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We have difficulty getting sufficient exposure in 2 preclinical animal
species (rabbit, monkey).The rat shows good exposure when administered
in gelatin mannitol solution. At Cmax ~900 ng/ml (50 mg/kg) in rat and
~42 ng/ml (dose 50-500 mg/kg) in monkey and 20 ng/ml in rabbit (50-500
ng/ml). Changing from gelatine mannitol to 100% PEG single dose in
monkey resulted in a Cmax of ~500 ng/ml at 50 mg/kg. Our hypothesis is
that we have a dissolution problem which is mainly due to the the
dissolution rate which is slower from the cristaline batch than from the
amorfe batch. The funny thing is that the rat does not show any
exposure problem after oral dosing. We think that the continuous
production of bile might be responsible for this difference.
Does anyone experienced a similar issue? What kind of excipeient was
then selecetd for the preclinical studies? We think that both po and sc
dosing route should solve the problem of the exposure. However, due to
our hypothesis the compound needs to be dissolved in the vehicle for
both routes to get different plasma levels for a proper tox study. Does
anyone has experience with PEG via sc route for a 4 week tox study in
monkey and a reprotox study in rabbit? How much could we give daily of
this PEG 400?
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If you're thinking it is a dissolution problem do you base that on a
delay in Tmax? Are the AUCs affected in the same manner?
(By the way, i suppose the gelatin mannitol is not really a solution?
Have you considered cyclodextrin as a vehicle?) More questions than
answers i'm afraid...
With best regards, Jan
Jan de Jong, PhD
Global Preclinical Development
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
1000 US Rt. 202, Raritan, NJ 08869, USA
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