Combined use of pharmacokinetic modeling and a steady-state delivery approach allows early assessment of IkappaB kinase-2 (IKK-2) target safety and efficacy

J Pharm Sci. 2010 Mar;99(3):1278-87. doi: 10.1002/jps.21909.


NF-kappaB activation is clearly linked to the pathogenesis of multiple inflammatory diseases including arthritis. The prominent role of IkappaB kinase-2 (IKK-2) in regulating NF-kappaB signaling in response to proinflammatory stimuli has made IKK-2 a primary anti-inflammation therapeutic target. PHA-408, a potent and selective IKK-2 inhibitor, was identified internally and used for our studies to assess this target. In early in vivo studies, PHA-408 demonstrated efficacy at high doses; however, the correlation between PHA-408 exposure and efficacy could not be established using standard dosing paradigms for the rat disease models. Similar concerns arose from early in vivo safety studies where appropriate NOAEL margins were not achieved. Following a full investigation of the physicochemical properties of the molecule and pharmacokinetic modeling, an oral steady-state delivery strategy was designed to administer PHA-408 to the rat for both efficacy and safety studies. Using this steady-state delivery, a clear dose-response relationship was established between plasma concentrations of PHA-408 and efficacy in the rat arthritis model. The same steady-state delivery approach was used to demonstrate the target safety. In summary, a combination of pharmacokinetic modeling with a steady-state delivery approach allowed us to establish confidence in both the mechanism and safety of the target.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents / administration & dosage*
  • Anti-Inflammatory Agents / adverse effects
  • Anti-Inflammatory Agents / pharmacokinetics
  • Anti-Inflammatory Agents / pharmacology*
  • Arthritis, Experimental / drug therapy
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Delivery Systems / methods*
  • Drug Evaluation, Preclinical / methods
  • Female
  • I-kappa B Kinase / antagonists & inhibitors*
  • Indazoles / administration & dosage*
  • Indazoles / adverse effects
  • Indazoles / pharmacokinetics
  • Indazoles / pharmacology
  • Isonicotinic Acids / administration & dosage*
  • Isonicotinic Acids / adverse effects
  • Isonicotinic Acids / pharmacokinetics
  • Isonicotinic Acids / pharmacology
  • Male
  • Models, Biological
  • Rats
  • Rats, Inbred Lew
  • Rats, Wistar
  • Tumor Necrosis Factor-alpha / drug effects


  • Anti-Inflammatory Agents
  • Indazoles
  • Isonicotinic Acids
  • PHA 408
  • Tumor Necrosis Factor-alpha
  • I-kappa B Kinase