Population pharmacokinetics and exposure-uric acid analyses after single and multiple doses of ABT-639, a calcium channel blocker, in healthy volunteers

AAPS J. 2015 Mar;17(2):416-26. doi: 10.1208/s12248-014-9709-1. Epub 2015 Jan 8.


ABT-639 is a selective T-type calcium channel blocker with efficacy in a wide range of preclinical models of nociceptive and neuropathic pain. In the current first-in-human (FIH) study, the pharmacokinetics, tolerability, and safety of ABT-639 after single- (up to 170 mg) and multiple doses (up to 160 mg BID) were evaluated in healthy volunteers in a randomized, double-blinded, placebo-controlled manner. ABT-639 demonstrated acceptable safety and pharmacokinetic profiles in human. Results from assessment of the routine laboratory variables showed an unexpected statistically significant and clinically relevant decrease in blood uric acid with the increase in ABT-639 dose, which is possibly due to inhibition in URAT1 transporter. Pharmacokinetic/pharmacodynamic models were constructed to characterize the relationship between ABT-639 exposure and uric acid response. The final model was a mechanism-based indirect response pharmacodynamic model with the stimulation of uric acid elimination by ABT-639. The model estimated K in values in males and females were 10.2 and 7.13 μmol/h, respectively. The model estimated K out was 0.033 1/h. ABT-639 concentration that can produce 50% stimulation in uric acid elimination was estimated to be 8,070 ng/mL. Based on the final model, further simulations were conducted to predict the effect of ABT-639 on uric acid in gout patients. The simulation results indicated that, if the urate-lowering response to ABT-639 in gout patients is similar to that in healthy subjects, ABT-639 BID doses of 140 mg or higher would be expected to provide clinically meaningful lowering of blood uric acid levels below the 380 μmol/L solubility limit of monosodium urate.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Calcium Channel Blockers / administration & dosage*
  • Calcium Channel Blockers / adverse effects
  • Calcium Channel Blockers / pharmacokinetics
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Gout / drug therapy
  • Heterocyclic Compounds, 2-Ring / administration & dosage*
  • Heterocyclic Compounds, 2-Ring / adverse effects
  • Heterocyclic Compounds, 2-Ring / pharmacokinetics
  • Humans
  • Male
  • Middle Aged
  • Models, Biological*
  • Sex Factors
  • Sulfonamides / administration & dosage*
  • Sulfonamides / adverse effects
  • Sulfonamides / pharmacokinetics
  • Uric Acid / blood*
  • Young Adult


  • 4-chloro-2-fluoro-N-(2-fluorophenyl)-5-(hexahydropyrrolo(1,2-a)pyrazin-2(1H)-ylcarbonyl)benzenesulfonamide
  • Calcium Channel Blockers
  • Heterocyclic Compounds, 2-Ring
  • Sulfonamides
  • Uric Acid