Welchol (Colesevelam Hydrochloride) - Description and Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism of Action

Primary Hyperlipidemia:  Colesevelam hydrochloride, the active pharmaceutical ingredient in WELCHOL, is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption. As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7-α-hydroxylase, is upregulated, which increases the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase, and increasing the number of hepatic LDL receptors. These compensatory effects result in increased clearance of LDL-C from the blood, resulting in decreased serum LDL-C levels. Serum TG levels may increase or remain unchanged.

Type 2 Diabetes Mellitus:  The mechanism by which WELCHOL improves glycemic control is unknown.

Pharmacodynamics

A maximum therapeutic response to the lipid-lowering effects of WELCHOL was achieved within 2 weeks and was maintained during long-term therapy. In the diabetes clinical studies, a therapeutic response to WELCHOL, as reflected by a reduction in hemoglobin A1C (A1C), was initially noted following 4-6 weeks of treatment and reached maximal or near-maximal effect after 12-18 weeks of treatment.

Pharmacokinetics

Absorption:  Colesevelam hydrochloride is a hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed.

Distribution:  Colesevelam hydrochloride is not absorbed, and therefore, its distribution is limited to the gastrointestinal tract.

Metabolism:  Colesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P-450.

Excretion:  In 16 healthy volunteers, an average of 0.05% of administered radioactivity from a single ¹⁴C-labeled colesevelam hydrochloride dose was excreted in the urine.

Drug Interactions:  Drug interactions between colesevelam and concomitantly administered drugs were screened through in vitro studies and confirmed in in vivo studies. In vitro studies demonstrated that cephalexin, metformin, and ciprofloxacin had negligible binding to colesevelam hydrochloride. Therefore, an in vivo pharmacokinetic interaction of WELCHOL with these drugs is unlikely. WELCHOL was found to have no significant effect on the bioavailability of digoxin, fenofibrate, lovastatin, metoprolol, quinidine, valproic acid, pioglitazone, and warfarin. The results of additional in vivo drug interactions of WELCHOL are presented in Table 4.

Drug interactions between WELCHOL and other commonly co-administered drugs in patients with type 2 diabetes (including rosiglitazone maleate, glimepiride, glipizide, sitagliptin phosphate, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, sustained-release formulations of anti-diabetic and anti-hypertensive drugs, and aspirin) have not been evaluated.

Table 4 Mean Change in Drug Exposure (AUC0-∞ and Cmax) when Administered with WELCHOL (3.75 g)^a

a With verapamil, the dose of WELCHOL was 4.5 g
b Should be administered at least 4 hours prior to WELCHOL. [See Drug Interactions (7) ]
* Oral contraceptive containing norethindrone and ethinyl estradiol.
N/A — Not Available
Drug	Dose	Co-administered		1 hr prior to WELCHOL		4 hr prior to WELCHOL
		AUC0-∞ Cmax		AUC0-∞ Cmax		AUC0-∞ Cmax
Verapamil sustained-release	240 mg	-31%	-11%	N/A	N/A	N/A	N/A
Glyburideb	3 mg	-32%	-47%	-20%	-15%	-7%	4%
Levothyroxineb	600 µg	-22%	-33%	6%	-2%	1%	8%
Norethindrone*b	1 mg	-1%	-20%	5%	-3%	6%	7%
Ethinyl Estradiol*b	0.035 mg	-24%	-24%	-18%	-1%	-12%	0%
Repaglinide	2 mg	-7%	-19%	-6%	-1%	N/A	N/A

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

CLINICAL STUDIES

Primary Hyperlipidemia

WELCHOL reduces TC, LDL-C, apolipoprotein B (Apo B), and non-HDL-C when administered alone or in combination with an HMG-CoA reductase inhibitor in patients with primary hyperlipidemia.

Approximately 1400 patients were studied in 8 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 WELCHOL 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), WELCHOL was given for 24 weeks in divided doses with the morning and evening meals.

As shown in Table 5, 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. WELCHOL at both doses increased HDL-C by 3%. Increases in TG of 9-10% were observed at both WELCHOL doses but the changes were not statistically different from placebo.

Table 5 Response to WELCHOL Monotherapy in a 24-Week Trial - Percent Change in Lipid Parameters from Baseline

* p<0.05 for lipid parameters compared to placebo, for Apo B compared to baseline.
a Median % change from baseline.
Grams/Day	N	TC	LDL-C	Apo B	HDL-Ca	Non-HDL-C	TGa
Placebo	88	+1	0	0	-1	+1	+5
3.8 g (6 tablets)	95	-7*	-15*	-12*	+3*	-10*	+10
4.5 g (7 tablets)	94	-10*	-18*	-12*	+3	-13*	+9

In a study in 98 patients with LDL-C between 145 mg/dL and 250 mg/dL (mean 169 mg/dL), WELCHOL 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.

Combination Therapy:  Co-administration of WELCHOL and an HMG-CoA reductase inhibitor (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 156-236 mg/dL), 171 mg/dL in the lovastatin study (range 115-247 mg/dL), and 188 mg/dL in the simvastatin study (range 148-352 mg/dL). As demonstrated in Table 6, WELCHOL 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 HMG-CoA reductase inhibitor alone.

