Presented at the 2013 AAPM Annual Meeting « Back

New Oral Opioid Analgesic NKTR-181 Demonstrates Analgesic Response in Cold Pressor Test in Healthy Subjects

Michael A. Eldon, PhD FCP, meldon@nektar.com¹, Aleksandrs Odinecs, PhD², Susan Herzog, RN¹, Robert A. Medve, MD¹, Nacer Abrouk, PhD¹, Lynn R. Webster, MD³, (1) Nektar Therapeutics, San Francisco, California, (2) ACCP, AAPS, San Francisco, California, (3) CRILifetree, Salt Lake City, Utah

Background: NKTR-181 is a new mu-opioid agonist designed to provide clinically relevant analgesia while reducing CNS mediated side effects. NKTR-181 is currently in Phase 2 development for the treatment of chronic pain in patients with osteoarthritis of the knee. This abstract describes results from NKTR-181 PK/PD analysis of pupil diameter and cold pressor test (CPT) responses in healthy subjects. Methods: Healthy subjects in groups of 15 received single 10, 20, 40, 80, 160, 320, or 500 mg oral doses of NKTR-181 solution (n=12) or placebo (n=3). Serial observations including pupillometery and cold pressor test were recorded; blood samples were collected for analysis of NKTR-181 pharmacokinetics. Results: The extent and duration of miosis and pain tolerance increased with dose and was related to plasma NKTR-181 concentration. Measurements of pain tolerance in CPT tests were well correlated with CNS opioid effect indicated by the extent and duration of miosis. Although NKTR-181 was rapidly absorbed and detected in plasma within 15 min, the maximum central effect was consistently observed 2 to 3 hours after NKTR-181 Tmax, indicating a significant time lag between plasma and CNS. The population mean plasma-to-effect compartment equilibrium t1/2 determined through PK/PD modeling was 2.9 hr (0.18 hr reported for oxycodone), demonstrating slower rate of CNS entry. Conclusions: NKTR-181 produces concentration/dose-dependent central analgesic response in healthy subjects as measured by the cold pressor model. The time course of the central opioid response to NKTR-181 significantly lags the time course of drug in plasma, consistent with reduced rate of CNS uptake.

Funding: None