philipn / Dosing ARBs for COVID-19 dee83f98e9517413ff17a2ae05b174540e6c6d27

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. This was an acute injury. 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 in 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. This was an acute injury. Result: "losartan abolished prothrombotic effect of Ang II"
  • Cannot be easily translated to human dosing, as was given I.V. Losartan is metabolized by the liver into longer-lasting AT1R agonist EXP3174. But if this was oral, the human equivalent dose (80kg human) would be 195 mg losartan.
• 30mg/kg losartan, p.o., in mice. Induced arterial thrombosis. This was an acute injury. 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. This was an acute injury.  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 rats. This was an acute injury in surfactant‐depleted rat lungs. Result: attenuation of increase of TUNEL positivity in pneumocytes.
  • Human equivalent dose (80kg human): 39 mg losartan.
• 30mg/kg losartan, p.o., in rats. This was a semi-acute injury; losartan was given 30 minutes before the first of two daily smoke exposures. Result: "ameliorated pulmonary vascular remodeling, inhibited the smoke-induced RVSP and Ang II elevation and partially reversed the ACE2 decrease in rat lungs"
  • Human equivalent dose (80kg human): 389 mg losartan.
• 15 mg/kg losartan, intraperitoneal, in mice. Result: "alleviated the severity of influenza H7N9 virus-induced lung injury significantly in WT mice" and greatly improved lung injury in H7N9-infected ACE2-knockout mice.
  • Human equivalent dose (80kg human): 97 mg losartan.
• 50 mg/kg losartan, intravenous once per day, in mice. Result: "significantly improved the survival rate in H5N1 virus-infected mice", alleviated lung edema and improved lung histopathology.
  • Cannot be easily translated to human dosing, as was given I.V. Losartan is metabolized by the liver into longer-lasting AT1R agonist EXP3174. But if this was oral, the human equivalent dose (80kg human) would be 324 mg losartan.
• 200 mg losartan, p.o., in swine. Losartan was given orally 30 minutes before infusion of Ang II and bolus of ACE2 blocker MLN-4760.  Result: partial attenuation of lung damage in dysregulated renin-angiotensin system model.
  • Human equivalent dose (80kg human): Swine to human conversion not available on calculator.

Dose & medication used in clinical trials

• Losartan:
  • 12.5mg bid. 200 participants total.
  • 25mg od for 14 days. Multi-arm trial, estimate ~1000 participants given losartan.
  • 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.
  • 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.
  • 40mg od for 10 days. Multi-arm trial, estimated ~98 participants given telmisartan.
  • 80mg bid. 400 participants total.
• Candesartan:
  • 4mg od, "titrated to normotension". Multi-arm trial, estimated ~50 participants given candesartan.
• Unspecified ARB/dose:
  • CLARITY trial. 605 participants total.

Dosing for AT1R blockade

ARBs may deliver adequate antihypertensive effects with common doses, but larger doses may be needed for high blockade of AT1R. In "Angiotensin II Receptor Blockade in Normotensive Subjects," 50mg losartan od (Fig. 3) displaced ~42% of Ang II at 4 hours and ~18% at 24 hours, or an average of 30% displacement of Ang II over 24 hours. In comparison, 100mg losartan bid was found to displace 80% of Ang II at 4 hours and 55% at 24 hours (Table 4), or an average of 68% displacement of Ang II over 24 hours.  In this same study of normotensive subjects, 80mg bid telmisartan had similar effects as 100mg bid losartan on displacement of Ang II.

High dose ARBs in normotensives

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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.

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. This was an acute injury. 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 in 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. This was an acute injury. Result: "losartan abolished prothrombotic effect of Ang II"
  • Cannot be easily translated to human dosing, as was given I.V. Losartan is metabolized by the liver into longer-lasting AT1R agonist EXP3174. But if this was oral, the human equivalent dose (80kg human) would be 195 mg losartan.
• 30mg/kg losartan, p.o., in mice. Induced arterial thrombosis. This was an acute injury. 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. This was an acute injury.  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 rats. This was an acute injury in surfactant‐depleted rat lungs. Result: attenuation of increase of TUNEL positivity in pneumocytes.
  • Human equivalent dose (80kg human): 39 mg losartan.
• 30mg/kg losartan, p.o., in rats. This was a semi-acute injury; losartan was given 30 minutes before the first of two daily smoke exposures. Result: "ameliorated pulmonary vascular remodeling, inhibited the smoke-induced RVSP and Ang II elevation and partially reversed the ACE2 decrease in rat lungs"
  • Human equivalent dose (80kg human): 389 mg losartan.
• 15 mg/kg losartan, intraperitoneal, in mice. Result: "alleviated the severity of influenza H7N9 virus-induced lung injury significantly in WT mice" and greatly improved lung injury in H7N9-infected ACE2-knockout mice.
  • Human equivalent dose (80kg human): 97 mg losartan.
• 50 mg/kg losartan, intravenous once per day, in mice. Result: "significantly improved the survival rate in H5N1 virus-infected mice", alleviated lung edema and improved lung histopathology.
  • Cannot be easily translated to human dosing, as was given I.V. Losartan is metabolized by the liver into longer-lasting AT1R agonist EXP3174. But if this was oral, the human equivalent dose (80kg human) would be 324 mg losartan.
• 200 mg losartan, p.o., in swine. Losartan was given orally 30 minutes before infusion of Ang II and bolus of ACE2 blocker MLN-4760.  Result: partial attenuation of lung damage in dysregulated renin-angiotensin system model.
  • Human equivalent dose (80kg human): Swine to human conversion not available on calculator.

Dose & medication used in clinical trials

• Losartan:
  • 12.5mg bid. 200 participants total.
  • 25mg od for 14 days. Multi-arm trial, estimate ~1000 participants given losartan.
  • 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.
  • 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.
  • 40mg od for 10 days. Multi-arm trial, estimated ~98 participants given telmisartan.
  • 80mg bid. 400 participants total.
• Candesartan:
  • 4mg od, "titrated to normotension". Multi-arm trial, estimated ~50 participants given candesartan.
• Unspecified ARB/dose:
  • CLARITY trial. 605 participants total.

Dosing for AT1R blockade

Larger doses than those used for hypertension may be needed to achieve high blockade of AT1R. In "Angiotensin II Receptor Blockade in Normotensive Subjects," 50mg losartan od (Fig. 3) displaced ~42% of Ang II at 4 hours and ~18% at 24 hours, or an average of 30% displacement of Ang II over 24 hours. In comparison, 100mg losartan bid was found to displace 80% of Ang II at 4 hours and 55% at 24 hours (Table 4), or an average of 68% displacement of Ang II over 24 hours.  In this same study of normotensive subjects, 80mg bid telmisartan had similar effects as 100mg bid losartan on displacement of Ang II.

Conditions in which ARBs are used for high AT1R blockade rather than just antihypertensive effects include heart failure, where the HEAAL study found 150mg od losartan superior to 50mg od losartan; and Marfan syndrome.

High dose ARBs in normotensives

In Marfan syndrome, high doses of losartan are used by normotensives; 100mg of losartan daily has been shown to be beneficial. In the COMPARE trial of 100mg losartan for Marfan syndrome, "mean arterial pressure 3 years after inclusion was 86 mmHg in the losartan group and 87 mmHg in the control group."

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.