Zetia (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 × the human exposure at 10 mg daily based on AUC_0–24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 × the human exposure at 10 mg daily based on AUC_0–24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice.

No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test.

In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 × the human exposure at 10 mg daily based on AUC_0–24hr for total ezetimibe).

13.2 Animal Toxicology and/or Pharmacology

The hypocholesterolemic effect of ezetimibe was evaluated in cholesterol-fed Rhesus monkeys, dogs, rats, and mouse models of human cholesterol metabolism. Ezetimibe was found to have an ED₅₀ value of 0.5 µg/kg/day for inhibiting the rise in plasma cholesterol levels in monkeys. The ED₅₀ values in dogs, rats, and mice were 7, 30, and 700 µg/kg/day, respectively. These results are consistent with ZETIA being a potent cholesterol absorption inhibitor.

In a rat model, where the glucuronide metabolite of ezetimibe (SCH 60663) was administered intraduodenally, the metabolite was as potent as the parent compound (SCH 58235) in inhibiting the absorption of cholesterol, suggesting that the glucuronide metabolite had activity similar to the parent drug.

In 1-month studies in dogs given ezetimibe (0.03 to 300 mg/kg/day), the concentration of cholesterol in gallbladder bile increased ~2- to 4-fold. However, a dose of 300 mg/kg/day administered to dogs for one year did not result in gallstone formation or any other adverse hepatobiliary effects. In a 14-day study in mice given ezetimibe (0.3 to 5 mg/kg/day) and fed a low-fat or cholesterol-rich diet, the concentration of cholesterol in gallbladder bile was either unaffected or reduced to normal levels, respectively.

A series of acute preclinical studies was performed to determine the selectivity of ZETIA for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of ¹⁴ C-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins A and D.

In 4- to 12-week toxicity studies in mice, ezetimibe did not induce cytochrome P450 drug metabolizing enzymes. In toxicity studies, a pharmacokinetic interaction of ezetimibe with statins (parents or their active hydroxy acid metabolites) was seen in rats, dogs, and rabbits.

14 CLINICAL STUDIES

14.1 Primary Hyperlipidemia

ZETIA reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia. Maximal to near maximal response is generally achieved within 2 weeks and maintained during chronic therapy.

Monotherapy

In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary hyperlipidemia, ZETIA significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo (see Table 6). Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.

TABLE 6: Response to ZETIA in Patients with Primary Hyperlipidemia (Mean * % Change from Untreated Baseline †)

	Treatment Group	N	Total-C	LDL-C	Apo B	Non-HDL-C	TG *	HDL-C
* For triglycerides, median % change from baseline. † Baseline — on no lipid-lowering drug. ‡ ZETIA significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo.
Study 1‡	Placebo	205	+1	+1	-1	+1	-1	-1
	Ezetimibe	622	-12	-18	-15	-16	-7	+1
Study 2‡	Placebo	226	+1	+1	-1	+2	+2	-2
	Ezetimibe	666	-12	-18	-16	-16	-9	+1
Pooled Data ‡ (Studies 1 & 2)	Placebo	431	0	+1	-2	+1	0	-2
	Ezetimibe	1288	-13	-18	-16	-16	-8	+1

Combination with Statins

ZETIA Added to On-going Statin Therapy

In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients with primary hyperlipidemia, known coronary heart disease or multiple cardiovascular risk factors who were already receiving statin monotherapy, but who had not met their NCEP ATP II target LDL-C goal were randomized to receive either ZETIA or placebo in addition to their on-going statin.

ZETIA, added to on-going statin therapy, significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared with a statin administered alone (see Table 7). LDL-C reductions induced by ZETIA were generally consistent across all statins.

