Dosing ARBs for COVID-19

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 od for 21 days. 40 participants total.
  • 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."

In this trial in healthy, normotensive subjects, 100mg losartan od as well as 80mg bid telmisartan were found to be safe. The authors state:

"One may also be concerned by safety considerations when administering higher doses of AT1 receptor blockers. This is hardly an issue, since AT1 receptor antagonists do not exhibit any dose-dependent adverse effects. Indeed, AT1 receptor blockers have been used safely at higher doses...inhibition of the renin-angiotensin system hardly causes a decrease in blood pressure in normotensive subjects."

In this preliminary report on a trial of telmisartan 80mg bid for COVID-19 treatment, "no differences were observed in blood pressure between telmisartan and control group at day 5 or 8."

Could some ARBs work better than others?

Is it possible that some ARBs would work better than others in the context of COVID-19?

Half-life & lipophilicity

Some ARBs, such as telmisartan, have a terminal elimination half-life of around 24 hours, while other such as losartan have a half-life of around 6-9 hours (via active metabolite EXP3179).

Lipophilicity is discussed in "Telmisartan as tentative angiotensin receptor blocker therapeutic for COVID‐19":

Liposolubility is relevant for absorption after oral administration and for tissue penetration. Telmisartan stands out among all the representatives of the ARBs for being markedly more lipophilic, expressed both in partition coefficients (octanol/neutral pH buffer), distribution coefficients and distribution volumes (Vd). Telmisartan has a Vd of approximately 500 L, irbesartan 93 L, and both valsartan and olmesartan, candesartan and losartan, approximately 17 L.

Further discussion is available in "Pharmacology and clinical efficacy of angiotensin receptor blockers."

Non-class effects

Telmisartan induces the strongest PPAR-γ activity among ARBs. PPAR-γ activation may be beneficial in dampining inflammatory responses to viral infections. At the same time, PPAR-γ activation may expediate thymic senescence.

Losartan has been shown to have anti-thrombotic effects independent of its AT1R antagonism. Losartan has also been shown to have antiplatelet effects, whereas its long-lasting metabolite EXP 3174 (as well as other tested ARBs) show weaker effects. When given orally or intraperitoneally, losartan is metabolized by the liver into EXP 3174, its longer-lasting, higher-affinity metabolite.

Olmesartan and losartan, but not irbesartan or enalapril, have been shown to defend against ventilator‐induced diaphragm dysfunction in animal studies (losartan study); in these studies, olmesartan and losartan blocked mechanical activation of AT1R, whereas irbesartan and enalpril did not. However, losartan was given via I.V. in this animal study, so it is unclear whether its metabolite EXP 3174 has this property.

Animal evidence

Losartan was used in all of the animal studies of viral lung injury that were found while compiling this page.

See also

• List of COVID-19 ARB trials
• COVID-19 therapeutics