A Phase 1 Study to Evaluate the Bioavailability and Food Effect of 2 Solid‐Dispersion Formulations of the TRPV1 Antagonist ABT‐102, Relative to the Oral Solution Formulation, in Healthy Human Volunteers

Abstract

ABT-102 is a selective TRPV1 antagonist designed for treatment of nociceptive pain. The objective of this study was to characterize the bioavailability and the food effect of 2 solid-dispersion (melt-extrusion [Meltrex] and spray-dried) tablet formulations of ABT-102 relative to the solution formulation used in initial clinical trials. The study followed a 2-part, single-dose (2-mg), open-label, randomized, 3-period, crossover design in 24 healthy adults, where in each study part, 1 of the 2 solid-dispersion formulations (under fasting and nonfasting conditions) was compared to the solution formulation (under nonfasting conditions). Under nonfasting conditions, the melt-extrusion and spray-dried formulations had 53% and 87% higher Cmax and 42% and 70% higher AUC∞ than the solution formulation, respectively. The 2 solid-dispersion formulations provided comparable absolute ABT-102 exposures (mean ± SD AUC∞ of 116 ± 35 ng·h/mL [melt-extrusion] and 112 ± 55 ng·h/mL [spray-dried]). There was no effect of food (high-fat/high-calorie breakfast) on the bioavailability of the melt-extrusion formulation with the fasting and nonfasting regimens meeting bioequivalence. Food increased Cmax and AUC∞ central values of the spray-dried formulation by an estimated 11% and 17%, respectively. Based on the results of the study, the melt-extrusion formulation of ABT-102 was selected to replace the solution formulation for subsequent clinical development.

An oral TRPV1 antagonist attenuates laser radiant‐heat‐evoked potentials and pain ratings from UVB‐inflamed and normal skin

“…In the present study, ABT‐102 plasma exposure increased with dose in the 0.5 to 6 mg single dose range and the increase in exposure appeared to be less than dose‐proportional (12‐fold increase in dose resulted in 7‐fold increase in exposure; Table ). ABT‐102 is a low solubility high permeability drug, the bioavailability of which increases with food with some formulations . Therefore, administration of ABT‐102 solution formulation following a 10 h fast in the present study is most likely responsible for the less than dose‐proportional increase in exposure.…”

“…Ensure Plus was selected to mask taste differences between placebo and ABT‐102. This method of administration was utilized in prior clinical trials of ABT‐102 . Tramadol capsules, etoricoxib tablets and corresponding placebos were taken with 100 ml of tap water.…”

Non‐Aqueous Phospholipid Concentrates for Increasing the Bioavailability of Poorly Soluble Compounds

“…A conclusion that a liquid solution would not be feasible as dosage form for ABT‐102 is therefore premature. [ 39 ]…”

Ion channels in cancer-induced bone pain: from molecular mechanisms to clinical applications

“…It exhibits good oral bioavailability and enhanced analgesic activity after repeated administration ( Gomtsyan et al, 2008 ; Honore et al, 2009 ). In clinical trials, ABT-102 also demonstrated excellent bioavailability as a melt extrusion formulation, increasing the heat pain thresholds without intolerable hyperthermic events in participants ( Rowbotham et al, 2011 ; Othman et al, 2012 ). Many other inhibited TRPV1 compounds, such as JNJ-17203212, JNJ-39439335, and JNJ-38893777, have been found to be effective in various pain models, and some, such as SB366791, demonstrate potential analgesic effects in bone cancer pain ( Niiyama et al, 2009 ).…”