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proceed to an ecacy study to treat acute pain after molar extraction. In this
Phase Ib study, subjects were administered a single dose of placebo, 2, 8, or
15mg of AMG 517 as soon as they experienced moderate to severe post-
operative pain. Body temperature measurements obtained from this study are
illustrated in Figure 13.15B. A 2mg (or approximately 29 mgkg
1
) dose of
AMG 517 triggered hyperthermia that exceeded 40 1C in one subject, with
hyperthermia of 439 1C that persisted for three days despite multiple doses of
antipyretic medication. Similar marked hyperthermia that persisted for two or
more days was also observed in two subjects who received a 15mg dose of
AMG 517 after molar extraction. Hyperthermia of 438 1C was observed in
three out of four subjects who received 8 mg of AMG 517. Body temperatures
of 39-40.2 1C persisted for 1-4 days in 33% of the subjects who received AMG
517 after molar extraction, with no other observed cause for this marked and
persistent hyperthermia. These studies also indicated that the largest-magni-
tude hyperthermia (440 1C), which occurred in one out of three subjects who
received 2mg of AMG 517, appeared to be related to individual susceptibility.
The emergence of this marked and persistent hyperthermia observed in subjects
undergoing molar extraction presented a major hurdle for the clinical devel-
opment of AMG 517. Although the plasma concentrations of AMG 517
observed in this Phase Ib study were similar to those obtained in the first
pharmacokinetic and safety study, such large magnitude and persistent
hyperthermia was not observed after exposure to AMG 517 in healthy subjects.
It is possible that the surgical procedure and TRPV1 blockade may have acted
additively or synergistically to produce an undesirable, marked, and persistent
hyperthermia in susceptible individuals. Alternately, access of AMG 517 in
solution to normal or sensitized TRPV1 receptors in the surgical wound may
have contributed to the differences in hyperthermia produced by AMG 517 in
these two populations.
Because of hyperthermia after exposure to single and multiple doses of AMG
517 in healthy volunteers, and due to marked and persistent hyperthermia after
exposure to single doses of this molecule in subjects who underwent molar
extraction, clinical studies of AMG 517 were discontinued. Unfortunately, too
few subjects were evaluated to determine the potential analgesic effect of AMG
517 due to the early termination of this study and therefore the target coverage
of AMG 517 required for analgesia in humans remains unknown. Because the
second-generation backup compound, AMG 628, had a similar in vitro profile
as AMG 517 and it also caused hyperthermia in preclinical models, it was not
advanced into clinical trials.
13.6 Approaches to Address the Hyperthermic
Response
Due to the undesirable hyperthermia observed for AMG 517 in humans, we
examined the effect of TRPV1 antagonists on body temperature regulation
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