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From: "Jacqueline Gibbons"
Subject: Cmax with an IV Infusion
Date: Sat, 14 Jun 2003 23:55:53 -0700
PharmPK Question:
I'm working on an NCE that's showing unusual IV kinetics: when administered as a constant-rate IV infusion over 1 hour, the observed Cmax occurs at the first sample time after the start of the infusion, 15 minutes. Thereafter, plasma concentrations show log-linear decline, with no apparent change in slope at the end of the infusion. The monexponential decline persists through the end of the sampling period (4 to 6 hours after the cessation of the infusion). Thus the plasma concentration-time plots look exactly like plots expected for IV injections (not IV infusions!). This observation has been made in a number of studies (fairly large numbers of animals), and in more than 1 species, so it seems "real" (i.e., not an experimental aberration). Does anyone have insights to share concerning potential mechanism(s) for these kinetics?
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From: Rostam Namdari
Date: Mon, 16 Jun 2003 18:18:36 -0700 (PDT)
Subject: Re: PharmPK Cmax with an IV Infusion
The following message was posted to: PharmPK
Dear Jacqueline,
I have seen this but it would be useful if you can
provide more info. 1) What is the infusion volume (in
each species), 2) MW and lipid solublility of the
drug?
Rostam
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The following message was posted to: PharmPK
This pk behaviour may be explained by a drug with an elimination process
faster than the infusion rate.
José Antonio Cordero
Ipsen Pharma S.A.
Barcelona
Spain
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The following message was posted to: PharmPK
Dear Nathalie,
How much longer after the end of the infusion do you see the Cmax? If
your
observed Cmax occurs in the first sample taken after cessation of the
infusion, then the explanation offered below (by Jose) seems reasonable
(clearance exceeds the infusion rate). If the Cmax occurs later than
this
(e.g., the concentration-time data indicate a peak in serum levels
after the
infusion is finished), it's possible that the molecule is subject to
enterohepatic cycling.
Best regards,
Jackie
Jacqueline Gibbons, Ph.D.
Piedmont, CA 94611
gibbonsj.-a-.pacbell.net
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Hi to All:
I've received a few requests for more details on this puzzling NCE (see
below). I apologize for not providing more complete information in the
first place. Here are the specifics:
Molecular Weight ~ 650 Daltons
Molecular Properties: Highly lipophilic; based on data with an analog
compound, we expect a large degree of partitioning into adipose
Infusion Parameters: In both dogs and rats, the NCE has been infused IV
in
volumes ranging from 1 to 10 mL/kg. The infusions have been set at
constant
rate and last for 1 hour. The dose sizes have ranged from 15 to 2000
mg/kg.
Recap the problem: In 4 separate preclinical studies in which the NCE
was
infused IV over 1 hour, the plasma concentration-time profile looked
almost
exactly like the profile of an IV injection, not an IV infusion
(monoexponential decline DURING the infusion and beyond the end of the
infusion). This phenomenon occurs regardless of the dose size. I'm
hoping
for insights concerning potential mechanism(s) underlying the kinetics.
Many thanks,
Jackie
Jacqueline Gibbons, Ph.D.
Piedmont, California
gibbonsj.-at-.pacbell.net
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Dear Jacqueline,
What is puzzling is that in some subjects the Cmax happens much later.
Furthermore, the molecule is not subject to EHC, and is highly
soluble...
Any other idea from anybody?
Best regards
Nathalie
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