DMP 504, a novel hydrogel bile acid sequestrant: III. Safety, tolerability, and cholesterol-lowering in healthy hypercholesterolemic subjects

James W. Hainer, Donald B. Hunninghake, Irma H. Benedek, Francis E. Broyles, Dennis M. Garner, Rhonda M. Jenkins, Andrew McGinn, Henry J. Pieniaszek, Erv London, Peter J. Gillies

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

This multiple-dose study of DMP 504, a hydrogel bile acid sequestrant, employed a randomized, double-blind, sequential-cohort design with placebo (blinded) and open-label cholestyramine (CS) controls. Ninety-three healthy primary hypercholesterolemic subjects (serum LDL cholesterol 130 to 200 mg/dL; triglycerides ≤80 mg/dL) maintaining a stable diet (NCEP Step One) for 3 weeks received either DMP 504 or placebo DMP 504 in capsules, or CS powder for suspension (16 g/d). The DMP 504 dose (0.9, 1.8, 2.7, 3.6, 5.4, 7.2 g/d) escalated with sequential enrollment of cohorts (DMP 504 n = 10, placebo n = 2, and CS n = 3 for Cohorts I-V; DMP 504 n = 8, placebo n = 2 for Cohort VI). An additional cohort (VII) included DMP 504 3.6 g/d, n = 9, and placebo, n = 2. LDL cholesterol (LDL-C) decreased in a dose-dependent manner (-15.8% to -34.1%; r = -0.56; P < 0.001) over the dose range 0.9 g/d to 7.2 g/d after 2 weeks of dosing with DMP 504 and +0.8% to -19.7% (r = -0.48; P < 0.001) over doses 0.9 g/d to 5.4 g/d after 6 weeks. LDL-C did not change with placebo but declined with cholestyramine by -28.3% at 2 weeks and -23.9% at 6 weeks. Plasma 7-α-hydroxy-4-cholesten-3-one, a marker of hepatic cholesterol 7-α-hydroxylase activity, increased dose-dependently with DMP 504 and with CS; change in LDL-C correlated inversely with 7-α-hydroxy-4-cholesten-3-one (r = -0.46; P < 0.001). There was no dose-limiting toxicity with DMP 504. One subject (DMP 504 2.7 g/d) withdrew because of gastrointestinal disturbance. Subject complaints were largely gastrointestinal in nature (flatulence, abdominal discomfort, diarrhea/constipation) occurring in 53% of the 64 DMP 504, 60% of 15 CS, and 29% of 14 placebo subjects. The novel hydrogel DMP 504 can induce significant LDL cholesterol lowering at doses of several grams/day with an acceptable side effect profile.

Original languageEnglish (US)
Pages (from-to)76-84
Number of pages9
JournalDrug Development Research
Volume41
Issue number2
DOIs
StatePublished - Jun 1997
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Drug Discovery

Keywords

  • Bile acid sequestrants
  • Cholesterol 7-α- hydroxylase
  • Cholestyramine
  • DMP 504

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