Absorption of Colesevelam Hydrochloride in Healthy Volunteers

Heller, Dennis; Burke, Steven K.; Davidson, Denise; Donovan, Joanne M.

doi:10.1345/aph.1a143

Cited by 39 publications

(19 citation statements)

References 41 publications

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“…The methodology for characterizing plasma drug content is irrelevant as resins rarely appear as such in blood circulation and are not easily characterizable as a drug entity because of their very large molecular weight and polydisperse nature; more typically impurities and degradation products are first identified in stress-stability testing or in vitro metabolism studies and then monitored in plasma. However, the gold standard method remains radioactive labeling with 14 C and measuring the distribution of the label in urine, feces, and body tissues; typically synthetic crosslinked resins are almost quantitatively recovered in the feces, with yields ranging from 82% [11] to 99% [12]. Certain sequestering materials are made of insoluble metallic inorganic materials that release soluble metallic salts (Fe, Mg, La), which can potentially be absorbed.…”

Section: Non-absorption Criteria Across Classes Of Non-absorbable Drugsmentioning

confidence: 99%

Non-Systemic Drugs: A Critical Review

Charmot¹

2012

CPD

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Non-systemic drugs act within the intestinal lumen without reaching the systemic circulation. The first generation included polymeric resins that sequester phosphate ions, potassium ions, or bile acids for the treatment of electrolyte imbalances or hypercholesteremia. The field has evolved towards non-absorbable small molecules or peptides targeting luminal enzymes or transporters for the treatment of mineral metabolism disorders, diabetes, gastrointestinal (GI) disorders, and enteric infections. From a drug design and development perspective, non-systemic agents offer novel opportunities to address unmet medical needs while minimizing toxicity risks, but also present new challenges, including developing a better understanding and control of non-transcellular leakage pathways into the systemic circulation. The pharmacokinetic-pharmacodynamic relationship of drugs acting in the GI tract can be complex due to the variability of intestinal transit, interaction with chyme, and the complex environment of the surface epithelia. We review the main classes of non-absorbable agents at various stages of development, and their therapeutic potential and limitations. The rapid progress in the identification of intestinal receptors and transporters, their functional characterization and role in metabolic and inflammatory disorders, will undoubtedly renew interest in the development of novel, safe, non-systemic therapeutics.

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Section: Non-absorption Criteria Across Classes Of Non-absorbable Drugsmentioning

confidence: 99%

Non-Systemic Drugs: A Critical Review

Charmot¹

2012

CPD

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“…Kinetic studies performed in healthy adult volunteers have shown that colesevelam is a hydrophilic, insoluble polymer with minimal systemic absorption and distribution 32. After administration of a single dose of [ 14 C]-colesevelam to 16 healthy adult volunteers after receiving 28 days of colesevelam 1.9 g twice daily, the maximum detectable plasma concentration 72 hours after administration was 0.04%, consistent with residual [ 14 C].…”

Section: Pharmacokineticsmentioning

confidence: 64%

Role of colesevelam in managing heterozygous familial hypercholesterolemia in adolescents and children

Sonnett¹,

Robinson²,

Milani³

et al. 2010

AHMT

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BackgroundColesevelam hydrochloride is a synthetic, nonsystemically absorbed polymer that functions as a bile acid sequestrant for the treatment of hypercholesterolemia. Recently, colesevelam was investigated for the treatment of heterozygous familial hypercholesterolemia (HeFH) in the pediatric/adolescent population aged 10–17 years.ObjectiveThe purpose of this article is to review the disease state of HeFH in children and adolescents, review the pharmacologic mechanism of action, kinetics, and safety profile of colesevelam, analyze the results of a recent clinical trial of colesevelam in the pediatric/adolescent HeFH population, and discuss the role of colesevelam as a viable treatment option for HeFH.MethodsA literature search using Medline (1966–03 May 2010), PubMed (1950–03 May 2010), Science Direct (1994–03 May 2010), and International Pharmaceutical Abstracts (2004–2010) was performed using the search term colesevelam. English language, original research, and review articles were examined, and citations from these articles were also assessed. The manufacturer’s prescribing information and the Food and Drug Administration review of the new drug application for the powder formulation were also examined.ResultsA 32-week trial was performed investigating the efficacy of colesevelam as monotherapy or combination therapy with a stable statin regimen. Upon completion of the trial, significant benefits were found in regard to the treatment of HeFH and the lowering of low-density lipoprotein cholesterol, total cholesterol, and other secondary measures. Safety and tolerability were also examined throughout the duration of the clinical trial, with adverse drug reactions considered mild in severity.ConclusionColesevelam has been shown to reduce low-density lipoprotein cholesterol levels significantly in pediatric/adolescent patients with HeFH, while maintaining a mild side effect profile. Although further research would be beneficial for long-term effects in this population, colesevelam should be considered when developing a treatment regimen for HeFH in the pediatric/adolescent population.

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“…1,6 Colesevelam HCI is not absorbed from the intestine. 7 In pharmacokinetic studies, colesevelam HCl did not demonstrate clinically significant interactions with several drugs that are often prescribed concomitantly in patients who require cholesterol-lowering pharmacotherapy (e.g., lovastatin, fenofibrate, warfarin, digoxin, metoprolol). [8][9][10] By contrast, conventional BAS have been shown to interfere with the pharmacokinetics of several other drugs, including warfarin, [11][12][13] thiazide diuretics, 14,15 cardiac glycosides, 16,17 and propranolol.…”

Section: Introductionmentioning

confidence: 93%