Colesevelam HCL (Page 4 of 5)
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility
A 104-week carcinogenicity study with colesevelam hydrochloride was conducted in CD-1 mice, at oral dietary doses up to 3 g/kg/day. This dose was approximately 50 times the maximum recommended human dose of 4.5 g/day, based on body weight, mg/kg. There were no significant drug-induced tumor findings in male or female mice. In a 104-week carcinogenicity study with colesevelam hydrochloride in Harlan Sprague-Dawley rats, a statistically significant increase in the incidence of pancreatic acinar cell adenoma was seen in male rats at doses greater than 1.2 g/kg/day (approximately 20 times the maximum human dose, based on body weight, mg/kg) (trend test only). A statistically significant increase in thyroid C-cell adenoma was seen in female rats at 2.4 g/kg/day (approximately 40 times the maximum human dose, based on body weight, mg/kg).
Colesevelam hydrochloride and 4 degradants present in the drug substance have been evaluated for mutagenicity in the Ames test and a mammalian chromosomal aberration test. The 4 degradants and an extract of the parent compound did not exhibit genetic toxicity in an in vitro bacterial mutagenesis assay in S. typhimurium and E. coli (Ames assay) with or without rat liver metabolic activation. An extract of the parent compound was positive in the Chinese Hamster Ovary (CHO) cell chromosomal aberration assay in the presence of metabolic activation and negative in the absence of metabolic activation. The results of the CHO cell chromosomal aberration assay with 2 of the 4 degradants, decylamine HCl and aminohexyltrimethyl ammonium chloride HCl, were equivocal in the absence of metabolic activation and negative in the presence of metabolic activation. The other 2 degradants, didecylamine HCl and 6-decylamino-hexyltrimethyl ammonium chloride HCl, were negative in the presence and absence of metabolic activation.
Impairment of Fertility
Colesevelam hydrochloride did not impair fertility in rats at doses up to 3 g/kg/day (approximately 50 times the maximum human dose, based on body weight, mg/kg).
13.2 Animal Toxicology and/orPharmacology
Reproductive Toxicology Studies
Reproduction studies have been performed in rats and rabbits at doses up to 3 g/kg/day and 1 g/kg/day, respectively (approximately 50 and 17 times the maximum human dose, based on body weight, mg/kg) and have revealed no evidence of harm to the fetus due to colesevelam hydrochloride.
14 CLINICAL STUDIES
14.1 Primary Hyperlipidemia
Colesevelam hydrochloride reduces total cholesterol (TC), LDL-C, apolipoprotein B (Apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) when administered alone or in combination with a statin in patients with primary hyperlipidemia.
Approximately 1600 patients were studied in 9 clinical trials with treatment durations ranging from 4 to 50 weeks. With the exception of one open-label, uncontrolled, long-term extension study, all studies were multicenter, randomized, double-blind, and placebo-controlled. A maximum therapeutic response to colesevelam hydrochloride was achieved within 2 weeks and was maintained during long-term therapy.
Monotherapy In a study in patients with LDL-C between 130 mg/dL and 220 mg/dL (mean 158 mg/dL), colesevelam hydrochloride was given for 24 weeks in divided doses with the morning and evening meals.
As shown in Table 7, the mean LDL-C reductions were 15% and 18% at the 3.8 g and 4.5 g doses. The respective mean TC reductions were 7% and 10%. The mean Apo B reductions were 12% in both treatment groups. Colesevelam hydrochloride at both doses increased HDL-C by 3%. Increases in TG of 9 to 10% were observed at both colesevelam hydrochloride doses but the changes were not statistically different from placebo.
Response to Colesevelam Hydrochloride Monotherapy in a 24-Week Trial -Percent Change in Lipid Parameters from Baseline
|Grams/ Day||N||TC||LDL-C||Apo B||HDL-C*||Non-HDL-C||TG*|
|3.8 g (6 tablets)||95||–7†||–15†||–12†||+3†||–10†||+10|
|4.5 g (7 tablets)||94||–10†||–18†||–12†||+3||–13†||+9|
* Median % change from baseline. †p less than 0.05 for lipid parameters compared to placebo, for Apo B compared to baseline.
In a study in 98 patients with LDL-C between 145 mg/dL and 250 mg/dL (mean 169 mg/dL), colesevelam hydrochloride 3.8 g was given for 6 weeks as a single dose with breakfast, as a single dose with dinner, or as divided doses with breakfast and dinner. The mean LDL-C reductions were 18%, 15%, and 18% for the 3 dosing regimens, respectively. The reductions with these 3 regimens were not statistically different from one another.
