Back to the Top
We have standard IV 2mpk and IV 10mpk rat PK study
Three rat bioavailability are 656%, 112%, 124% which led to mean F% = 297%
What is possible cause for the nonlinear PK? The clearance is extremely low -1.10 mL/min/kg. So self-inhibition metabolism should not be the cause?
Many Thanks
Back to the Top
The following message was posted to: PharmPK
Dean,
You said:
"We have standard IV 2mpk and IV 10mpk rat PK study
Three rat bioavailability are 656%, 112%, 124% which led to mean F% = 297%
What is possible cause for the nonlinear PK? The clearance is extremely low
-1.10 mL/min/kg. So self-inhibition metabolism should not be the cause?"
Have you considered enterohepatic circulation?
Best regards,
Walt
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
Back to the Top
The following message was posted to: PharmPK
Hi there,
I'd love to try to help but I'll need some more information first.
I think it would be helpful to have some more experimental details:
Did you really do two IV groups, or is the 10 mg per kg group PO? Is the bioavalibility from a different experiment? If so, what was that experiment?
If they are both IV, what do you mean by %F?
Was your experimental design, with time points for both groups?
What were the formulations? Were they solutions? Suspensions? Does your drug have good solubility that would be maintained at blood pH?
-Rachel
Back to the Top
The following message was posted to: PharmPK
Hello Dean
Take a look at this paper.
Xenobiotica. 2004 Apr;34(4):367-77.
Apparent absolute oral bioavailability in excess of 100% for a vitronectin receptor antagonist (SB-265123) in rat. II. Studies implicating transporter-mediated intestinal secretion.
Ward KW, Hardy LB, Kehler JR, Azzarano LM, Smith BR.
regards
David
David Turner PhD
Principle Scientist
Simcyp Limited
Sheffield
S2 4SU
UK
www.simcyp.com
Back to the Top
The following message was posted to: PharmPK
Hello Dean,
Bioavailability >100% can also be caused by problems in the
bioanalytics. If you have ion suppression in your IV arm due to the
formulation, then the IV plasma levels are underestimated which can lead
to an erroneous Fabs >100%. Especially formulations like PEG400 and
tween in IV could cause these problems.
Regards,
Ronald
Back to the Top
The following message was posted to: PharmPK
Dear Dean,
There are several possible reasons. 1- You may have not well characterized your iv PK profile due to analytical sensitivity , which may lead to underestimation of the AUC after iv and thus overestimation of absolute bioavailability. 2- There may be a saturable clearance at the high dose given orally and not with the lower iv dose.
You can easily check point no. 1. To adress the second possibility a study with similar iv and po dose would be useful.
I do not understand the design of your current study whether the 3 values reflect 3 different animals or three different experiments. Details would help in further explanation.
Regards, YH
Dr Youssef Hijazi
Drug Metabolism and Pharmacokinetics
Novartis Pharma AG
Basel, Switzerland
Back to the Top
The following message was posted to: PharmPK
Dear Dean and Ronald,
It is possible to avoid ion suppression by tweeking the gradient a bit,
to push coeluting PEG peek away from the analyte. Although FDA does not
stipulate any limit for IS response variation, it is a good idea to keep
a tight limit, say 20 % ,throughout the batch. This would ensure that
signal suppression will not have adverse effect on estimation of
analyte.
Regards,
Vinayak Nadiger
Vinayak Nadiger
Manager, Bioanalytical
Forma Therapeutics(Singapore)
11,Biopolis Way ,Helios # 08-05
Singapore 1386607
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "Non linear bioavailabilty" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)