Hello, i have been looking to get either D159797 (BNP) or D159687; i have found only one source for the first, but its at 1g/$5950 which is too much since tetra used 10mg/20mg orally a day in its trial.
the latter can be found in many chimical site, and one of them (chinese) seems to be selling it at 785 per gram, i have sent them an email, lets see.
800$ would be still to much, since the dose of D159687 would still be in the range of 10-20mg orally; BUT i have done some math, making comparisons between tetra dose and the monkey study to see how much D159687 we would need to inject to have about the same effect of D159687 and BNP used orally:
a)to same mg equal about the same improvement in BNP and D159687.
1: lets make a comparison of the 10/20mg BNP used by tetra with the data from the monkey's study:
they used in the tests: 0.005, 0.5 mg/kg and 1 mg/kg; converting the dosa in the middle to human using (2): H = 1 mg/kg * (12/37) = 0.3 mg/kg for human [0.5 in moneky = 0.3 human]
Comparing it with tetra trials: In the clinical trial they used 10 and 20mg that is about the same dose used in monkey: 0.3 mg/kg *70kg = 20mg. So its confirmed that 0.5mg/kg monkey = 0.3mg/kg human. {B,C}
2: lets compare IV to oral
2a) BNP and D159687 in the same dosage gave the same results. Even if plasma exposure of BNP is about *10 of D159687. So we aim to have a IV dose for humans of D159687 with the same plasma exposure of D159687 ORAL at 0.5 mg/kg MONKEY. {A}
as for BNP monkey study claim IV (injection) should give about the same plasma exposure using 1/5 of the oral dose. [as you can see from the photo {A}: IV of 1mg/kg = plasma exp of about 1100 nM after 2 hours, while orally 5mg/kg is about 1000 nM after 2 hours] {A}
2b) for D159687 instead 1mg/kg IV = 500 nM, after 2 hours while oral administration of 5mg/kg = 100 nM; so to have the same plasma exposure (of 100 nM) we need 0.2mg/kg IV *PS
0.2 mg/kg IV = 5mg/kg ORAL
but we wanted 0.5mg/kg ORAL to have about the same dose used by Tetra (0.3 mg/kg Human = 0.5 mg/kg orally for monkey):
proportion: 0.5 / 0.2 = 5 / x
so x= 0.2 / 10 = 0.02mg/kg IV MONKEY
now need to convert it to human:
HUM = 0.02 * 12/37 = 0.0064 mg/kg IV 0.0064 mg/kg is the dose we would need to IV {C}
so: 0.0064 mg/kg * 70kg = 0.44 mg IV
IN conclusion to have the same effect of 20 mg BNP (oral) we need to inject 0.44 (or 0.22 looking at *PS) mg of D159687.
even if the math is not for sure right, monkey did not have any side effect with 5mg/kg ORAL, our dose (0.44 or 0.22mg) that should be equal to 0.5mg/kg oral should be widely "safe"
*PS: But its written that oral bioavailability of D159687 is "only" of 6-13%, so the is the possibility that 5mg/kg oral = about 0.1mg/kg and not 0.2 like i thought (using the figure); this can be easly explained by the fact that i have used the plasma exposure of "2hours after administration", while the max exposure for IV is about * 10 the max exposure of ORAL
A: http://journals.plos...ne.0102449.s002
B: http://tetradiscover...CTAD-102517.pdf
C: https://www.longecit...nimal-to-human/
sorry english, hope you can understand
Edited by Painkillerrr, 28 April 2018 - 09:10 PM.
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