA polymerase, causing premature termination of RNA transcription, inhibit SARS-CoV-1 and MERS -CoV

Dosage: D1: 200mg, Loading; D2-D10 or discharge: 100mg maintenance

Remdesivir is recommended for hospitalized patients with COVID-19 disease

Remdesivir: shorter time to recovery , in the ordinal scale score at day 15 Lower mortality at D15, prevented the progression to more severe respiratory

disease

Remdesivir for the Treatment of Covid-19 — Final Report. N Engl J Med 2020;383:1813-26. DOI: 10.1056/NEJMoa2007764 14

簡報者

簡報註解

Enrollment for ACTT-1 began on February 21, 2020, and ended on April 19, 2020. There were 60 trial sites and 13 subsites in the United States (45 sites), Denmark (8), the United Kingdom (5), Greece (4), Germany (3), Korea (2), Mexico (2), Spain (2), Japan (1), and Singapore (1).

Recommendation 10: In patients on supplemental oxygen but not on mechanical ventilation or ECMO, the IDSA panel suggests treatment with five days of remdesivir rather than 10 days of remdesivir.• Remark: In patients on mechanical ventilation or ECMO, the duration of treatment is 10 days.

Recommendation 9: In hospitalized patients with severe* COVID-19, the IDSA panel suggests remdesivir over no antiviral treatment. • Remdesivir appears to demonstrate the most benefit in those with severe COVID-19 on supplemental oxygen rather than in patients on mechanical ventilation or ECMO.

http://www.idsociety.org/COVID19guidelines

IDSA guideline1

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Remdesivir for the Treatment of Covid-19 — Final Report

The mortality rate (day 15) was 6.7% (remdesivir): 11.9% (placebo)

Median time to recovery:

10 (remdesivir) vs. 15( placebo)=> Lower mortality and Faster recovery !!

Serious adverse events were reported in 24.6% of remdesivir patients and 31.6% of placebo patients

Remdesivir for the Treatment of Covid-19 — Final Report. N Engl J Med 2020;383:1813-26.

Adaptive Covid-19 Treatment Trial (ACTT-1)

16

Remdesivir for the Treatment of Covid-19 — Final Report. N Engl J Med 2020;383:1813-26. 17

International Journal of Infectious Diseases 106 (2021) 71–7774

Real world data: Symptoms onset to RDV Tx <9 days Better survival

簡報者

簡報註解

1, not hospitalized and no limitations of activities 2, not hospitalized, with limitation of activities, home oxygen requirement, or both 3, hospitalized, not requiring supplemental oxygen and no longer requiring ongoing medical care (used if hospitalization was extended for infection-control or other nonmedical reasons); 4, hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (related to Covid-19 or to other medical conditions) 5, hospitalized, requiring any supplemental oxygen 6, hospitalized, requiring noninvasive ventilation or use of high-flow oxygen devices 7, hospitalized, receiving invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) 8, death

Remdesivir for the Treatment of Covid-19 — Final Report. N Engl J Med 2020;383:1813-26.

Hospitalized+O2 NIV MV/ECMO

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簡報者

簡報註解

因應【公費 COVID-19 抗病毒藥劑領用方案｜110年6月5日第四次修訂】，remdesivir 建議使用範圍更改：「需使用機械式呼吸器或已裝 ECMO 之病患 "不建議" 使用」。並更新 remdesivir 申請方式。

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55 y/o FBH:150cm, BH: 86Kg* 5/26 COV(+)* 5/30 喘* Refer from 趣淘檢疫旅館5/31, 1: 37AM 抵達ER , SpO2:74-80% at room air* 3:27AM Dexamethasone6mg, iv st* CRP: 15.1 ,RR: 45/min, SpO2 89-90% under NRM 15L/min* 6:48AM intubation * 7:30AM TCZ , 600mg , ivd* 8:45AM ICU

D4-D6

6/10 拔管

ANTI-INFLAMMATIONCorticosteroid , tocilizumab (TCZ)

