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The following message was posted to: PharmPK
We completed a clinical study of one of our compounds with the
objective of investigating the effect of hepatic impairment on the PK
of this drug. This drug is given orally, is metabolized mainly by
CYP3A4, is a substrate of P-gp and is also known to inhibit 3A4. The
protein binding for the drug is approximately 60% and it is excreted
in the feces (% excreted in the urine is less than 1%). We compared
the PK of this drug in healthy volunteers and in subjects with mild
and moderate hepatic impairment. The results show that while there are
no siginificant differences in PK parameters between healthy
volunteers and subjects with mild hepatic impairment, the exposure in
subjects with moderate hepatic impairment is much LOWER than in
healthy volunteers. Given the metabolism of this compound by CYP3A4,
we would have expected the exposure to be higher. The Cmax and AUC
seen in subjects with moderate hepatic impairment are approximately
half of that seen in healthy volunteers while the half-life is
1.5-fold higher. Can anyone help us understand what may be going on
here? What are some of the possible explanations for these
observations? Thanks for the help.
--
Hong Lu
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The following message was posted to: PharmPK
Dear Hong Lu,
With 3A4 substrates dosed orally, gut metabolism can be significant. In
fact, for some drugs, more first pass extraction occurs in gut than in
liver. Given that you would expect liver metabolism to be lower with
hepatic
impairment, and that systemic clearance is observed to be lower (longer
half-life), a possible explanation is that gut metabolism is higher.
This
would occur if the expression level of 3A4 in gut is somehow up-
regulated as
a result of the hepatic impairment. I have no idea whether such
up-regulation occurs.
Another possibility is increased efflux. You noted that the compound
is also
a P-gp substrate. Greater expression of P-gp would lead to greater
efflux in
the lower intestinal tract. You mention that you measure parent drug in
feces, but you did not say how much. Is it more in impaired patients?
This is an ideal problem for analysis with GastroPlus(tm)!
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
E-mail: walt.-a-.simulations-plus.com
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Hong,
Another possibility is absorption related. If compound exhibits pH-
dependent solubility and solubiity limited absortion, it is likely
that there is reduced absorption in moderate or severe hepatic
impaired subjects. In this population, gastric pH and incidence of
hypochlorhydria could be ususally high compared to normal subjects.
Shruti
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