Erratum to: Population Pharmacokinetics and Exposure-Uric Acid Analyses After Single and Multiple Doses of ABT-639, a Calcium Channel Blocker, in Healthy Volunteers

Abstract

The PDF version of the published article contains errors throughout the text, which were introduced by the typesetter when performing the author's proof corrections. This erratum contains the corrected PDF.The online version of the original article can be found at http:// dx.doi.org/10.1208/s12248-014-9709-1. Abstract. 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, placebocontrolled 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.

A randomized double-blind, placebo-, and active-controlled study of T-type calcium channel blocker ABT-639 in patients with diabetic peripheral neuropathic pain

“…These observations indicate that steady-state concentrations were within the concentration range observed in the phase 1 study for the same dose. 1 …”

“…This is particularly noteworthy given that the tolerability and safety profile from a phase 1 study and the current trial was benign and there were no significant safety issues identified. 1 However, based on the findings from animal toxicology studies, 4 it was determined that 100-mg twice daily ABT-639 was the appropriate highest dose with an adequate safety margin for this proof-of-concept study. In addition, the dose used in this study was predicted to provide an exposure level above what was required for efficacy in humans based on the projection from preclinical animal models.…”

“…Dose selection of ABT-639 was based on the results from a phase 1 study along with the data obtained from preclinical pharmacology and toxicology studies. 1 , 4 A 100-mg twice daily dose of ABT-639 was selected for this study as this dose was tolerated in the phase 1 study and was expected to be safe and to demonstrate an adequate tolerability profile in this 6-week outpatient study. 1 In addition, this dose was projected to be efficacious based on preclinical animal pain model data.…”

“… 1 , 4 A 100-mg twice daily dose of ABT-639 was selected for this study as this dose was tolerated in the phase 1 study and was expected to be safe and to demonstrate an adequate tolerability profile in this 6-week outpatient study. 1 In addition, this dose was projected to be efficacious based on preclinical animal pain model data. 4 For pregabalin, the dose of 300 mg/d was chosen in accordance with the approved dosage for diabetic neuropathic pain.…”

“… 4 In a phase 1 first-in-human study, ABT-639 demonstrated an acceptable safety profile at all single- and multiple-dose levels evaluated. 1 …”