The Discovery of TRPV1 Antagonists: Turning up the Heat - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 300

increased in an approximately dose-proportional manner; Figure 13.14A).
Consistent with the long half-life of this molecule in rats, dogs, and monkeys, a
long mean t 1/2 range of 13-23 days was observed in humans across the dose
range evaluated. No indications of safety issues were observed upon AMG 517
administration except moderate, generally dose- and plasma concentration-
dependent, increases in body temperature (Figure 13.14B). An increase in body
temperature typically occurred between 1 and 4 h after AMG 517 administra-
tion, and returned to baseline values within 24 h, suggesting the transient nature
of hyperthermia induced by AMG 517. In addition, the C max was observed at
1-2 h post-dosing, usually earlier than the peak increase in body temperature,
suggesting that the development of hyperthermia after exposure to AMG 517 in
healthy subjects was the result of a physiologic response to TRPV1 blockade.
During this study, an exception to plasma concentration-dependent hyper-
thermia was observed in one subject (in the 25mg dose group) whose body
temperature was increased to 39.9 1C, although this person did not have the
highest C max (Figure 13.14B). Thus, despite overall dose- and plasma con-
centration-dependent hyperthermia, the magnitude of temperature elevation
after exposure to single doses of AMG 517 also reflected individual suscept-
ibility to the hyperthermic effect of TRPV1 blockade.
As mentioned previously, when AMG 517 was administered daily to rats,
dogs, or monkeys, hyperthermia was attenuated to values indistinguishable from
the vehicle-treated groups. This habituation, or attenuation, to the hyperthermic
effects of AMG 517 supported the initiation of a Phase I multiple-dose study in
humans. When subjects were exposed to daily single oral doses of AMG 517 (2,
5, or 10mg) for seven days, they had dose-dependent increases in body tem-
perature, with the mean maximal temperature reaching 38.3 þ 0.1 1C on the first
day of drug administration (Figure 13.15A). There was a statistically significant

Figure 13.14 (A) Pharmacokinetic profile of several doses of AMG 517 in human

volunteers (1-25mg). (B) Mean of the maximum body temperature
(tympanic) vs. maximum observed plasma concentration following oral
administration of single doses of AMG 517 (1-25mg). Reproduced
with permission of the International Association for the Study of Pain.