Pharmacokinetics questions

– Losartan is normally bound to albumin (>99%). This should help to target Losartan to inflamed tissue, where we want it, where vessels are highly permeabel to albumin. Losartan usually reaches AT1R from the vascular side. Is there proof that Losartan aerosol reaches AT1R at the alveolar epithelial II cells and actually blocks them?

We don’t have any direct evidence that Losartan-N will reach alveolar epithelial II cells . However we do know that active ingredients do reach intestinal epithelial cells , permeate the epithelium  and remain there for extended periods of time.

– Losartan is metabolized into active metabolites (14%), by Cyp2C9 in the liver. Cyp2C9 is not expressed in the lungs, so I assume losartan aerosol is not converted to active metabolites at all. Does losartan have the same potential to block AT1R as its active metabolite does?

The answer is probably not, as we do not expect any convertsion of Losartan into more active metabolites in the lungs where CYP450 enzymes are not expressed . However losartan itself has some activity, though 10 to 40 fold lower. https://doi.org/10.1016/j.jconrel.2013.06.036  At the same time,  we expect that losartan concentrations will be quite high, but only locally, at the surface of lung epithelial cells. 
Should we fail to observe clinical benefit, wqe have also formulated Valsartan-N which need not be metabolized to deploy its full activity. So we have both a presumabely moderately potent and a very potent durg.

-Plasma t1/2 of losartan is 2h. (6-9h for active metabolites). It is excreted by feces (58%) and urine (35%). How is losartan aerosol excreted if it doesn’t enter the blood stream? What is its functional halftime?

Because Losartan-N will be essentially covering the lung epithelial surface with a “two dimensial” film we believe that losartan will be cleared pulmonary* and owing to the more rapid turnoever of lung epithelial cells in case of inflammation**.

*Inhaled Therapy in Respiratory Disease: The Complex Interplay of Pulmonary Kinetic Processes  https://doi.org/10.1155/2018/2732017

**  Airway epithelial repair: breathtakingly quick and multipotentially pathogenic http://dx.doi.org/10.1136/thx.52.11.1010 

-How does the t1/2 translate to the interval time of treatment? Should we fear a reboundeffect, which means that AT1Rs activation is increased during periods of insufficient availability of losartan?

We do not have an answer to the first question. However Novochizol ensures sustained release of the formulated active ingredients over long periods of time and we do not expect to see signifcan peaks of release, followed by “withdrawal”.

-We know that SARS-CoV enters the CNS through the olfactory bulb, bypassing the BBB. We also know that albumin nosespray reaches the CNS. So I assume that losartan aerosol also reaches the brain. Is there any information on the concentrations reached in the CNS? And on how it is excreted? And on the t1/2 of losartan aerosol in the CNS?

Based on all the evidence we have so far with losartan  and other active ingredients formulated with Novochizol, there is undetectable systemic distribution.  Lasartan-N will only act in the lungs.

-patients on mechanical ventilation, getting aerosol through the tube, will not get losartan aerosol in the brain

We believe that this would indeed be the case.

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