Evaluation of safety and pharmacokinetics of sodium 2,2 dimethylbutyrate, a novel short chain fatty acid derivative, in a phase 1, double-blind, placebo-controlled, single-dose, and repeat-dose studies in healthy volunteers

Susan P. Perrine, William A. Wargin, Michael S. Boosalis, Wayne J. Wallis, Sally Case, Jeffrey Keefer, Douglas V. Faller, William C. Welch, Ronald J. Berenson

Research output: Contribution to journalArticle

Abstract

Pharmacologic induction of fetal globin synthesis is an accepted therapeutic strategy for treatment of the beta hemoglobinopathies and thalassemias, as even small increases in hemoglobin F (HbF) levels reduce clinical severity in sickle cell disease (SCD) and reduce anemia in beta thalassemia. Prior generation short chain fatty acid therapeutics, arginine butyrate (AB), and phenylbutyrate, increased fetal and total hemoglobin levels in patients, but were limited by high doses or intravenous (IV) infusion. A fetal globin-inducing therapeutic with convenient oral dosing would be an advance for these classic molecular diseases. Healthy adult human subjects were treated with a novel short chain fatty acids (SCFA) derivative, sodium 2,2 dimethylbutyrate (SDMB), or placebo, with 1 of 4 single dose levels (2, 5, 10, and 20 mg/kg) or daily doses (5, 10, or 15 mg/kg) over 14 days, and monitored for adverse clinical and laboratory events, drug levels, reticulocytes, and HbF assays. SDMB was well-tolerated with no clinically significant adverse events related to study medication. The terminal half-life ranged from 9 to 15 hours. Increases in mean absolute reticulocytes were observed at all dose levels in the 14-day study. The favorable pharmacokinetics (PK) profiles and safety findings indicate that SDMB warrants further investigation for treatment of anemic subjects with beta hemoglobinopathies.

Original languageEnglish (US)
Pages (from-to)1186-1194
Number of pages9
JournalJournal of Clinical Pharmacology
Volume51
Issue number8
DOIs
StatePublished - Aug 2011

Fingerprint

2,2-dimethylbutyric acid
Volatile Fatty Acids
Healthy Volunteers
Pharmacokinetics
Fetal Hemoglobin
Placebos
Safety
Hemoglobinopathies
Globins
beta-Thalassemia
Reticulocytes
Phenylbutyrates
Therapeutics
Sickle Cell Anemia
Intravenous Infusions
Half-Life
Anemia

Keywords

  • anemias
  • erythropoiesis
  • fetal hemoglobin
  • pharmacokinetic profiles
  • short chain fatty acids

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Evaluation of safety and pharmacokinetics of sodium 2,2 dimethylbutyrate, a novel short chain fatty acid derivative, in a phase 1, double-blind, placebo-controlled, single-dose, and repeat-dose studies in healthy volunteers. / Perrine, Susan P.; Wargin, William A.; Boosalis, Michael S.; Wallis, Wayne J.; Case, Sally; Keefer, Jeffrey; Faller, Douglas V.; Welch, William C.; Berenson, Ronald J.

In: Journal of Clinical Pharmacology, Vol. 51, No. 8, 08.2011, p. 1186-1194.

Research output: Contribution to journalArticle

Perrine, Susan P. ; Wargin, William A. ; Boosalis, Michael S. ; Wallis, Wayne J. ; Case, Sally ; Keefer, Jeffrey ; Faller, Douglas V. ; Welch, William C. ; Berenson, Ronald J. / Evaluation of safety and pharmacokinetics of sodium 2,2 dimethylbutyrate, a novel short chain fatty acid derivative, in a phase 1, double-blind, placebo-controlled, single-dose, and repeat-dose studies in healthy volunteers. In: Journal of Clinical Pharmacology. 2011 ; Vol. 51, No. 8. pp. 1186-1194.
@article{7838c3c2248845f5ac42c7dc18737cc9,
title = "Evaluation of safety and pharmacokinetics of sodium 2,2 dimethylbutyrate, a novel short chain fatty acid derivative, in a phase 1, double-blind, placebo-controlled, single-dose, and repeat-dose studies in healthy volunteers",
abstract = "Pharmacologic induction of fetal globin synthesis is an accepted therapeutic strategy for treatment of the beta hemoglobinopathies and thalassemias, as even small increases in hemoglobin F (HbF) levels reduce clinical severity in sickle cell disease (SCD) and reduce anemia in beta thalassemia. Prior generation short chain fatty acid therapeutics, arginine butyrate (AB), and phenylbutyrate, increased fetal and total hemoglobin levels in patients, but were limited by high doses or intravenous (IV) infusion. A fetal globin-inducing therapeutic with convenient oral dosing would be an advance for these classic molecular diseases. Healthy adult human subjects were treated with a novel short chain fatty acids (SCFA) derivative, sodium 2,2 dimethylbutyrate (SDMB), or placebo, with 1 of 4 single dose levels (2, 5, 10, and 20 mg/kg) or daily doses (5, 10, or 15 mg/kg) over 14 days, and monitored for adverse clinical and laboratory events, drug levels, reticulocytes, and HbF assays. SDMB was well-tolerated with no clinically significant adverse events related to study medication. The terminal half-life ranged from 9 to 15 hours. Increases in mean absolute reticulocytes were observed at all dose levels in the 14-day study. The favorable pharmacokinetics (PK) profiles and safety findings indicate that SDMB warrants further investigation for treatment of anemic subjects with beta hemoglobinopathies.",
keywords = "anemias, erythropoiesis, fetal hemoglobin, pharmacokinetic profiles, short chain fatty acids",
author = "Perrine, {Susan P.} and Wargin, {William A.} and Boosalis, {Michael S.} and Wallis, {Wayne J.} and Sally Case and Jeffrey Keefer and Faller, {Douglas V.} and Welch, {William C.} and Berenson, {Ronald J.}",
year = "2011",
month = "8",
doi = "10.1177/0091270010379810",
language = "English (US)",
volume = "51",
pages = "1186--1194",
journal = "Journal of Clinical Pharmacology",
issn = "0091-2700",
publisher = "SAGE Publications Inc.",
number = "8",