TABLE 7: Response to Addition of ZETIA to On-Going Statin Therapy * in Patients with Hyperlipidemia (Mean † % Change from Treated Baseline ‡)

Treatment (Daily Dose)	N	Total-C	LDL-C	Apo B	Non-HDL-C	TG †	HDL-C
* Patients receiving each statin: 40% atorvastatin, 31% simvastatin, 29% others (pravastatin, fluvastatin, cerivastatin, lovastatin). † For triglycerides, median % change from baseline. ‡ Baseline — on a statin alone. § ZETIA + statin significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to statin alone.
On-going Statin + Placebo §	390	-2	-4	-3	-3	-3	+1
On-going Statin + ZETIA §	379	-17	-25	-19	-23	-14	+3

ZETIA Initiated Concurrently with a Statin

In four multicenter, double-blind, placebo-controlled, 12-week trials, in 2382 hyperlipidemic patients, ZETIA or placebo was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin.

When all patients receiving ZETIA with a statin were compared to all those receiving the corresponding statin alone, ZETIA significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and, with the exception of pravastatin, increased HDL-C compared to the statin administered alone. LDL-C reductions induced by ZETIA were generally consistent across all statins. (See footnote ‡^, Tables 8 to 11.)

TABLE 8: Response to ZETIA and Atorvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean * % Change from Untreated Baseline †)

Treatment (Daily Dose)	N	Total-C	LDL-C	Apo B	Non-HDL-C	TG *	HDL-C
* For triglycerides, median % change from baseline. † Baseline — on no lipid-lowering drug. ‡ ZETIA + all doses of atorvastatin pooled (10–80 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of atorvastatin pooled (10–80 mg).
Placebo	60	+4	+4	+3	+4	-6	+4
ZETIA	65	-14	-20	-15	-18	-5	+4
Atorvastatin 10 mg	60	-26	-37	-28	-34	-21	+6
ZETIA + Atorvastatin 10 mg	65	-38	-53	-43	-49	-31	+9
Atorvastatin 20 mg	60	-30	-42	-34	-39	-23	+4
ZETIA + Atorvastatin 20 mg	62	-39	-54	-44	-50	-30	+9
Atorvastatin 40 mg	66	-32	-45	-37	-41	-24	+4
ZETIA + Atorvastatin 40 mg	65	-42	-56	-45	-52	-34	+5
Atorvastatin 80 mg	62	-40	-54	-46	-51	-31	+3
ZETIA + Atorvastatin 80 mg	63	-46	-61	-50	-58	-40	+7
Pooled data (All Atorvastatin Doses)‡	248	-32	-44	-36	-41	-24	+4
Pooled data (All ZETIA + Atorvastatin Doses)‡	255	-41	-56	-45	-52	-33	+7

TABLE 9: Response to ZETIA and Simvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean * % Change from Untreated Baseline †)

Treatment (Daily Dose)	N	Total-C	LDL-C	Apo B	Non-HDL-C	TG *	HDL-C
* For triglycerides, median % change from baseline. † Baseline — on no lipid-lowering drug. ‡ ZETIA + all doses of simvastatin pooled (10–80 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of simvastatin pooled (10–80 mg).
Placebo	70	-1	-1	0	-1	+2	+1
ZETIA	61	-13	-19	-14	-17	-11	+5
Simvastatin 10 mg	70	-18	-27	-21	-25	-14	+8
ZETIA + Simvastatin 10 mg	67	-32	-46	-35	-42	-26	+9
Simvastatin 20 mg	61	-26	-36	-29	-33	-18	+6
ZETIA + Simvastatin 20 mg	69	-33	-46	-36	-42	-25	+9
Simvastatin 40 mg	65	-27	-38	-32	-35	-24	+6
ZETIA + Simvastatin 40 mg	73	-40	-56	-45	-51	-32	+11
Simvastatin 80 mg	67	-32	-45	-37	-41	-23	+8
ZETIA + Simvastatin 80 mg	65	-41	-58	-47	-53	-31	+8
Pooled data (All Simvastatin Doses)‡	263	-26	-36	-30	-34	-20	+7
Pooled data (All ZETIA + Simvastatin Doses)‡	274	-37	-51	-41	-47	-29	+9

TABLE 10: Response to ZETIA and Pravastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean * % Change from Untreated Baseline †)

