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Please could someone advise on the following scenario?
There are two potent CNS compounds in early development. For each
compound, there is good in vitro human microsomal and hepatocyte data
and PK in rats, dogs and monkeys.
In vitro-in vivo scaling and allometry predict that Compound X has low
hepatic metabolism and is predominantly eliminated by renal clearance
with net tubular secretion (~3-fold GFR in rats). Oral bioavailability
is predicted to be ~90% and consistent.
For compound Y, elimination is mainly by hepatic metabolism, with
lower renal clearance (equivalent to GFR in rats; fu~1);
bioavailability is modest (19-50%) and variable.
Only one compound is allowed to be selected for further development.
Which compound should be selected (potency, half-life, Vss etc are
equivalent).
Many thanks for any response.
Best Regards,
Charlie Brindley
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Hello
My personal opinion:
You have to consider if the drug will be used in monotherapy or in
adjunctive setting (combination with other drugs). If used in
combination with drugs that can inhibit its metabolism, then you might
have more inter-patient variability in PK and probably in
pharmacodynamics.
Atul
Venkatesh Atul Bhattaram
Pharmacometrics
Office of Clinical Pharmacology
US Food and Drug Administration
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Any in vivo receptor occupancy or fu brain/ CSF level data available?
Toxicity data may also be important.
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Charlie,
The answer depends on what you know about the safety and effectiveness
(see Holford 1999). If variability is too large for safe and effective
therapy when everyone is given the same dose then it becomes important
to be able to predict PK.
If this is the case then this seems to be a 'no-brainer'. Any drug
with minimal variability in bioavailability and whose clearance is
easily predictable (e.g. from creatinine clearance) will be easier to
use in a safe and effective way than a drug with variable
bioavailability and unpredictable hepatic metabolism.
Nick
Holford NHG. Target Concentration Intervention: Beyond Y2K. Br J Clin
Pharmacol. 1999;48:9-13.
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Charlie,
Other criteria you may want to add to your equation might be the
target patient population (age, ethnicity, type of disease and its
effect on the eliminating organs) and possible polymorphism in enzyme
activity.
In general, I would take the renally cleared compound as my first
choice. You have a good bioavaiiability, probably less variability
caused by first-pass effect, and possibly a better scalability from
your animal models.
Toufigh
Toufigh Gordi, PhD
Clinical Pharmacology, PK/PD analysis consultant
www.tgordi.com
E-mail: tg.-a-.tgordi.com
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Hi Satya Jadhav,
Thank you for your response; we do have information on brain/CSF:plasma
concentrations and CSF correlates with efficacy. There's nothing to
chose
between the two compounds by this approach.
Charlie
--
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Hi Nick and Toufigh,
Many thanks for your responses; my query largely stems from a
colleague at a
major pharmaceutical company indicating that they de-select compounds
with
high renal clearance. Perhaps, it's their experience in a specific
therapeutic area?
My understanding is that drugs eliminated predominantly renally scale
better
than those metabolised. Furthermore, clinical use could be more
effective
(e.g. dose adjustment for carboplatin).
Would you have any concerns on possible renal secretion in man?
Bets Regards,
Charlie
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Dear Charlie:
I would go with the one with good bioavailability
(reproducible uptake) and renally eliminated. You can develop really
good dosing guidelines for that. The other drug has variable
bioavailability, and is more likely to need TDM because of that,
perhaps for effectiveness.
Very best regards,
Roger Jelliffe
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Hello,
The compound X with high and consistent oral bioavailability seems to
be better. And also as already been pointed, if the compound (Y) is
subjected to CYP metabolism, there could be a possibility of drug-drug
interactions for which you need to do a whole range of studies.
Do you their brain penetration ratio? I don't know whether any of
these is also a substrate of any efflux pumps that could be important
especially at BBB.
What is the therapeutic range? Will it fall into narrow therapeutic
range? Do you have any toxicity data?
I think Css and dosing interval (Tau) should also be looked at before
going ahead.
Thanks
Ravi Talluri
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Hi Charlie,
Some other factors helpful in your making decision
- Bioavailability and disposition in higher species (dog / monkey)
- I will go one with similar metabolites across species
- Brain/plasma ratio (important for CNS compounds)
- PD and early toxicity (AMES mutagenicity, hERG binding) data
Best regards,
Jayasagar
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What do the two drugs displace competitively from tubular secretion and
hepatic metabolism respectively? Will either influence metabolism of
concomitant drugs or an endogenous hormone or neurotransmitter to a
remarkable level?
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I suppose the other thing to think about would be dosing to
renally-impaired patients, I don't know whether this is or isn't
relevant to your target population. Could that be a reason why the major
pharmaceutical company you mentioned in a previous email de-select
compounds with high renal clearance?? But as mentioned, knowing
creatinine clearance will help assess renal function before dosing...
Kathryn
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I inquired with Prof. Uwe Christians, a PK/TK expert at UC Denver who
was
trained under Les Benet at UCSF - if Les is the godfather of PK, as many
have called him, then Uwe is the godson. His particular area of
expertise is
renal toxicity. His comment, in his typical matter-of-fact fashion,
was as
follows:
"Based on the data provided, compound X is the candidate that should be
chosen. Y seems to be a CYP3A/ p-glycoprotein/ drug-drug interaction
mess."
Mickey
Mickey O'Brien, MS
Global Head of Business Development
GEL Analytics
701 Pine Ridge Road
Golden, CO 80403
www.gel.com
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