Chemistry Reference
In-Depth Information
A
B
39
41
Placebo (N=7)
AMG 517 2mg (N=12)
AMG517 5mg (N=6)
AMG517 10mg (N=6)
40
38
39
38
37
37
36
36
placebo
2 mg
8 mg
15 mg
-1
1
2
3
4
5
6
7
AMG 517
Study Day
Figure 13.15
(A) Mean of the maximum body temperature (tympanic) after daily
oral administration of multiple doses of AMG 517 (2, 5, 10mg) for 7
days. Maximum tympanic temperature on day 1 for 10mg AMG 517
dose group was significantly higher compared to days -1 and 2-7.
Maximum tympanic temperature on day 1 for 5mg AMG 517 dose
group was significantly higher compared to days -1 and 2, 4-7. Mean
maximum body temperatures of all doses of AMG 517 were sig-
nificantly greater than placebo on days 1-7. There was no significant
temperature change for placebo group. (B) Tympanic body temperature
measurements of subjects exposed to placebo or different doses of
AMG 517 after third-molar extraction. Reproduced with permission of
the International Association for the Study of Pain.
attenuation of hyperthermia at the highest dose (10mg dose of AMG 517) on
days 2 through 7; however, the mean maximal body temperatures of all subjects
administered with all doses of AMG 517 were still significantly higher compared
to placebo-treated group over the 7-day dosing period. The reasons for unam-
biguous attenuation of hyperthermia after repeated exposure to all doses of
AMG 517 in preclinical species but not in humans are unclear. One possibility is
the differences in the doses used in preclinical species and in human studies. Rats
and monkeys received 3mg kg
1
and 30-500mg kg
1
, respectively, whereas the
maximum repeated dose for humans was 10 mg, or approximately 0.14mg kg
1
(199
36 ngmL
1
plasma concentration), which is about 20-fold lower than the
lowest dose used in rats. Doses greater than 0.14mg kg
1
were not used for
repeated dosing studies in humans because of the undesirable hyperthermia
observed at the higher doses in the first Phase I study, and because the long half-
life of AMG 517 in humans was expected to cause an accumulation during
repeated dosing. The plasma concentration of 10 mg dose of AMG 517 on day 8
was 199
36 ngmL
1
, which was approximately equivalent to the C
max
obtained
at 20 and 25mg doses used in the first Phase I study.
Although AMG 517 caused a generally plasma concentration-dependent
hyperthermia, it was unknown what plasma concentration of AMG 517 would
produce analgesia in humans and whether that concentration could be reached
without triggering hyperthermia. Since TRPV1 is expressed in the dental pulp
and is believed to contribute to pain after molar extraction, we decided to
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