A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Tricor Pharmacology, Pharmacokinetics, Studies, Metabolism - Fenofibrate
Tricor Pharmacology, Pharmacokinetics, Studies, Metabolism - Fenofibrate
CLINICAL PHARMACOLOGY
A variety of clinical studies have demonstrated that elevated
levels of total cholesterol (total-C), low density lipoprotein cholesterol (LDL-C),
and apolipoprotein B (apo B), an LDL membrane complex, are associated with human
atherosclerosis. Similarly, decreased levels of high density lipoprotein cholesterol
(HDL-C) and its transport complex, apolipoprotein A (apo AI and apo AII) are
associated with the development of atherosclerosis. Epidemiologic investigations
have established that cardiovascular morbidity and mortality vary directly with
the level of total-C, LDL-C, and triglycerides,and inversely with the level
of HDL-C. The independent effect of raising HDL-C or lowering triglycerides
(TG) on the risk of cardiovascular morbidity and mortality has not been determined.
Fenofibric acid, the active metabolite of fenofibrate, produces
reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides
and triglyceride rich lipoprotein (VLDL) in treated patients. In addition, treatment
with fenofibrate results in increases in high density lipoprotein (HDL) and
apoproteins apoAI and apoAII.
The effects of fenofibric acid seen in clinical practice have
been explained in vivo in transgenic mice and in vitro in human
hepatocyte cultures by the activation of peroxisome proliferator activated receptor
a (PPARa). Through this
mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich
particles from plasma by activating lipoprotein lipase and reducing production
of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting
fall in triglycerides produces an alteration in the size and composition of
LDL from small, dense particles (which are thought to be atherogenic due to
their susceptibility to oxidation), to large buoyant particles. These larger
particles have a greater affinity for cholesterol receptors and are catabolized
rapidly. Activation of PPARa also induces an increase
in the synthesis of apoproteins A-I,A-II and HDL-cholesterol.
Fenofibrate also reduces serum uric acid levels in hyperuricemic
and normal individuals by increasing the urinary excretion of uric acid.
Pharmacokinetics/Metabolism
Plasma concentrations of fenofibric acid after administration
of 54 mg and 160 mg tablets are equivalent under fed conditions to 67 and 200
mg capsules, respectively.
Absorption
The absolute bioavailability of fenofibrate cannot be determined
as the compound is virtually insoluble in aqueous media suitable for injection.
However, fenofibrate is well absorbed from the gastrointestinal tract. Following
oral administration in healthy volunteers, approximately 60% of a single dose
of radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid
and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma
levels of fenofibric acid occur within 6 to 8 hours after administration.
The absorption of fenofibrate is increased when administered
with food. With fenofibrate tablets, the extent of absorption is increased by
approximately 35% under fed as compared to fasting conditions.
Distribution
In healthy volunteers, steady-state plasma levels of fenofibric
acid were shown to be achieved within 5 days of dosing and did not demonstrate
accumulation across time following multiple dose administration. Serum protein
binding was approximately 99% in normal and hyperlipidemic subjects.
Metabolism
Following oral administration, fenofibrate is rapidly hydrolyzed
by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate
is detected in plasma.
Fenofibric acid is primarily conjugated with glucuronic acid
and then excreted in urine. A small amount of fenofibric acid is reduced at
the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated
with glucuronic acid and excreted in urine.
In vivo metabolism data indicate that neither fenofibrate
nor fenofibric acid undergo oxidative metabolism (e.g.,cytochrome P450) to a
significant extent.
Excretion
After absorption, fenofibrate is mainly excreted in the urine
in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide.
After administration of radiolabelled fenofibrate, approximately 60% of the
dose appeared in the urine and 25% was excreted in the feces.
Fenofibric acid is eliminated with a half-life of 20 hours,
allowing once daily administration in a clinical setting.
Special Populations
Geriatrics
In elderly volunteers 77 - 87 years of age, the oral clearance
of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/h,
which compares to 1.1 L/h in young adults. This indicates that a similar dosage
regimen can be used in the elderly, without increasing accumulation of the drug
or metabolites.
