Replies to post #216584 on Biotech Values

[GD]

PTLA: Bevyxxa's different pharmacokinetics , that is why Bevyxxa succeed
while Eilquis and Xarelto failed. B is a strong competition to Eilquis and
Xarelto in the future just because Bevyxxa's different pharmacokinetics.
PTLA is a small company, they can not get lucky with "new" FDA's
approval with a good broad label. Data is what FDA looking at, IMO.
I respect your opinion, we may see the results of launch and
uptake by year end.

[GD]

PTLA: here is a view from norseml what is the difference between
Eliquis and Xarelto, and it make sense of why Eliquis is a better
drug than Xarelto, but Bevyxxa is the best of three. IMO, this is
the strategic reasons for PFE or JNJ to own PTLA, instead of say
MRK or SNY which may put in aggressive plans to go after them.



I have provided the quickest page that kind of comes close to explaining how the factors:
1. Clearance rate
2. Dosing
3. Peak to trough concentration of drug
4. Patient's inherent renal health influence when serious adverse events happen.

For a quick approximation (it is taking me for ever to find the Ki values for rivaroxaban and apixaban), I am going to assume they bind to Factor Xa with roughly similar affinity. (Betrixaban at 117 picomolar is almost at the extreme end in a good sense that this does not hurt my thesis here).
In a trial, a single cohort of patients being treated will receive the same dose. Notice from the table, I have reproduced it at the bottom of this message for your convenience, both rivaroxaban and apixaban get protein bound at ~90% (meaning 10% of the dose is freely circulating in plasma) whereas Betrixaban has 40% circulating in plasma (60% protein bound). However, rivaroxaban is getting cleared at a 66% rate, which by the way is for the total (bound+unbound), roughly 7 times as fast as betrixaban. Apixaban obviously at 25% clearance is definitely better and still about 2.5 times faster than Betrixaban. The combination of higher protein binding with higher clearance makes it difficult to maintain an optimal plasma concentration.
But the drug has to be in plasma concentration at a level above its level of efficacy in order to provide the pharmacological benefit. Think of clearance as a hole at the bottom of the vessel in which you have to keep liquid a certain mark for success. Rivaroxaban has a large hole. Apixaban a medium sized one. Betrixaban a small one. Imagine you can pour liquid into this container only once a day. You will put a lot lot more of rivaroxaban, a moderate amount of apixaban and a smaller amount of betrixaban so the level stays at the mark, while the drug is being lost because of the leak in the container.

In other words, because of the clearance, a problem that drains your drug, you put more drug than the efficacious concentration, which remember you have to maintain for half a day or full day. This is the peak to trough difference. We would like the trough to be higher than efficacious concentration. So larger the peak to trough, the more the possibility some patients are receiving a dose that is much higher than needed.

In essence, the clearance rate forces you keep a higher peak than optimal. Guess what? Not all of the patients have identical clearance rates. So a small subset of patients with slightly compromised renal function have far more drug in their plasma than optimal. They bleed.

You can look now at the clearance rate and make a projection that rivaroxaban causes the most bleeding, apixaban less and betrixaban lot less. The high T-half actually comes to the rescue of betrixaban. Why? Since the drug hangs around you dose it less in the first place and your peak to trough difference is small. Even if the patients differ a bit in their renal clearance capability, you don't overdose some of the patients because you have not increased the dosage to compensate for a sizeable clearance rate.

https://www.investorvillage.com/smbd.asp?mb=18338&mn=118&pt=msg&mid=16846191