| Abstrakt: |
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 (Cmax) 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 (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 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. [ABSTRACT FROM AUTHOR] |
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