Co-administration of colesevelam hydrochloride and a statin (atorvastatin, lovastatin, or simvastatin) in 3 clinical studies demonstrated an additive reduction of LDL-C. The mean baseline LDL-C was 184 mg/dL in the atorvastatin study (range 156 to 236 mg/dL), 171 mg/dL in the lovastatin study (range 115 to 247 mg/dL), and 188 mg/dL in the simvastatin study (range 148 to 352 mg/dL). As demonstrated in Table 8, colesevelam hydrochloride doses of 2.3 g to 3.8 g resulted in an additional 8% to 16% reduction in LDL-C above that seen with the statin alone.
Response to Colesevelam Hydrochloride in Combination with Atorvastatin, Simvastatin, or Lovastatin -Percent Change in Lipid Parameters
|Atorvastatin Trial (4-week)|
|Atorvastatin 10 mg||18||–27†||–38†||–32†||+8||–35†||–24†|
|Colesevelam hydrochloride 3.8 g/ Atorvastatin 10 mg||18||–31†||–48†||–38†||+11||–40†||–1|
|Atorvastatin 80 mg||20||–39†||–53†||–46†||+6||–50†||–33†|
|Simvastatin Trial (6-week)|
|Simvastatin 10 mg||35||–19†||–26†||–20†||+3†||–24†||–17†|
|Colesevelam hydrochloride 3.8 g/ Simvastatin 10 mg||34||–28†||–42†||–33†||+10†||–37†||–12†|
|Simvastatin 20 mg||39||–23†||–34†||–26†||+7†||–30†||–12†|
|Colesevelam hydrochloride 2.3 g/ Simvastatin 20 mg||37||–29†||–42†||–32†||+4†||–37†||–12†|
|Lovastatin Trial (4-week)|
|Lovastatin 10 mg||26||–14†||–22†||–16†||+5||–19†||0|
|Colesevelam hydrochloride 2.3 g/ Lovastatin 10 mg Together||27||–21†||–34†||–24†||+4||–27†||–1|
|Colesevelam hydrochloride 2.3 g/ Lovastatin 10 mg Apart||23||–21†||–32†||–24†||+2||–28†||–2|
*Median % change from baseline.
†p less than 0.05 for lipid parameters compared to placebo, for Apo B compared to baseline.
In all 3 studies, the LDL-C reduction achieved with the combination of colesevelam hydrochloride and any given dose of statin therapy was statistically superior to that achieved with colesevelam hydrochloride or that dose of the statin alone. The LDL-C reduction with atorvastatin 80 mg was not statistically significantly different from the combination of colesevelam hydrochloride 3.8 g and atorvastatin 10 mg.
The safety and efficacy of colesevelam hydrochloride in pediatric patients were evaluated in an 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study followed by an open-label phase, in 194 boys and postmenarchal girls 10 to 17 years of age (mean age 14.1 years) with HeFH, taking a stable dose of an FDA-approved statin (with LDL-C greater than 130 mg/dL) or naïve to lipid-lowering therapy (with LDL-C greater than 160 mg/dL). This study had 3 periods: a single-blind, placebo stabilization period; an 8-week, randomized, double-blind, parallel-group, placebo-controlled treatment period; and an 18-week, open-label treatment period. Forty-seven (24%) patients were taking statins and 147 (76%) patients were statin-naïve at screening. The mean baseline LDL-C at Day 1 was approximately 199 mg/dL.
During the double-blind treatment period, patients were assigned randomly to treatment: colesevelam hydrochloride 3.8 g/day (n=64), colesevelam hydrochloride 1.9 g/day (n=65), or placebo (n=65). In total, 186 patients completed the double-blind treatment period. After 8 weeks of treatment, colesevelam hydrochloride 3.8 g/day significantly decreased plasma levels of LDL-C, non-HDL-C, TC, and Apo B and significantly increased HDL-C. A moderate, non-statistically significant increase in TG was observed versus placebo (Table 9).
Response to Colesevelam Hydrochloride 3.8 g Compared to Placebo in Pediatric Patients 10 to 17 Years of Age – Mean Percent Change in Lipid Parameters from Baseline to Week 8
|Treatment Difference||TC (N=128)||LDL-C (N=128)||Apo B (N=124)||HDL-C (N=128)||Non-HDL-C (N=128)||TG* (N=128)|
|Colesevelam Hydrochloride3.8 g vs Placebo||-7†||-13†||-8†||+6†||-11†||+5|
*For triglycerides, median % change from baseline.
†p≤0.05 for lipid parameters compared to placebo Values represent LS mean. Only patients with values at both study baseline and endpoint are included in this table. Study baseline was defined as the last value measured before or on Day 1 prior to the first dose of randomized study medication.
Results were based on the ITT population with LOCF
During the open-label treatment period patients were treated with colesevelam hydrochloride 3.8 g/day. In total, 173 (89%) patients completed 26 weeks of treatment. Results at Week 26 were consistent with those at Week 8.
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