philipn / Dosing ARBs for COVID-19 457b6a339f0f06ed19dba6c37d384adc1f094a59

If ARBs (or other drugs modulating the renin-angiotensin system) help in COVID-19, what would be the ideal dosing and medication to use?  This page explores this question.

Dose & medication used in animal studies

ACE2-knockout animal studies:

• 15 mg/kg losartan (route of administration unspecified) in mice. Result: attenuation of lung injury from SARS spike protein + acid combination. Note that this was an acute injury: the mice were challenged with acid once after losartan was given.
  • Human equivalent dose (80kg human): 97 mg losartan.
• 50 mg/kg/day (route of administration unspecified) irbesartan in mice. Result: "rescued the systolic dysfunction, normalized altered signaling pathways, flow-mediated dilation, and the increased oxidative stress in the cardiovascular system."
  • Human equivalent dose (80kg human): 324 mg irbesartan.

Other animal studies of AT1R blockade:

• 30 mg/kg losartan, intravenous, in mice. Ang II and thrombosis. Result: "losartan abolished prothrombotic effect of Ang II"
  • Human equivalent dose (80kg human): 195 mg losartan. But the mouse study used I.V. dosing, not oral.
• 30mg/kg losartan, p.o., in mice. Induced arterial thrombosis. Result: significantly attenuated thrombosis (42% versus control)
  • Human equivalent dose (80kg human): 195 mg losartan.
• 10 mg/kg losartan, p.o., in mice.  Induction of venous thrombosis.  Result: significantly decreased thrombus weight.
  • Human equivalent dose (80kg human): 65 mg losartan.
• 30 mg/kg losartan, in drinking water, in mice. ACE2 deficiency increases NADPH‐mediated oxidative stress. Result: normalization of NADPH oxidase activity in ACE2-knockout mice.
  • Human equivalent dose (80kg human): 195 mg losartan.

Dose & medication used in clinical trials

• Losartan:
  • 12.5mg bid. 200 participants total.
  • 25mg od for 14 days. Multi-arm trial, estimate ~1000 participants total.
  • 25mg od for 10 days. 580 participants total.
  • 25mg bid. 20 participants total.
  • 25mg bid for 14 days. 100 participants total.
  • 25 od, escaled to 50mg. 34 participants total.
  • 50mg od. 200 participants total.
  • 50mg od for 15 days. 176 participants total.
  • 100mg od. Multi-arm trial, estimate ~5000 participants.
  • Titration up to 100mg od over 3 days. 1372 participants total.
• Valsartan:
  • Titrated based on BP, max 160mg bid. 651 participants total.
• Telmisartan:
  • 20mg od. 338 participants total.
  • 40mg od for 21 days. 40 participants total.
  • 40mg od for 14 days. 60 participants total.
  • 80mg bid. 400 participants total.
• Candesartan:
  • 4mg od, "titrated to normotension". Multi-arm trial, estimated ~50 participants total.
• Unspecified ARB/dose:
  • CLARITY trial. 605 participants total.

If ARBs (or other drugs modulating the renin-angiotensin system) help in COVID-19, what would be the ideal dosing and medication to use?  This page explores this question.

Dose & medication used in animal studies

ACE2-knockout animal studies:

• 15 mg/kg losartan, intraperitoneal, in mice. Result: attenuation of lung injury from SARS spike protein + acid combination. Note that this was an acute injury: the mice were challenged with acid once after losartan was given.
  • Human equivalent dose (80kg human): 97 mg losartan.
  • Confirmed as intraperitoneal via private correspondence with authors.
• 50 mg/kg/day (route of administration unspecified) irbesartan in mice. Result: "rescued the systolic dysfunction, normalized altered signaling pathways, flow-mediated dilation, and the increased oxidative stress in the cardiovascular system."
  • Human equivalent dose (80kg human): 324 mg irbesartan.
•  15 mg/kg losartan, intravenous, in mice. Result: attenuation of RSV-induced lung injury in ACE2-KO mice.
  • Human equivalent dose (80kg human): 97 mg losartan.
• 10 mg/kg/day losartan in drinking water. Result: improvements in lung fibrosis model
  • Human equivalent dose (80kg human): 65 mg losartan.

Other animal studies of AT1R blockade:

• 30 mg/kg losartan, intravenous, in mice. Ang II and thrombosis. Result: "losartan abolished prothrombotic effect of Ang II"
  • Human equivalent dose (80kg human): 195 mg losartan. But the mouse study used I.V. dosing, not oral.
• 30mg/kg losartan, p.o., in mice. Induced arterial thrombosis. Result: significantly attenuated thrombosis (42% versus control)
  • Human equivalent dose (80kg human): 195 mg losartan.
• 10 mg/kg losartan, p.o., in mice.  Induction of venous thrombosis.  Result: significantly decreased thrombus weight.
  • Human equivalent dose (80kg human): 65 mg losartan.
• 30 mg/kg losartan, in drinking water, in mice. ACE2 deficiency increases NADPH‐mediated oxidative stress. Result: normalization of NADPH oxidase activity in ACE2-knockout mice.
  • Human equivalent dose (80kg human): 195 mg losartan.
• 3 mg/kg losartan, intraperitoneal, in mice. Result: <<<add here>>>

Dose & medication used in clinical trials

• Losartan:
  • 12.5mg bid. 200 participants total.
  • 25mg od for 14 days. Multi-arm trial, estimate ~1000 participants total.
  • 25mg od for 10 days. 580 participants total.
  • 25mg bid. 20 participants total.
  • 25mg bid for 14 days. 100 participants total.
  • 25 od, escaled to 50mg. 34 participants total.
  • 50mg od. 200 participants total.
  • 50mg od for 15 days. 176 participants total.
  • 100mg od. Multi-arm trial, estimate ~5000 participants.
  • Titration up to 100mg od over 3 days. 1372 participants total.
• Valsartan:
  • Titrated based on BP, max 160mg bid. 651 participants total.
• Telmisartan:
  • 20mg od. 338 participants total.
  • 40mg od for 21 days. 40 participants total.
  • 40mg od for 14 days. 60 participants total.
  • 80mg bid. 400 participants total.
• Candesartan:
  • 4mg od, "titrated to normotension". Multi-arm trial, estimated ~50 participants total.
• Unspecified ARB/dose:
  • CLARITY trial. 605 participants total.

Would some ARBs work better than others?

Several of the animal studies use I.V. losartan. When given orally or intraperitoneally, losartan is metabolized by the liver into EXP3174, its longer-lasting, higher-affinity metabolite. When given via I.V., losartan is not metabolized into EXP3174 ("EXP3 174: The Major Active Metabolite of Losartan", Tamaki, et al).

Thrombosis and losartan versus first-pass metabolite EXP3174.

https://ascpt.onlinelibrary.wiley.com/doi/10.1111/cts.12916 - mechanical activation of AT1R versus Ang II-activation of AT1R

..however, in this trial losartan was given both intraperitoneally (first dose), and then via i.v. With i.v. administration, the first-pass effect would be skipped and losartan would not be metabolized into EXP3174, its longer-lasting, higher-affinity metabolite.

..but in a follow-up study, olmesartan, but not irbesartan, attenuated ventilator-induced diaphragm dysfunction as well.