An investigational, alcohol-free form of the nonsteroidal anti-inflammatory drug (NSAID) ketorolac was well tolerated, according to a phase I study funded by the manufacturer.
Among healthy adults, the continuous infusion formulation, called NTM-001, maintained steady plasma concentrations across 24 hours as was predicted by pharmacokinetic modeling, which also predicted an achieved durable analgesic effect, reported Ilona Steigerwald, MD, of Neumentum in Palo Alto, California, during a poster presentation at the 2019 PAINWeek conference.
It also met safety targets, with no signs of renal injury; only a few mild gastrointestinal events reported in the continuous infusion arm; and no serious events or deaths, she said.
“[With this formulation] you save 20% of the dose, you will have a better analgesia because you don’t have peaks and troughs, and you will probably also have a better safety profile because ketorolac side effects are dose-dependent,” Steigerwald told MedPage Today. “Thus you have an efficacy and safety gain, you have an infusion that is alcohol free and makes no irritation, and I will also say you don’t have to give boli every 6 hours.”
The approved intravenous form of ketorolac (Toradol) is typically administered as a 30-mg bolus every six hours, and results in high peaks and low troughs in plasma concentrations between repeat doses, Steigerwald said. While the high plasma concentration peaks occurring after the therapy is injected can pose safety risks, the troughs may not effectively provide analgesia, she added.
This form was designed to provide more stable pain relief without unnecessary overexposure in postsurgical patients, Steigerwald and her team noted. Administered at a loading dose of 12.5 mg and an infusion rate of 3.5 mg/hour, it also has a reduced total daily dose compared to the traditional form (96.5 mg vs 120 mg).
This novel formulation has the potential to fulfill an “unmet need” for meaningful and durable analgesia, said co-author Joseph Pergolizzi, MD, of NEMA Research in Naples, Florida.
Performance in older patients
The blinded pharmacokinetic study involved 28 adults, half of which were white and female. But the authors also presented another study that examined three cohorts of individuals age 65 and older: those with zero renal impairment (15), mild renal impairment (16), or moderate renal impairment (8).
In these small cohorts, a dose reduction of up to 50% is used in the standard ketorolac therapy, such that 15 mg is administered every 6 hours for patients 65 or older, the authors reported.
The continuous infusion formulation, administered in this more vulnerable population at a 6.25-mg loading dose followed by an immediate continuous infusion of 1.75 mg/hour, also maintained steady plasma levels, with concentrations greater than trough values for the ketorolac bolus dose regardless of renal function and dosing, the authors reported.
As was seen in healthy volunteers, only a few gastrointestinal events of mild intensity occurred with no signs of acute renal injury and no participants in either arm undergoing serum creatinine change of 0.3 or more, or reduction in creatinine clearance of 30% or more within 96 hours. However, moderate fluctuations in hemoglobin were observed in the older patients, though they were not associated with bleeding events, the authors reported.
Drugmaker Neumentum has submitted these findings to the FDA and is moving forward with a phase III study, Steigerwald said.
“We are trying to eliminate co-opioid use and in the phase III that’s coming we’ll be comparing directly to IV morphine to see that we have the opioid-level analgesia and that you hardly need anything else for the vast majority of people,” Steigerwald said. “That’s the goal.”
The study was funded by Neumentum.
Steigerwald is an employee of Neumentum and co-authors reported several relationships with industry.
Primary Source
PAINWeek
Secondary Source
PAINWeek
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