Pharmacokinetics and Safety of Single Oral Doses of VX‐366 (Isobutyramide) in Healthy Volunteers

Abstract

VX‐366 (isobutyramide) is an orally available branched chain amide that may offer an alternative to current treatments for β‐hemoglobinopathy. A phase I, double‐blind, randomized, placebo‐controlled study was conducted to investigate four single oral doses of VX‐366 (1, 7, 14, or 28 grams or approximately 14, 100, 200 or 400 mg/kg) administered to four male volunteers each, with two other subjects in each group receiving a matching placebo. The total number of volunteers enrolled in this study was 24, with a mean age of 27 ± 6.4 years. VX‐366 was well tolerated at all dose levels studied, and peak plasma concentrations (C_max) of 18.88 ± 1.02 μg/mL (0.2 mmol/L), 171.13 ± 32.13 μg/mL (2 mmol/L), 331.58 ± 35.48 μg/mL (3.8 mmol/L), and 538.83 ± 54.19 μg/mL (6 mmol/L) were achieved after the four respective doses. The half‐life (t_1/2) of VX‐366 was more than 7 hours, and there was evidence of nonlinear pharmacokinetics. It is likely that nonrenal (metabolic) clearance plays a predominant role in elimination. Based on these data, VX‐366 given as a single daily dose of 100 to 150 mg/kg should be well tolerated and can be expected to result in peak plasma levels in excess of 170 μg/mL (2 mmol/L) and in trough plasma levels in excess of 40 μg/mL (0.5 mmol/L). These plasma levels exceed the concentrations previously shown to stimulate gamma globin synthesis both in vitro and in baboons.