PharmPK Discussion - Flip-Flop

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On 15 Feb 2003 at 08:04:42, Norman tat (normantat.-a-.yahoo.com) sent the message


The following message was posted to: PharmPK

Dear everyone,

Our NCE (small molecule) shows 100% oral
bioavailability with flip-flop PK profiles. However the
molecule shows efficacy only by IV not by PO. I do not
know why.
Could anyone give me any explanation and/or suggestion
to see efficacy by PO?

Thank you in advance.

Norman

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On 15 Feb 2003 at 11:26:38, Walt Woltosz (walt.aaa.simulations-plus.com) sent the message


What are the differences in plasma concentration-time between your iv
and PO doses - especially Cmax?

Since you say it shows flip-flop kinetics, absorption is slow, so one
would suspect that the plasma concentration-time profile for the PO is
long and flat compared to a sharp peak followed by clearance for the iv
dose. If efficacy requires reaching a certain minimum concentration,
the PO dose may not be doing so.

If you have the data, a pharmacodynamic model could be fitted from the
iv effect-time data and then used to predict the effect for the PO
plasma concentration-time curve to see if it would predict a measurable
effect.

Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.-a-.simulations-plus.com

Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.-a-.simulations-plus.com

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