Dear All,Back to the Top
We are working on CPT Derivative(Anti-cancer NCE molecule). We
carried out Oral pk with Suspension which contains NCE, cremophor,
DMSO, Sodium taurcholate and Ethanol, which gave exposure (AUC)of 7
microg/ml, while IVPK of same NCEwith Cyclodextrin and captisol gave
exposure of 1.8 microg/ml and vary in clearance and volume of
distribution with that of Suspension.
I am greatful if any one can suggest why there is 3 fold decrease in
AUC with IVPK and how variation in the composition of suspension and
Solution for IVPK will matter.
Thanks in advance
Venkatesh.P
Senior Pharmacologist,
Dept of Drug Metabolism and Pharmacokinetics,
Discovery Research, Dr.Reddy's Labs.
Hyderabad, India-500050.
Back to the Top
Dear Venkatesh,
Give your oral formulation in the same vehicle (i.e.
cyclodextrin/captisol)
and you would get the same AUC's by oral route as that of IV.
We have extensively studied this phenomenon in our work on
anti-infectives,
where cyclodextrin given IV brings down the AUC as compared to the oral
route where the NCE is given in Tween formulation. Seems cyclodextrin
brings down the AUC's.
Let me know about your findings !.
Yati Chugh
Wockhardt Research Centre.
Aurangabad.
Back to the Top
Hello all,
"We carried out Oral pk with Suspension which contains NCE, >cremophor,
DMSO, Sodium taurcholate and Ethanol, which gave >exposure (AUC)of 7
microg/ml, while IVPK of same NCEwith >Cyclodextrin and captisol gave
exposure of 1.8 microg/ml and vary in >clearance and volume of
distribution with that of Suspension.
I am greatful if any one can suggest why there is 3 fold decrease in
AUC with IVPK and how variation in the composition of suspension and
Solution for IVPK will matter.
"
How can we get such surprising results ?
1- Are your respective PO and IV doses comparable ? I mean "was the
same dose administered or are your results normalized with the
respective doses ?
2- The PO vehicles used (Cremophor at least) can be absorption
promoters which means that you may probably have overestimated the
absorption but never mind your po results should not be higher than iv
data if comment 1 is respected.
3- Cyclodextrin is responsible for drug complexation leading to some
reduction in drug exposure levels if the drug remains complexed. You
should perform a complexation constant calculation to ensure your drug
can easily leave he cyclodextrin complex.
4- Captisol may solubilize the drug at a quite high level. When this
formulation is dosed in the blood circulation there is a massive
precipitation leading to a great loss of solubilized drug molecules.
In conclusion each time you have such surprising results (ivAUCI would recommend first to investigate on the precipitation hypothesis
before going on with other ones.
I hope this helps,
Frederic Doc
Back to the Top
Venkatesh.P,
Maybe this great difference in bioavailability of oral formulation when
compared with iv formulation could be explained by use of cremophor in
your suspension. Cremophor is not an inert additive in pharmaceutical
formulations because its has been shown to inhibit P-glycoprotein in
vitro(*).
Please, take a look at this article: Martin-Facklam, M et al.
Dose-dependent increase of saquinavir bioavailability by the
pharmaceutic aid cremophor EL. Br.J.Clin.Pharmacol 2002; 53: 576-581.
Regards,
Daniel Rossi de Campos, M.Sc
Brazil
(*) Cornaire, G et al. Effect of polyoxyl 35 castor oil and polysorbate
80 on the intestinal absorption of digoxin in vitro.
Arzneimittel-Forschung 2000; 50: 576-579
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)