}

TY - JOUR

T1 - Evaluation of safety and pharmacokinetics of sodium 2,2 dimethylbutyrate, a novel short chain fatty acid derivative, in a phase 1, double-blind, placebo-controlled, single-dose, and repeat-dose studies in healthy volunteers

AU - Perrine, Susan P.

AU - Wargin, William A.

AU - Boosalis, Michael S.

AU - Wallis, Wayne J.

AU - Case, Sally

AU - Keefer, Jeffrey

AU - Faller, Douglas V.

AU - Welch, William C.

AU - Berenson, Ronald J.

PY - 2011/8

Y1 - 2011/8

N2 - Pharmacologic induction of fetal globin synthesis is an accepted therapeutic strategy for treatment of the beta hemoglobinopathies and thalassemias, as even small increases in hemoglobin F (HbF) levels reduce clinical severity in sickle cell disease (SCD) and reduce anemia in beta thalassemia. Prior generation short chain fatty acid therapeutics, arginine butyrate (AB), and phenylbutyrate, increased fetal and total hemoglobin levels in patients, but were limited by high doses or intravenous (IV) infusion. A fetal globin-inducing therapeutic with convenient oral dosing would be an advance for these classic molecular diseases. Healthy adult human subjects were treated with a novel short chain fatty acids (SCFA) derivative, sodium 2,2 dimethylbutyrate (SDMB), or placebo, with 1 of 4 single dose levels (2, 5, 10, and 20 mg/kg) or daily doses (5, 10, or 15 mg/kg) over 14 days, and monitored for adverse clinical and laboratory events, drug levels, reticulocytes, and HbF assays. SDMB was well-tolerated with no clinically significant adverse events related to study medication. The terminal half-life ranged from 9 to 15 hours. Increases in mean absolute reticulocytes were observed at all dose levels in the 14-day study. The favorable pharmacokinetics (PK) profiles and safety findings indicate that SDMB warrants further investigation for treatment of anemic subjects with beta hemoglobinopathies.

AB - Pharmacologic induction of fetal globin synthesis is an accepted therapeutic strategy for treatment of the beta hemoglobinopathies and thalassemias, as even small increases in hemoglobin F (HbF) levels reduce clinical severity in sickle cell disease (SCD) and reduce anemia in beta thalassemia. Prior generation short chain fatty acid therapeutics, arginine butyrate (AB), and phenylbutyrate, increased fetal and total hemoglobin levels in patients, but were limited by high doses or intravenous (IV) infusion. A fetal globin-inducing therapeutic with convenient oral dosing would be an advance for these classic molecular diseases. Healthy adult human subjects were treated with a novel short chain fatty acids (SCFA) derivative, sodium 2,2 dimethylbutyrate (SDMB), or placebo, with 1 of 4 single dose levels (2, 5, 10, and 20 mg/kg) or daily doses (5, 10, or 15 mg/kg) over 14 days, and monitored for adverse clinical and laboratory events, drug levels, reticulocytes, and HbF assays. SDMB was well-tolerated with no clinically significant adverse events related to study medication. The terminal half-life ranged from 9 to 15 hours. Increases in mean absolute reticulocytes were observed at all dose levels in the 14-day study. The favorable pharmacokinetics (PK) profiles and safety findings indicate that SDMB warrants further investigation for treatment of anemic subjects with beta hemoglobinopathies.

KW - anemias

KW - erythropoiesis

KW - fetal hemoglobin

KW - pharmacokinetic profiles

KW - short chain fatty acids

UR - http://www.scopus.com/inward/record.url?scp=79960730507&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79960730507&partnerID=8YFLogxK

U2 - 10.1177/0091270010379810

DO - 10.1177/0091270010379810

M3 - Article

C2 - 21422239

AN - SCOPUS:79960730507

VL - 51

SP - 1186

EP - 1194

JO - Journal of Clinical Pharmacology

JF - Journal of Clinical Pharmacology

SN - 0091-2700

IS - 8

ER -