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Dear all,
I was wondering if someone has came across a case where a compound
shows a significantly higher activity when administered IP in mice
(50mg/kg) as a 0.5% methylcellulose suspension compared to a 0.2% HPMC
suspension.
The compound is poorly soluble in both vehicles at this dose level and
even less soluble in 0.5% MC suspension (200ug/mL in HPMC suspension
and 20 ug/mL in MC suspension for a target concentration of 5000ug/mL).
The target organ/tissues for the activity are liver and muscle.
The drug concentration in plasma, liver and muscle 1h after
administration is as followed:
- MC: plasma: 36 ug/mL; liver: 28 ug/mL; muscle: 8ug/mL
- HPMC: plasma: 48 ug/mL; liver: 34 ug/mL; muscle: 2ug/mL
-
Whereas the activity observed was:
- MC: -55%
- HPMC: -26%
I would highly appreciate your thoughts and comments
Thanks in advance
Sebastien
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The following message was posted to: PharmPK
Dear Sebastien,
Obtaining different activities with different formulations is not
unexpected, generally due to PK reasons, you yourself mention how
solubility in both media is different although they both are modified
cellulose.
As no precise information is given on actual activity measurement (and
this may be sensitive information) it is difficult to discuss
precisely. Nonetheless it is interesting to note that muscle
concentration (ng/mL or ng/g?) is 4-fold after 0.5%MC compared to
0.2%HPMC and activity is -55% compared to -26% in the respective
groups, the ratios do actually fit well with what might be expected
from a saturation curve with a slope of 1. Was the activity
measurement made in muscle (one of target tissues)?
Beyond the actual concentration in muscle the ratio of levels in
tissue / plasma may be interesting to look at. 1h after administration
the plasmatic concentrations Cp are similar in both groups, the
Cliver /Cp ratios are also equivalent, as may be expected for a fast
equilibrating tissue. Muscle, a slower equilibrating tissue, on the
other hand looks quite different, Cmuscle / Cp ratios show a 5 fold
difference between groups; I think the most probable cause for this
would be that the earlier plasmatic levels were higher in the MC than
in the HPMC group. You could monitor plasmatic levels with both
formulation to check on this (I would be curious to know what you find
out). If this is the case early Cp and AUC0-1h in the MC group are
much higher, despite similar Cp at 1h; then systemic activity, or
activity in the liver, would also be higher.
It comes as a surprise that the formulation offering lower solubility
appears to perform best. If the data presented is thermodynamic
(equilibrium) solubility it may be that kinetic solubility is
different and is favored in 0.5%MC, allowing faster absorption at
earlier times. It may be that both formulations behave differently
once injected in the biological environment, although I'm not sure
what it could be in this case.
Patrice
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Hello Sebastin,
Is there any significant difference in Tmax (rate of absorption) and
AUC (exposure) between the two formulations? I am suspecting the role
of their rheological properties like viscosity (flow) of 0.2% HPMC vs
0.5% MC. As we know, any significant differences in the rheological
properties could influence the rate of drug absorption.
If one of the formulations had formed a depot (high viscosity) there
could be a sustained release and the other having a good spreadability
(low viscosity) could result in rapid absorption (low Tmax). This
could highly influence the exposure (AUC) and thus the activity.
If you have time dependent conc profile in plasma as well as your
target tissue, we could get more information on the absorption pattern.
As you have used higher percent of MC compared to HPMC there could be
such a possibility.
However, if both the excipients you have used have similar viscosity,
this may not be a plausible explanation.
Thanks
Ravi Talluri Ph.D
Sai Advantium, Pune
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Dear Sebastien,
What activity are you looking for ? in which organ, muscle, liver or
both ?
Best regards,
Benjamin
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Dear Ravi and Benjamin,
The viscosity of both preparation has not been checked and we don't
have unfortunately the comparison of the full plasma PK profile for
both vehicles for this compound. However, structural analogues give
the same pattern with the following plasma time concentration profile:
Time: 0;0,25;0,5;1;3;6;8 (h)
HPMC: 0;3700;6250;4510;3020;1180;697 (ng/mL)
MC: 0;3250;4340;2300;3420;1550;1760 (ng/mL)
The activity is systematically higher when the compound is dose with
MC 0,5% as a vehicle. We are looking for an activity which is mediated
in part via the muscle and in part via the liver.
Thank you for your thoughts
Best regards
Sebastien
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The following message was posted to: PharmPK
Hello Sebastien,
Thanks for sharing the data with us.
These are my comments
- Your drug seems to have better plasma exposure basing on the 1h data
you have shared earlier with both the formulations (MC - 36 vs 2.3ug/
mL; HPMC- 48 vs 4.5 ug/mL)
- The plasma profile with MC seems to have some flips in between (3 &
8h)-drug being same this could be something related to uniformity of
the formulation.
- I haven't done the pK analysis but it looks like exposure (AUClast)
could be similar with both the formulations.
- However, Clast was quite significantly different (697 for HPMS vs
1760 ng/mL for MC) - This could due to low clearance in case of MC.
However, assuming same drug and dose, chances are unlikely - could be
again related to change in the formulation.
- We can observe this predominantly, if we look at the data for few
more time points (12, 24 48h...)
- More importantly, the difference between the Cmax and Clast was much
lower for MC (5500 (MC) vs 2580 (HPMC))-sustained absorption???
- The comparison of Ka values would give us better picture- I guess
even MRT and/or MAT would be more with MC formulation - We should be
cautious in interpreting the rate constants as there could be a
possibility of flip-flop kinetics.
- Basing on these observations I still feel that MC has resulted in
slow and sustained release of the drug compared to HPMC which again
could be related to viscosity or formation of a depot as I have
mentioned earlier.
Thus inspite of resulting similar exposure, the sustained release from
MC could have lead to higher activity.
I donno....May be I am more biased towards formulation aspects and
ignored other important physiological and/or pharmacological issues.
The other experts could shed some light on this...
Thanks
Ravi Talluri
Sai Advantium,
Pune, India
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