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.
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Authors | L R Brettman, P R Chaturvedi |
Journal | Journal of clinical pharmacology
(J Clin Pharmacol)
Vol. 36
Issue 7
Pg. 617-22
(Jul 1996)
ISSN: 0091-2700 [Print] England |
PMID | 8844444
(Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial)
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Chemical References |
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Topics |
- Administration, Oral
- Adult
- Amides
(adverse effects, blood, pharmacokinetics, urine)
- Double-Blind Method
- Hemoglobinopathies
(metabolism)
- Humans
- Male
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