Treatment (Daily Dose)	N	Total-C	LDL-C	Apo B	Non-HDL-C	TG *	HDL-C
* For triglycerides, median % change from baseline. † Baseline — on no lipid-lowering drug. ‡ ZETIA + all doses of pravastatin pooled (10–40 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG compared to all doses of pravastatin pooled (10–40 mg).
Placebo	65	0	-1	-2	0	-1	+2
ZETIA	64	-13	-20	-15	-17	-5	+4
Pravastatin 10 mg	66	-15	-21	-16	-20	-14	+6
ZETIA + Pravastatin 10 mg	71	-24	-34	-27	-32	-23	+8
Pravastatin 20 mg	69	-15	-23	-18	-20	-8	+8
ZETIA + Pravastatin 20 mg	66	-27	-40	-31	-36	-21	+8
Pravastatin 40 mg	70	-22	-31	-26	-28	-19	+6
ZETIA + Pravastatin 40 mg	67	-30	-42	-32	-39	-21	+8
Pooled data (All Pravastatin Doses)‡	205	-17	-25	-20	-23	-14	+7
Pooled data (All ZETIA + Pravastatin Doses)‡	204	-27	-39	-30	-36	-21	+8

TABLE 11: Response to ZETIA and Lovastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean * % Change from Untreated Baseline †)

Treatment (Daily Dose)	N	Total-C	LDL-C	Apo B	Non-HDL-C	TG *	HDL-C
* For triglycerides, median % change from baseline. † Baseline — on no lipid-lowering drug. ‡ ZETIA + all doses of lovastatin pooled (10–40 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of lovastatin pooled (10–40 mg).
Placebo	64	+1	0	+1	+1	+6	0
ZETIA	72	-13	-19	-14	-16	-5	+3
Lovastatin 10 mg	73	-15	-20	-17	-19	-11	+5
ZETIA + Lovastatin 10 mg	65	-24	-34	-27	-31	-19	+8
Lovastatin 20 mg	74	-19	-26	-21	-24	-12	+3
ZETIA + Lovastatin 20 mg	62	-29	-41	-34	-39	-27	+9
Lovastatin 40 mg	73	-21	-30	-25	-27	-15	+5
ZETIA + Lovastatin 40 mg	65	-33	-46	-38	-43	-27	+9
Pooled data (All Lovastatin Doses)‡	220	-18	-25	-21	-23	-12	+4
Pooled data (All ZETIA + Lovastatin Doses)‡	192	-29	-40	-33	-38	-25	+9

Combination with Fenofibrate

In a multicenter, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidemia, 625 patients were treated for up to 12 weeks and 576 for up to an additional 48 weeks. Patients were randomized to receive placebo, ZETIA alone, 160-mg fenofibrate alone, or ZETIA and 160-mg fenofibrate in the 12-week study. After completing the 12-week study, eligible patients were assigned to ZETIA coadministered with fenofibrate or fenofibrate monotherapy for an additional 48 weeks.

ZETIA coadministered with fenofibrate significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to fenofibrate administered alone. The percent decrease in TG and percent increase in HDL-C for ZETIA coadministered with fenofibrate were comparable to those for fenofibrate administered alone (see Table 12).

TABLE 12: Response to ZETIA and Fenofibrate Initiated Concurrently in Patients with Mixed Hyperlipidemia (Mean * % Change from Untreated Baseline † at 12 weeks)

Treatment (Daily Dose)	N	Total-C	LDL-C	Apo B	TG *	HDL-C	Non-HDL-C
* For triglycerides, median % change from baseline. † Baseline — on no lipid-lowering drug.
Placebo	63	0	0	-1	-9	+3	0
ZETIA	185	-12	-13	-11	-11	+4	-15
Fenofibrate 160 mg	188	-11	-6	-15	-43	+19	-16
ZETIA + Fenofibrate 160 mg	183	-22	-20	-26	-44	+19	-30

The changes in lipid endpoints after an additional 48 weeks of treatment with ZETIA coadministered with fenofibrate or with fenofibrate alone were consistent with the 12-week data displayed above.