Chemistry Reference
In-Depth Information
with the mechanism of action, was also observed, which was smaller than a
9.4% increase in MAP observed for duloxetine at a similar free plasma
concentration.
Finally, compound 14 did not produce dose-limiting toxicity in sub-chronic
(14-day) oral rat (up to 30mg kg
1
) and dog toxicology studies (up to
7.5mg kg
1
). It was also clean in in vitro and in vivo genetic toxicology screens
and did not produce significant effects on spontaneous locomotor activity
compared to vehicle control when administered orally up to 15mg kg
1
in rats.
12.3 Pre-clinical and Clinical Pharmacokinetics of
PF-184298
Preclinical pharmacokinetic studies with PF-184298 following intravenous
administration to male Sprague Dawley rats and male beagle dogs showed the
compound to have moderate to high plasma clearance (38mLmin
1
kg
1
and
40mLmin
1
kg
1
, respectively) and volumes of distribution of 3.4 L kg
1
and
7.1 L kg
1
, respectively. These properties resulted in terminal elimination half-
life values of 1.2 h in the rat and 2.2 h in the dog (Table 12.1). The high volumes
of distribution were in keeping with the physicochemistry of PF-184298 (log
D
7.4
¼
0.6, pK
a
¼
10.0). Following oral administration, PF-184298 was rapidly
absorbed in rat and dog, and showed moderate oral bioavailability (50% and
28%, respectively), despite liver blood flow-limited clearance in the dog (dog
liver blood flow assumed to be 40mLmin
1
kg
1
) (Table 12.2). Bioavailability
in the rat suggested complete absorption from the gut, based on a clearance of
38mLmin
1
kg
1
and an assumed liver blood flow of 70mLmin
1
kg
1
. This
was in keeping with high solubility of 412mgmL
1
in aqueous media
(including water and simulated gastric fluids), and high intrinsic membrane
permeability observed in CaCO-2 cells.
A number of studies were carried out in an attempt to understand the likely
clearance mechanism of PF-184298 in man and to aid in the clearance pre-
diction. In vitro metabolism studies showed that hepatic metabolism occurred
in rat and dog via oxidative (''Phase 1'') processes (Figure 12.13). Furthermore,
metabolites detected in vitro in rat hepatocytes were also present in vivo
(excreted in bile). Administration of [
3
H]-PF-184298 to dogs resulted in
Table 12.1 Pharmacokinetic parameters of PF-184298 in plasma following
intravenous administration to rats and dogs.
Rat (n
¼
2)
a
Dog (n
¼
2)
a
Dose (mg kg
1
)
2
0.0125
Cl (mLmin
1
kg
1
)
38 (29-48)
40 (25-54)
AUC
0
N
(ng hmL
1
)
933 (694-1171)
6.1 (3.8-8.3)
V
D
(L kg
1
)
3.4 (2.7-4.2)
7.1 (5.6-8.6)
T
1/2
(h)
1.2 (0.7-1.7)
2.2 (1.8-2.6)
a
Data presented as arithmetic mean; figures in parentheses represent range.
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