ARDS

Dexamethasone

SARS-CoV-2Cytokine storm

European Journal of Pharmacology 894 (2021) 173854

IL-6 antagonist

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IDSA guideline2

Recommendation 4: Among hospitalized critically ill patients* with COVID-19, the IDSA guideline panel recommends dexamethasone rather than no dexamethasone. (Strong recommendation, Moderate certainty of evidence)

equivalent : methylprednisolone 32 mg and prednisone 40 mg *Critical illness: Patients on mechanical ventilation and extracorporeal mechanical oxygenation (ECMO). In COVID-19, the most commonly reported form of end organ dysfunction is ARDS

**Severe illness: SpO2 ≤94% on room air, including patients on supplemental oxygen.

http://www.idsociety.org/COVID19guidelines2021/6/12 22

Systemic Corticosteroids

We recommend systemic corticosteroids for COVID-19 positive patients who are critically ill or require supplemental oxygen

Dosing regimens to consider include:✔ Dexamethasone 6mg IV or PO daily x 10 days✔ Hydrocortisone 50mg IV Q8h x 10 days✔ Methylprednisolone 15mg IV BID x 10 days✔ Prednisone 40mg PO daily x 10 days

)23

Dexamethasone in Hospitalized Patients with Covid-19 — N Engl J Med 2021;384:693-704

1. IMV at randomization 2. Age-adjusted

mortality reduction :12.3%

29.3% vs 41.4%22.9% vs. 25.7% (p<0.001) 23.3% vs. 26.2%

Age-adjusted mortality reduction : 4.2%

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Dexamethasone in Hospitalized Patients with Covid-19 — N Engl J Med 2021;384:693-7042021/6/12 25

JAMA. 2020;324(13):1330-1341

Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19There were 222 deaths randomized to corticosteroids (n=678) and 425 deaths randomized to usual care or placebo (n=1025) (odds ratio 0.66, 95% CI 0.53-0.82, p<0.001)A class effect of steroids (odds ratio 0.70, 95% CI 0.48-1.01,p=0.053)

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JAMA. 2020;324(13):1330-1341

Dexmethasone Hydrocortisone Methylprednisolone

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Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19. JAMA. 2020;324(13):1330-1341. 2021/6/12 28

IL-6 antagonists

IL-6: recombinant humanized monoclonal antibody, directed against both the soluble and the membrane bound IL-6 receptor,

Acute-phase response, released in response to infection, stimulates inflammatory pathways

Tocilizumab and sarilumab Treatment of Rheumatic arthritis and cytokine release syndrome

associated with CAR-T cell therapy Dosage: by BW, infusion>1hr , 2nd dose: 12-24hrs later Harms: risk of infections , 亦容易引起HBV reactivation

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~This article was published on February 25, 2021, at NEJM.org.

• Tocilizumab (TCZ): 353 8mg/kg/d

• Sarilumab (SAR) :48400mg

• Standard care (402)(Control)

• COVID-19 pts , < 24 hrsof organ support in ICU

21d OSFD- OR: 1.65

Improved 90d survival

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簡報者

簡報註解

An odds ratio greater than 1 represents improved survival, more organ support–free days

• 14 April 2020 and 24 January 2021 2022 TCZ: 2094 usual care 562 pts (14%) IMV, 1686 (41% ) noninvasive resp support

* Median CRP: 143 mg/L, 82% with corticosteroid * 28-d mortality : TCZ: Usual care (UC) =29% vs. 33% ((rate ratio 0·86, p=0.007 )* Discharge from hospital : TCZ: UC= 54% vs. 47% ( rate ratio 1·22 , p<0·0001 )• Receipt of IMV: 33% vs. 38% (RR: 0.85, p=0.0005)=> In COVID+ hypoxia+systemic inflammation , TCZ improved survival

this version posted February 11, 2021. ; https://doi.org/10.1101/2021.02.11.21249258doi: medRxiv preprint 2021/6/12 31

28-d mortality this version posted February 11, 2021. https://doi.org/10.1101/2021.02.11.21249258doi: medRxiv preprint

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reduced the likelihood of progression to MV

N Engl J Med 2021;384:20-30.