Table 6 Response to WELCHOL in Combination with Atorvastatin, Simvastatin, or Lovastatin - Percent Change in Lipid Parameters

*p<0.05 for lipid parameters compared to placebo, for Apo B compared to baseline.
a Median % change from baseline.
Dose/Day	N	TC	LDL-C	Apo B	HDL-Ca	Non-HDL-C	TGa
Atorvastatin Trial (4-week)
Placebo	19	+4	+3	-3	+4	+4	+10
Atorvastatin 10 mg	18	-27*	-38*	-32*	+8	-35*	-24*
WELCHOL 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)
Placebo	33	-2	-4	-4*	-3	-2	+6*
Simvastatin 10 mg	35	-19*	-26*	-20*	+3*	-24*	-17*
WELCHOL 3.8 g/Simvastatin 10 mg	34	-28*	-42*	-33*	+10*	-37*	-12*
Simvastatin 20 mg	39	-23*	-34*	-26*	+7*	-30*	-12*
WELCHOL 2.3 g/Simvastatin 20 mg	37	-29*	-42*	-32*	+4*	-37*	-12*
Lovastatin Trial (4-week)
Placebo	26	+1	0	0	+1	+1	+1
Lovastatin 10 mg	26	-14*	-22*	-16*	+5	-19*	0
WELCHOL 2.3 g/Lovastatin 10 mg Together	27	-21*	-34*	-24*	+4	-27*	-1
WELCHOL 2.3 g/Lovastatin 10 mg Apart	23	-21*	-32*	-24*	+2	-28*	-2

In all 3 studies, the LDL-C reduction achieved with the combination of WELCHOL and any given dose of HMG-CoA reductase inhibitor therapy was statistically superior to that achieved with WELCHOL or that dose of the HMG-CoA reductase inhibitor alone. The LDL-C reduction with atorvastatin 80 mg was not statistically significantly different from the combination of WELCHOL 3.8 g and atorvastatin 10 mg.

The effect of WELCHOL when added to fenofibrate was assessed in 122 patients with mixed hyperlipidemia (Fredrickson Type IIb). Inclusion in the study required LDL-C≥115 mg/dL and TG 150 mg/dL to 749 mg/dL. Patients were treated with 160 mg of fenofibrate during an 8-week open-label run-in period and then randomly assigned to receive fenofibrate 160 mg plus either WELCHOL 3.8 g or placebo for 6 weeks of double-blind treatment. The overall mean LDL-C at the start of randomized treatment was 144 mg/dL. The results of the study are summarized in Table 7.

Table 7 Response to WELCHOL Added to Fenofibrate in Patients with Mixed Hyperlipidemia (Mean % Change from Treated Baseline^b at 6 Weeks)

*p≤0.0002 compared to placebo.
a For triglycerides, median % change from baseline.
b Treated Baseline: following 8-week treatment with open-label fenofibrate 160 mg.
Treatment	N	TC	LDL-C	Apo B	HDL-C	Non-HDL-C	TGa
Placebo + Fenofibrate 160 mg	61	2	2	1	-1	2	-3
WELCHOL + Fenofibrate 160 mg	61	-6*	-10*	-7*	0	-8*	6

Type 2 Diabetes Mellitus

WELCHOL has been studied in combination with metformin, sulfonylureas, and insulin. WELCHOL has not been studied as monotherapy.

The efficacy of WELCHOL 3.8 g/day in patients with type 2 diabetes mellitus was evaluated in 3 double-blind, placebo-controlled add-on therapy trials involving a total of 1018 patients with baseline A1C 7.5-9.5%. Patients were enrolled and maintained on their pre-existing, stable, background anti-diabetic regimen. WELCHOL and placebo were administered either as 3 tablets twice daily with lunch and dinner or as 6 tablets with dinner alone.

In these studies, the overall mean age was 57 years (range 24-81 years), 47% were women, and 59% of the patients were Caucasian, 23% were Hispanic, 14% were Black, 3% were Asian, and 1% were of other racial groups. Statin use at baseline was reported in 42% of the WELCHOL-treated patients and 50% of the placebo-treated patients.

In all 3 pivotal add-on therapy trials, treatment with WELCHOL resulted in a statistically significant reduction in A1C of 0.5% compared to placebo. Similar placebo-corrected reductions in A1C occurred in patients who received WELCHOL in combination with metformin, sulfonylurea, or insulin monotherapy or combinations of these therapies with other anti-diabetic agents. In the metformin and sulfonylurea trials, treatment with WELCHOL also resulted in statistically significant reductions in fasting plasma glucose (FPG) of 14 mg/dL compared to placebo.

WELCHOL had consistent effects on A1C across subgroups of age, gender, race, body mass index, and baseline A1C. WELCHOL’s effects on A1C were also similar for the two dosing regimens (3 tablets with lunch and with dinner or 6 tablets with dinner alone).

The mean baseline LDL-C was 104 mg/dL in the metformin study (range 32-214 mg/dL), 106 mg/dL in the sulfonylurea study (range 41-264 mg/dL), and 102 mg/dL in the insulin study (range 35-204 mg/dL). In these trials, WELCHOL treatment was associated with a 12% to 16% reduction in LDL-C levels. The percentage decreases in LDL-C were of similar magnitude to those observed in patients with primary hyperlipidemia. WELCHOL treatment was associated with statistically significant increases in TG levels in the studies of patients on insulin and patients on a sulfonylurea, but not in the study of patients on metformin. The clinical significance of these increases is unknown. WELCHOL is contraindicated in patients with TG levels > 500 mg/dL [See Contraindications (4) ] and periodic monitoring of lipid parameters including TG and non-HDL-C levels is recommended [See Warnings and Precautions and Adverse Reactions ].

Body weight did not significantly increase from baseline with WELCHOL therapy, compared with placebo, in any of the 3 pivotal clinical studies.