title: 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 beta-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 (Cmax) of 18.88 +/- 1.02 micrograms/mL (0.2 mmol/L), 171.13 +/- 32.13 micrograms/mL (2 mmol/L), 331.58 +/- 35.48 micrograms/mL (3.8 mmol/L), and 538.83 +/- 54.19 micrograms/mL (6 mmol/L) were achieved after the four respective doses. The half-life (t1/2) 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 micrograms/mL (2 mmol/L) and in trough plasma levels in excess of 40 micrograms/mL (0.5 mmol/L). These plasma levels exceed the concentrations previously shown to stimulate gamma globin synthesis both in vitro and in baboons.
authors.affiliation: Vertex Pharmaceuticals Incorporated, Cambridge, Massachusets 02139-4211, USA.
authors.forename: L R
authors.initials: LR
authors.lastname: Brettman
authors.forename: P R
authors.initials: PR
authors.lastname: Chaturvedi
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000577:Amides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004311:Double-Blind Method; D006453:Hemoglobinopathies / Q000378:metabolism*; D006801:Humans; D008297:Male
chemical_list: D000577:Amides; C030197:isobutyramide