* For critical COVID-19 pneumonia , under HFNC or high level O2 flow ** Early after intubation

*IDSA Recommendation 7: progressive severe* or critical** COVID-19 who have elevated markers of systemic inflammation, the IDSA guideline panel suggests tocilizumab in addition to standard of care (i.e., steroids)**In the largest trial on the treatment of tocilizumab, criterion for systemic inflammation was defined as CRP ≥75 mg/L.

*ERS:- The patients most likely to benefit are those:o in the first 24 hours after receiving non-invasive or invasive

ventilatory support patients receiving supplementary oxygen and who are progressing despite corticosteroid treatment or who are considered at high risk of future requirement for ventilatory support.

Guidelines about IL-6 antagonists

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簡報者

簡報註解

75mg/L=7.5mg/dL

NIH guideline (2021-3-5) Tocilizumab ( 8 mg/kg of actual body weight, up to 800 mg) in

combination with dexamethasone (6 mg daily for up to 10 days) in rapid respiratory decompensation due to COVID-19

Ex: (ICU) within the prior 24 hours and who require invasive mechanical ventilation, or high-flow nasal canula (HFNC) oxygen (>0.4 FiO2/30 L/min of oxygen flow)

(not in an ICU) with rapidly increasing oxygen needs who require NIV or HFNC and have significantly increased markers of inflammation (CRP>75mg/L)

Suggestion for IL-6 antagonists2

~ REMAP-CAP preliminary report2021/6/12 34

簡報者

簡報註解

A Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia �REMAP-CAP a Use of tocilizumab should be avoided in patients with any of the following: (1) significant immunosuppression, particularly in those with a history of recent use of other biologic immunomodulating drugs; (2) alanine transaminase >5 times the upper limit of normal; (3) high risk for gastrointestinal perforation; (4) an uncontrolled, serious bacterial, fungal, or non-SARS-CoV-2 viral infection; (5) absolute neutrophil count <500 cells/µL; or (6) platelet count <50,000 cells/µL.�b As an alternative to dexamethasone, corticosteroids at a dose equivalent to dexamethasone 6 mg are acceptable (see Corticosteroids).�c Respiratory decompensation should be due to progressive COVID-19 and not due to alternative causes, such as volume overload or asthma exacerbation.�d For example, within 3 days. Median days of hospitalization until randomization was 1.2 days (IQR 0.8–2.8 days) in REMAP-CAP and 2 days (IQR 1–5 days) in the RECOVERY trial.

Baricitinib

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1. selective, efficient and safe janus kinase 1 (JAK1) and 2 (JAK2) inhibitor approved for usage in rheumatoid arthritis treatment2. inhibits the intracellular signaling pathway of cytokines implicated in severe COVID-19, including IL-2, IL-6,IL-10, IFN-, and granulocyte-macrophage colony-stimulating factor (GM-CSF)3. inhibition of both AP2-associated protein kinase 1 (AAK1) and cyclin G-associated kinase (GAK). Thus, preventing endocytosis and reducing viral assembly 4. Combined with RDV

Anticoagulant treatment in COVID-19

SARS-CoV-2 induced complement hyperactivation, endothelial dysfunction and cytokine storm have a prothrombotic effect.

COVID 19 patients develop a pro-coagulative state directly related to disease severity.

In COVID 19 critical patients, thrombotic lesions in pulmunarymicrovessels have a prevalence twice higher than critical non-COVID 19 patients. Prevalence of PE among COVID 19 in ICU : 20% Anticoagulant treatment is associated with lower in-hospital

mortality.

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Journal of Thrombosis and Thrombolysis (2021) 51:642–648CCM 2021 online

簡報者

簡報註解

ISTH-DIC score International Society on Thrombosis and Hemostasis (ISTH) scoring system)

Anticoagulants in COVID 19-proposed algorithm

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Journal of Thrombosis and Thrombolysis (2021) 51:642–648

* D dimer: 6 times the upper limit of normal

* ISTH score: PLT, D dimer, PT, fibrinogen

Better results inin patients with

respiratory failure requiring invasive

ventilation.