Pediatrics
TRICOR has not been investigated in adequate and well-controlled
trials in pediatric patients.
Gender
No pharmacokinetic difference between males and females has
been observed for fenofibrate.
Race
The influence of race on the pharmacokinetics of fenofibrate
has not been studied, however fenofibrate is not metabolized by enzymes known
for exhibiting inter-ethnic variability. Therefore, inter-ethnic pharmacokinetic
differences are very unlikely.
Renal insufficiency
In a study in patients with severe renal impairment (creatinine
clearance < 50 mL/min),the rate of clearance of fenofibric acid was greatly
reduced, and the compound accumulated during chronic dosage. However, in patients
having moderate renal impairment (creatinine clearance of 50 to 90 mL/min),the
oral clearance and the oral volume of distribution of fenofibric acid are increased
compared to healthy adults (2.1 L/h and 95 L versus 1.1 L/h and 30 L, respectively).
Therefore, the dosage of TRICOR should be minimized in patients who have severe
renal impairment, while no modification of dosage is required in patients having
moderate renal impairment.
Hepatic insufficiency
No pharmacokinetic studies have been conducted in patients
having hepatic insufficiency.
Drug-drug interactions
In vitro studies using human liver microsomes indicate
that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP)
P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of
CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic
concentrations.
Potentiation of coumarin-type anticoagulants has been observed
with prolongation of the prothrombin time/INR.
Bile acid sequestrants have been shown to bind other drugs
given concurrently. Therefore, fenofibrate should be taken at least 1 hour before
or 4-6 hours after a bile acid binding resin to avoid impeding its absorption
(see WARNINGS and PRECAUTIONS).
Clinical Trials
Hypercholesterolemia (Heterozygous Familial and Nonfamilial)
and Mixed Dyslipidemia (Fredrickson Types IIa and IIb)
The effects of fenofibrate at a dose equivalent to 160 mg TRICOR
per day were assessed from four randomized, placebo-controlled, double-blind,
parallel-group studies including patients with the following mean baseline lipid
values: total-C 306.9 mg/dL; LDL-C 213.8 mg/dL; HDL-C 52.3 mg/dL; and triglycerides
191.0 mg/dL. TRICOR therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio.
TRICOR therapy also lowered triglycerides and raised HDL-C (see Table 1).
|
Table 1 Mean Percent Change in Lipid Parameters at
End of Treatment†
|
|
Treatment Group
|
Total-C
|
LDL-C
|
HDL-C
|
TG
|
|
Pooled Cohort
|
|
|
|
|
|
Mean baseline lipid
|
|
|
|
|
|
values (n=646)
|
306.9 mg/dL
|
213.8 mg/dL
|
52.3 mg/dL
|
191.0 mg/dL
|
|
All FEN (n=361)
|
-18.7%*
|
-20.6%*
|
+11.0%*
|
-28.9%*
|
|
Placebo (n=285)
|
-0.4%
|
-2.2%
|
+0.7%
|
+7.7%
|
|
Baseline LDL-C > 160 mg/dL and TG < 150 mg/dL (Type
IIa)
|
|
Mean baseline lipid
|
|
|
|
|
|
values (n=334)
|
307.7 mg/dL
|
227.7 mg/dL
|
58.1 mg/dL
|
101.7 mg/dL
|
|
All FEN (n=193)
|
-22.4%*
|
-31.4%*
|
+9.8%*
|
-23.5%*
|
|
Placebo (n=141)
|
+0.2%
|
-2.2%
|
+2.6%
|
+11.7%
|
|
Baseline LDL-C > 160 mg/dL and TG ³
150 mg/dL (Type IIb)
|
|
Mean baseline lipid
|
|
|
|
|
|
values (n=242)
|
312.8 mg/dL
|
219.8 mg/dL
|
46.7 mg/dL
|
231.9 mg/dL
|
|
All FEN (n=126)
|
-16.8%*
|
-20.1%*
|
+14.6%*
|
-35.9%*
|
|
Placebo (n=116)
|
-3.0%
|
-6.6%
|
+2.3%
|
+0.9%
|
|
† Duration of study treatment was 3 to 6 months.
