Positive Results for NKTR-118 (oral PEG-naloxol) Presented at American Academy of Pain Manageme...(rug is ground-breaking. Going forward we...),Health

Phase 1 Clinical Study Design and Results

This single-dose, double-blind, placebo-controlled study was conducted to evaluate the safety, tolerability, pharmacokinetic, and pharmacodynamic profile of NKTR-118 in healthy male subjects. The trial measured the morphine-induced delay in GI transit time, a peripheral effect, using the lactulose hydrogen GI motility test. Pupillometry, a measurement of the diameter of the pupil of the eye, was used to monitor antagonism of morphine-induced pupil constriction, a central nervous system (CNS) effect. Escalating single oral doses of NKTR-118 up to 1,000 mg were studied. A total of 48 subjects received active NKTR-118 as compared to placebo.

Single oral doses of NKTR-118 antagonized morphine-induced delay in GI transit time demonstrating the potential of the drug to relieve constipation. Further, no diminution of morphine-induced construction of the pupil, a CNS effect, was observed at single oral doses of NKTR-118 of 125 mg or less. NKTR-118 was well-tolerated at single doses up to 1,000 mg. Further, NKTR-118 was rapidly absorbed with dose-proportional pharmacokinetics over the 8-1,000 mg dose range.

Preclinical Results for NKTR-118

Preclinical studies conducted in animals investigated the permeation rate of NKTR-118 administered as compared to naloxone, antipyrine (a high brain permeation standard) and atenolol (a low brain permeation standard with no appreciable blood brain barrier penetration). NKTR-118 showed brain permeation similar to atenolol. PEGylation of naloxol greatly reduced, by 15-fold, the permeation of the drug into the brain, as compared to naloxone.

Oral NKTR-118, administered at a dose of 30 mg/kg, demonstrated the ability to improve GI transit time in an animal model of mor
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