Gradual dosing may limit side effects of narcolepsy drugs

Dosing strategies aimed at gradually raising drug levels in the body, instead of increasing levels all at once, may help limit the harmful cardiovascular effects of narcolepsy treatments, a study done in rats found.

The data suggest that a rapid rise in drug levels can trigger a spike in blood pressure, but this can be avoided with treatment paradigms designed to increase levels more slowly.

The study, “Mitigation of cardiovascular adverse effects while preserving wake-promoting efficacy of orexin receptor 2 − selective agonists,” was published in Scientific Reports. 

Narcolepsy is marked by bouts of sudden sleepiness during daytime. The most common form, narcolepsy type 1 (NT1), is caused by a loss of brain cells that make orexin (also called hypocretin). Orexin normally helps to regulate wakefulness by binding to a protein receptor called OX2R.

Orzeyful (oveporexton), an oral therapy from Takeda Pharmaceutical, was recently approved in the U.S. as the first treatment targeting the underlying cause of NT1. Orzeyful works as an agonist (activator) of the receptor protein OX2R, effectively replacing the activity of orexin. Several other OX2R agonists are in development as treatments for narcolepsy.

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Comparing treatment strategies

While activating OX2R may be a useful strategy for treating narcolepsy, data have shown that activating this protein receptor may cause high blood pressure. In this Takeda-funded study, four scientists working at the company tested an experimental OX2R agonist, OX-202, in rats. Their goal was to better understand how the pharmacological activity of the OX2R agonist relates to its effects on wakefulness and blood pressure.

“To provide the best therapeutic option for individuals with NT1, we explored strategies to maintain potent wake-promoting efficacy while reducing potential [cardiovascular] adverse events of OX2R agonists,” the team wrote.

The researchers compared two basic paradigms. In one, high doses of OX-202 were given by mouth, leading to a rapid increase in drug levels throughout the body. In this paradigm, wakefulness increases quickly and remains elevated, and at the same time, blood pressure spikes shortly after administration, then returns to normal.

In the other paradigm, OX-202 was given by injection under the skin, which allows levels of the drug in the body to rise more gradually. This led to improvements in wakefulness that occurred more slowly, but without the spike in blood pressure.

These data suggest that the increase in blood pressure in response to OX2R agonists isn’t driven by total drug levels in the body. Instead, this side effect seems to be triggered when drug levels rise rapidly. A slower rise in drug levels, by contrast, doesn’t trigger changes in blood pressure.

The researchers said this likely reflects differences in how the body responds to increased orexin signaling. They found that OX-202 can activate cells in a specific brain region, rostral ventrolateral medulla, that helps regulate unconscious bodily processes such as blood pressure.

The researchers proposed that it might be possible to quickly trigger wakefulness, without spiking blood pressure, by using preexposure. They gave the rats a low dose of OX-202 — not enough to promote wakefulness or alter blood pressure, but enough to start increasing drug levels in the body — then a second dose to get drug levels up to the level needed to promote wakefulness. As expected, the researchers found that this staggered treatment approach effectively improved wakefulness without increasing blood pressure.

The team noted that their data were limited to rat experiments, highlighting the need for additional studies to determine the safest ways to dose OX2R agonists in people.

“Continued preclinical and clinical optimization of OX2R-selective agonists is ongoing and may support the identification of suitable therapeutic options for individuals with [sleep] disorders,” they said.