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Are there any examples of drugs for which the plasma concentration-effect
relationship is better defined using a surrogate marker, such as the plasma
concentration of a metabolite? Please provide literature references or
other substantiating evidence if possible.
Bertil Wagner, Pharm.D.
Hoffmann-La Roche, Inc.
340 Kingsland Street
Nutley, NJ 07110-1199
tel: (973) 562-5515
fax: (973) 562-5509
e-mail: bertil_k.wagner.-at-.roche.com
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[Two replies - db]
Sender: acy62.-at-.pop.dial.pipex.com
Subject: Re: PharmPK Pharmacodynamics Question
Date: Wed, 25 Nov 98 15:52:13 +0000
x-sender: acy62.aaa.pop.dial.pipex.com
From: Andrew Sutton
To: "Pharm PK"
Mime-Version: 1.0
One of the best examples must be Roche's own diazepam, the metabolites of
which contribute much activity, more than the parent compound due to
longer elimination half lives. Desmethyl diazepam is I think the main one.
Some antivirals are inactive until metabolised and Beecham in the UK
before the SK merger produced a NSAID prodrug called nabumetone which is
very well documented. Another analgesic of interest would be morphine
where one of the glucuronidated metabolites (the 6) seems to be equal or
more active than the parent while another (the 3) may have no activity at
all..Another interesting product from Beecham in this regard is
clavulanic acid which blocks betalactamase defence by bacteria to the
beta-lactam antibiotic with which it is co-formulated. Levels of
clavulanic acid relate to activity against the enzyme though not
necessarily to the bactericidal capability of the combination...
You've opened an interesting topic here and I'd like to know what you
learn from it
Andrew Sutton, MD(London)
Guildford Clinical Pharmacology
ASutton.-a-.gcpl.co.uk.
Andrew Sutton
ASutton.-a-.gcpl.co.uk
Guildford Clinical Pharmacology
Telephone +44 (0) 1483 406886
---
From: "Piotrovskij, Vladimir [JanBe]"
To: "'BERTIL_K.WAGNER.at.roche.com'"
Cc: "'PharmPK.-at-.pharm.cpb.uokhsc.edu'"
Subject: RE: PharmPK Pharmacodynamics Question
Date: Wed, 25 Nov 1998 08:34:41 +0100
MIME-Version: 1.0
Dear Dr. Wagner,
One possible example is risperidone. The parent drug and its hydroxy
metabolite are equally potent and both should be measured in plasma for any
PK-PD correlation. In extensive metabolizers (CYP2D6) plasma levels of the
metabolite at steady state are far higher than those of parend compound.
However, in poor metabolizers the levels are comparable, and even
risperidone may exceed the metabolite.
References:
Snoeck E. Van Peer A. Sack M. et al. Influence of age, renal and liver
impairment on the pharmacokinetics of risperidone in man.
Psychopharmacology. 122(3):223-9, 1995
He H. Richardson JS. A pharmacological, pharmacokinetic and clinical
overview of risperidone, a new antipsychotic that blocks serotonin 5-HT2 and
dopamine D2 receptors. [Review] International Clinical Psychopharmacology.
10(1):19-30, 1995
Hope this helps
Vladimir
---
Vladimir Piotrovsky
Clinical Pharmacokinetics
Janssen Research Foundation
2340 Beerse, Belgium
e-mail: vpiotrov.-at-.janbe.jnj.com
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[Two replies - db]
Sender: acy62.aaa.pop.dial.pipex.com
Subject: Re: PharmPK Pharmacodynamics Question
Date: Wed, 25 Nov 98 15:52:13 +0000
x-sender: acy62.-at-.pop.dial.pipex.com
From: Andrew Sutton
To: "Pharm PK"
Mime-Version: 1.0
One of the best examples must be Roche's own diazepam, the metabolites of
which contribute much activity, more than the parent compound due to
longer elimination half lives. Desmethyl diazepam is I think the main one.
Some antivirals are inactive until metabolised and Beecham in the UK
before the SK merger produced a NSAID prodrug called nabumetone which is
very well documented. Another analgesic of interest would be morphine
where one of the glucuronidated metabolites (the 6) seems to be equal or
more active than the parent while another (the 3) may have no activity at
all..Another interesting product from Beecham in this regard is
clavulanic acid which blocks betalactamase defence by bacteria to the
beta-lactam antibiotic with which it is co-formulated. Levels of
clavulanic acid relate to activity against the enzyme though not
necessarily to the bactericidal capability of the combination...
You've opened an interesting topic here and I'd like to know what you
learn from it
Andrew Sutton, MD(London)
Guildford Clinical Pharmacology
ASutton.aaa.gcpl.co.uk.
Andrew Sutton
ASutton.at.gcpl.co.uk
Guildford Clinical Pharmacology
Telephone +44 (0) 1483 406886
---
From: "Piotrovskij, Vladimir [JanBe]"
To: "'BERTIL_K.WAGNER.aaa.roche.com'"
Cc: "'PharmPK.at.pharm.cpb.uokhsc.edu'"
Subject: RE: PharmPK Pharmacodynamics Question
Date: Wed, 25 Nov 1998 08:34:41 +0100
MIME-Version: 1.0
Dear Dr. Wagner,
One possible example is risperidone. The parent drug and its hydroxy
metabolite are equally potent and both should be measured in plasma for any
PK-PD correlation. In extensive metabolizers (CYP2D6) plasma levels of the
metabolite at steady state are far higher than those of parend compound.
However, in poor metabolizers the levels are comparable, and even
risperidone may exceed the metabolite.
References:
Snoeck E. Van Peer A. Sack M. et al. Influence of age, renal and liver
impairment on the pharmacokinetics of risperidone in man.
Psychopharmacology. 122(3):223-9, 1995
He H. Richardson JS. A pharmacological, pharmacokinetic and clinical
overview of risperidone, a new antipsychotic that blocks serotonin 5-HT2 and
dopamine D2 receptors. [Review] International Clinical Psychopharmacology.
10(1):19-30, 1995
Hope this helps
Vladimir
---
Vladimir Piotrovsky
Clinical Pharmacokinetics
Janssen Research Foundation
2340 Beerse, Belgium
e-mail: vpiotrov.aaa.janbe.jnj.com
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