簡報者

簡報註解

Diagnostic criteria for overt DIC Platelet count, cells x 109/L ≥100 0 50 to <100 +1 <50 +2 Elevated levels of a fibrin-related marker (e.g. D-dimer, fibrin degradation products) Use lab-specific cutoff values No increase 0 Moderate increase +2 Severe increase +3 Prolonged PT, seconds <3 0 3 to <6 +1 ≥6 +2 Fibrinogen level, g/L ≥1 0 <1 +1 Is this a COVID-19 patient? For research purposes only; answer does NOT impact results. Confirmed positive Suspected Unlikely Confirmed negative

Disease Severity Recommendations

NIH guidelines

Rapid resp decompendations: TCZ (8mg/kg)+ Dexamethasone (6mg/d)* 10 d

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Take home message

Pharmacotherapy strategy in different severity and different stages of COVID-19 illness Mild to moderate but high risk : casirivimab/ imdevimab,

bamlanivimab/etesevimab Severe illness : O2 needed to maintain SpO2>94% , hospitalization Remdesivir : organ support D1: 200mg, Loading; D2-D10 or discharge: 100mg maintenance

Critical illness: COVID-19 +end organ damage (ARDS, etc ) Dexamethasone iv/oral , 6mg/day *10 days +/- remdesivir Dexamethasone iv/oral + / followed by Tocilizumab addition

Rapid respiratory decompensation: 新的O2 setting 24 小時內+ CRP>75mg/L Dexamethasone *10 days + Tocilizumab (IL-6 antagonist) 8mg/d*1-2 doses

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簡報者

簡報註解

RDV 為凍晶劑型, 可泡濃一點 ( in NS 100ml, ivd>30min , MICU, in N/S 250ml , ivd>2hrs ) RDV 現不可用於MV or ECMO pt - Remdesivir 於肝腎功能障礙者之建議（利大於弊就打吧） - Tocilizumab 亦可能導致 HBV reactivation - Tocilizumab 如臨床狀況適合，可考慮自費給予第 2 劑 - Tocilizumab 的禁忌症仿單列很多，但或許用在 COVID-19 這種急症時，思考會不太一樣，像是 acute infection other than COVID-19 可能較傾向為 "uncontrolled acute infection other than COVID-19，以留予臨床醫師對 "uncontrolled" 的臨床裁量空間。 - VTE prophylaxis 的使用時機（各家醫院都不太一樣）

THANKS FOR YOUR ATTENTION

Therapy Recommendations Recommendation Quality of evidence

Corticosteroids

The panel recommends offeringtreatment with corticosteroids forpatients with COVID-19 requiringoxygen, non-invasive ventilation or invasive mechanical ventilation

Strong Moderate

IL-6 receptorantagonistmonoclonalantibody

The panel suggests offering IL-6receptor antagonist monoclonalantibody therapy to hospitalized patients with COVID-19 requiring oxygen or ventilatory support

Conditional Low

Remdesivir No recommendation is maderegarding the use of remdesivir inpatients hospitalised with COVID-19 and not requiring invasive mechanical ventilationThe panel suggests not to offerremdesivir to patients hospitalisedwith COVID-19 infection who require invasive mechanical ventilation

None

Conditional

Moderate

Moderate

A European Respiratory Society living guideline. Eur Respir J 2021; in press2021/6/12 42

ICU admission criteria

14% developed a severe form of the disease => hospitalization, 5% were critical => ICU admission

Severe: respiratory rates ≥ 30 breaths/min oxygen saturation ≤ 93%, lung infiltrates > 50% at high risk for clinical deterioration and critical illness => ARDS

在hospitalization中有 25% 需要 ICU admission , ICU admission中60-70% 為acute hypoxemic respiratory failure

Risk factors for ARDS: Age>65y/o, T>39C, Lab data abn ( lymphocytopenia, neutrophilia, hepato-renal failure,

inflammatory marker , coagulation abn )Hajjar et al. Ann. Intensive Care (2021) 11:36

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pharmacotherapy of covid-19

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