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Pharmacokinetics and Safety of Single Oral Doses of VX‐366 (Isobutyramide) in Healthy Volunteers
Author(s) -
Brettman Lee R.,
Chaturvedi Pravin R.
Publication year - 1996
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1996.tb04226.x
Subject(s) - pharmacokinetics , placebo , medicine , plasma concentration , oral dose , anesthesia , pharmacology , alternative medicine , pathology
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 .