Extended-release tablets of ralinepag, Arena Pharmaceuticals’ treatment candidate for pulmonary arterial hypertension (PAH), show a superior pharmacokinetic profile over both immediate-release ralinepeg capsules and approved immediate-release medication Uptravi (selexipag), according to two Phase 1 trials in healthy volunteers.
Pharmacokinetics (PK) refer to how a drug is absorbed, distributed, metabolized, and excreted in the body.
Trial data was presented by John Adams, PhD, Arena’s vice president of translational science, at the recent European Society of Cardiology Congress, held in Munich, in a presentation, titled “Relative bioavailability and pharmacokinetic (PK) performance of a ralinepag extended-release (XR) tablet oral formulation and the effect of food and gender in healthy human subjects.”
Ralinepag, also known as APD811, is a next-generation, selective prostacyclin receptor agonist designed to be taken orally. Prostacyclin is a hormone produced by cells lining the walls of blood vessels, with known vasodilator — blood vessel widening — and anti-inflammatory effects. It also is a potent inhibitor of platelet clumping and the growth of blood vessel muscle cells.
Ralinepag’s extended-release tablet is intended to allow for once-daily dosing. Prior research showed that its immediate-release capsule had an extended half-life (nearly 24 hours) over Arena’s Uptravi (up to 2.5 hours) and its active molecule MRE-269 (up to 13.5 hours). Half-life refers to the time required for the amount of a compound in the body to be reduced by half, an indicator of how long it has an effect.
The open-label Phase 1 trial included a total of 61 healthy individuals.
In the first trial, 12 participants who had fasted took single, oral doses of ralinepag in a sequential manner — 0.03 mg of the immediate-release capsule, and then 0.06, 0.12, and 0.18 mg doses of the extended-release tablet. This group was compared with oral, immediate-release tablets of Uptravi in sequential 0.2, 0.4, and 0.6 mg doses.
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In the second trial, extended-release ralinepag was given over 25 days, starting at 0.06 mg once daily and potentially increasing up to 0.3 mg, depending on the individual’s tolerability. The study included a group of 19 individuals who had fasted and a group of 18 individuals who had eaten.
Results showed that, as expected, the once-daily extended-release formulation led to a lower plasma level of ralinepag than the immediate-release capsules. However, the extended-release tablets had a superior half-life of 28-29 hours and maintained low peak-trough fluctuation, which means there was little variability in ralinepag’s plasma levels within each dosing.
Researchers also found that food had little effect on plasma levels of the therapy, and that a somewhat higher mean plasma exposure level was observed in females versus males.
“The ralinepag XR tablet formulation offers improved PK performance over both ralinepag and selexipag IR formulations,” the scientists wrote.
“With an extended half-life and low peak-to-trough fluctuation, the ralinepag XR tablet closely approximates the PK profile of continuously infused IV [intravenous]-prostacyclin,” Preston Klassen, MD, Arena’s chief medical officer, said in a press release.
In April, Arena reported results from a 13-week Phase 2 trial (NCT02279160) in 60 PAH patients, which showed that ralinepag reduced the risk of death. Key Phase 2 results presented in 2017 included improved blood flow in lung arteries and greater exercise capacity, as measured by the distance walked in six minutes.
The company is currently conducting a Phase 3 trial (NCT03626688) to evaluate the effectiveness and safety of ralinepag in PAH patients. The trial is recruiting participants in the U.S.; for more information on study locations and contacts, visit this link.
“These highly favorable and desirable PK characteristics further support the use of the ralinepag XR tablet in the ADVANCE Phase 3 clinical program,” Klassen said.