LOUISVILLE—Intravenous COL-144, a selective 5-HT1F receptor agonist, is effective in relieving migraine but, unlike triptans, does not cause vasoconstriction, according to research presented at the 14th Congress of the International Headache Society. An oral solution and a tablet formulation were also well tolerated with no significant adverse events, reported Alison J. Pilgrim, MD, PhD, and colleagues.
“COL-144 is orally bioavailable, and at doses of 50 mg and greater achieves plasma levels previously associated with acute migraine efficacy after IV administration,” stated Dr. Pilgrim. “The tablet formulation gives similar plasma profiles to an oral solution, with the expected slight delay in tmax associated with disintegration and dissolution of the tablet. By the oral route, COL-144 shows dose proportionality with similar pharmacokinetics in males and females.” Dr. Pilgrim is the Chief Medical Officer of CoLucid Pharmaceuticals based in Durham, North Carolina.
In a previous prospective, randomized, group sequential adaptive, placebo-controlled study, Dr. Pilgrim’s group had found that IV administration of COL-144 demonstrated a statistically significant dose response regarding headache relief at two hours, and the onset of headache relief was evident at 20 to 40 minutes after dosing.
Oral Solution and Tablet Forms of COL-144
Dr. Pilgrim and colleagues conducted a randomized placebo-controlled study of single oral solution doses of 25 mg to 400 mg of COL-144 in 30 healthy male subjects. In a second study, the researchers compared the oral solution and tablet formulation of 200 mg of COL-144 in a double-blind, randomized, double-dummy comparison. Twenty-eight healthy men received the oral solution and the tablet on two separate dosing days in crossover fashion. The investigators then conducted a double-blind, randomized dose comparison in which 14 men and 14 healthy women received 50 mg and 400 mg of COL-144 as tablets in crossover fashion on two separate dosing days.
The researchers assessed the safety and tolerability of the drug by monitoring adverse events, vital signs, 12-lead digital ECGs, hematology, clinical chemistry, and renal markers. Plasma samples were analyzed using a validated liquid chromatography with tandem mass spectrometric detection method.
“The pharmacokinetics of orally administered COL-144 showed dose linearity from 25 mg to 400 mg in both males and females,” Dr. Pilgrim noted. “No significant difference in bioavailability of 200 mg COL-144 was observed for the tablet and solution formulations. Median tmax after administration of 50 mg to 400 mg COL-144 tablet formulation ranged between 1.5 and 2.5 hours.”
As for the safety of COL-144, “All doses of the solution and tablet formulations were well tolerated, with no clinically significant effects on vital signs, ECGs, or safety labs,” stated Dr. Pilgrim.
“Drowsiness, dizziness, and paresthesia were the most common adverse events with both formulations—most reports were mild, and none were severe. Interestingly, paresthesia, which was the most common drug-related adverse event after IV administration of COL-144, was substantially less common after oral administration.
Adverse events were similar in both genders, except that fatigue was more common in females (50%) than in males (21%) after the 400-mg dose.”
A Therapeutically Effective Dose
Dr. Pilgrim’s group also sought to predict an oral dose range of COL-144 that would be at least as effective as sumatriptan in treating patients with acute migraine. They devised a population pharmacokinetic model to assess the concentration-time profile of COL-144 in plasma after oral administration. Using this model, along with the plasma concentration–headache response effect relationship, the researchers predicted an effective dose range for oral administration of the drug.
“The dose should give a faster onset of headache response and/or higher response rate than intranasal sumatriptan, 20 mg,” the investigators stated. “Pain relief should be at least 12% after 30 minutes. Placebo-corrected pain relief was used, because headache response in placebo-treated subjects differs between trials. “The predicted oral dose range needed to reach the desired therapeutic target is 170 mg and greater,” according to the researchers.
IV Administration of COL-144
In prior research, Dr. Pilgrim’s group included 130 patients (ages 18 to 65) who had migraine with or without aura for at least a year that met International Headache Society diagnostic criteria. The primary end point was headache response, which was defined as reduction in headache severity from moderate or severe at baseline to mild or no headache at two hours after initiation of drug infusion.
Participants were grouped into small cohorts, in which some received the drug and some received placebo. The first cohort received 2.5 mg COL-144, and doses given to later cohorts depended on the responses of the previous groups.
“The dose escalation was terminated after 130 patients, when the predefined stopping rules identified 20 mg as an effective dose,” stated Dr. Pilgrim.