Drug interactions with colesevelam hydrochloride, a novel, potent lipid-lowering agent.
Colesevelam hydrochloride (colesevelam) is a novel, potent, bile acid-binding agent that has been shown to lower LDL cholesterol a mean of 19% at a dose of 3.8 g/d. We studied the pharmacokinetics of colesevelam coadministered with six drugs: digoxin and warfarin, agents with narrow therapeutic indices; sustained-release verapamil and metoprolol; quinidine, an antiarrhythmic with a narrow therapeutic index; and valproic acid, an antiseizure medication. Six individual studies were single-dose, crossover, with or without a 4.5-g dose of colesevelam. Plasma levels were determined using validated analytical methods. Values for the ratio of ln[AUC(0-t)] with and without colesevelam were 107% for quinidine, 102% for valproic acid, 89% for digoxin, 102% for warfarin, 82% for verapamil, and 112% for metoprolol. Values for the ratio of ln[Cmax] with and without colesevelam were 107% for quinidine, 92% for valproic acid, 96% for digoxin, 99% for warfarin, 69% for verapamil, and 112% for metoprolol. The 90% confidence intervals for these ratios and for values of ln[AUC(0-inf)] that could be determined were within the 80-125% range, with the exception of verapamil. In this study, verapamil had great interindividual variability, with a 28-fold range in Cmax and an 11-fold range in AUC(0-t). In summary, pharmacokinetic studies with colesevelam did not show clinically significant effects on absorption of six other coadministered drugs.
Donovan
J M
JM
GelTex Pharmaceuticals Inc., Waltham, Massachusetts 02451, USA.
Stypinski
D
D
Stiles
M R
MR
Olson
T A
TA
Burke
S K
SK
D000499:Allylamine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D019540:Area Under Curve; D002317:Cardiovascular Agents / Q000493:pharmacokinetics*; D000069472:Colesevelam Hydrochloride; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male
D000924:Anticholesteremic Agents; D002317:Cardiovascular Agents; D000499:Allylamine; D000069472:Colesevelam Hydrochloride