|
|
* p = <0.05 vs. Placebo
|
|
In a subset of the subjects, measurements of apo B were
conducted. TRICOR treatment significantly reduced apo B from baseline
to endpoint as compared with placebo (-25.1% vs. 2.4%, p<0.0001, n=213
and 143 respectively).
|
Hypertriglyceridemia (Fredrickson Type IV and V)
The effects of fenofibrate on serum triglycerides were studied
in two randomized, double-blind, placebo-controlled clinical trials1 of
147 hypertriglyceridemic patients (Fredrickson Types IV and V). Patients were
treated for eight weeks under protocols that differed only in that one entered
patients with baseline triglyceride (TG) levels of 500 to 1500 mg/dL, and the
other TG levels of 350 to 500 mg/dL. In patients with hypertriglyceridemia and
normal cholesterolemia with or without hyperchylomicronemia (Type IV/V hyperlipidemia),
treatment with fenofibrate at dosages equivalent to 160 mg TRICOR per day decreased
primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol.
Treatment of patients with Type IV hyperlipoproteinemia and elevated triglycerides
often results in an increase of low density lipoprotein (LDL) cholesterol (see
Table 2).
|
Table 2 Effects of TRICOR in Patients With Fredrickson
Type IV/V Hyperlipidemia
|
|
Study 1
|
Placebo
|
|
|
|
TRICOR
|
|
|
|
Baseline TG levels
|
N
|
Baseline
|
Endpoint
|
%Change
|
N
|
Baseline
|
Endpoint
|
%Change
|
|
350 to 499 mg/dL
|
|
(Mean)
|
(Mean)
|
(Mean)
|
|
(Mean)
|
(Mean)
|
(Mean)
|
|
Triglycerides
|
28
|
449
|
450
|
-0.5
|
27
|
432
|
223
|
-46.2*
|
|
VLDL Triglycerides
|
19
|
367
|
350
|
2.7
|
19
|
350
|
178
|
-44.1*
|
|
Total Cholesterol
|
28
|
255
|
261
|
2.8
|
27
|
252
|
227
|
-9.1*
|
|
HDL Cholesterol
|
28
|
35
|
36
|
4
|
27
|
34
|
40
|
19.6*
|
|
LDL Cholesterol
|
28
|
120
|
129
|
12
|
27
|
128
|
137
|
14.5
|
|
VLDL Cholesterol
|
27
|
99
|
99
|
5.8
|
27
|
92
|
46
|
-44.7*
|
|
Study 2
|
Placebo
|
|
|
|
TRICOR
|
|
|
|
Baseline TG levels
|
N
|
Baseline
|
Endpoint
|
%Change
|
N
|
Baseline
|
Endpoint
|
%Change
|
|
500 to 1500 mg/dL
|
|
(Mean)
|
(Mean)
|
(Mean)
|
|
(Mean)
|
(Mean)
|
(Mean)
|
|
Triglycerides
|
44
|
710
|
750
|
7.2
|
48
|
726
|
308
|
-54.5*
|
|
VLDL Triglycerides
|
29
|
537
|
571
|
18.7
|
33
|
543
|
205
|
-50.6*
|
|
Total Cholesterol
|
44
|
272
|
271
|
0.4
|
48
|
261
|
223
|
-13.8*
|
|
HDL Cholesterol
|
44
|
27
|
28
|
5.0
|
48
|
30
|
36
|
22.9*
|
|
LDL Cholesterol
|
42
|
100
|
90
|
-4.2
|
45
|
103
|
131
|
45.0*
|
|
VLDL Cholesterol
|
42
|
137
|
142
|
11.0
|
45
|
126
|
54
|
-49.4*
|
|
* = p<0.05 vs. Placebo
|
|
The effect of TRICOR on cardiovascular morbidity and
mortality has not been determined.
|
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