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

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

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 133 KB
• Volume: 41
• Category: Article
• ISSN: 0272-4391
• DOI: 10.1002/(sici)1098-2299(199706)41:2<76::aid-ddr4>3.0.co;2-o

✦ Synopsis

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 ≤280 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-4cholesten-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.