Presented at the 2012 AAPM Annual Meeting « Back

Multiple Dose Pharmacokinetics and Pharmacodynamics of the New Oral Opioid Analgesic NKTR-181

Lynn R. Webster, MD, lrwebstermd@gmail.com¹, Aleksandrs Odinecs, PhD², Susan Herzog, RN², Michael Eldon, PhD², Robert Medve, MD², (1) Lifetree Clinical Research, Salt Lake City, Utah, (2) Nektar Therapeutics, San Francisco, California

In this Phase 1 multiple dose study, four cohorts received oral doses (100, 200, 300, or 400 mg) of NKTR-181 (n=12) or placebo (n=3) q12h for up to 8 days. The primary objective was to evaluate the safety and tolerability of ascending oral doses of NKTR-181; the secondary objectives were to determine the pharmacokinetic (PK) profile and pharmacodynamic (PD) activity of NKTR-181. NKTR-181 exhibited dose-linear pharmacokinetics across all dose levels on days 1 and 8. Pharmacokinetic steady state was achieved in approximately 4 days, with mean accumulation indexes of 1.4 to 1.5 for Cmax and 1.7 to 1.8 for AUC. Maximum concentration of NKTR-181 in plasma on both days 1 and 8 was achieved 2-3 hours after administration; however, central effect (miosis) was delayed relative to the plasma NKTR-181 concentration-time profile, with maximum effect between 3 and 6 hours following dosing. Maximal central effect increased approximately 20% from day 1 to day 8, reflecting increased drug exposure resulting from the modest drug accumulation. There was no evidence of pharmacological tolerance at any dose level. Results of this multiple dose study confirm the PK and PD observations from the single dose study. NKTR-181 was generally well tolerated; adverse events were generally mild and consistent with opioid effects. There were no serious adverse events reported. Based on PK/PD analysis, a twice-daily dose regimen was selected for a planned Phase 2 study.

Funding: Nektar Therapeutics