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
Baycol Pharmacology, Pharmacokinetics, Studies, Metabolism - Cerivastatin
Baycol Pharmacology, Pharmacokinetics, Studies, Metabolism - Cerivastatin
CLINICAL PHARMACOLOGY
Cholesterol and triglycerides
circulate as proof of lipoprotein
complexes throughout the bloodstream. These complexes can be separated
via ultracentrifugation
into high- density lipoprotein
(HDL), intermediate-density lipoprotein (IDL), low-density lipoprotein
(LDL) and very-low-density lipoprotein
VLDL fractions. In the liver,
cholesterol and
triglycerides
(T) are synthesized, incorporated into VLDL, and released into the
plasma for delivery
to peripheral tissues.
A variety of clinical
studies have demonstrated that elevated levels of total cholesterol
(total- C), LDL- C. and apolipoprotein
B (apo- B, a membrane
complex for LDLC) promote
human atherosclerosis.
Similarly, decreased levels of HDL- C (and its transport
complex, apolipoprotein
A) are associated with the development
of atherosclerosis. Epidemiologic Investigations have established
that cardiovascular
morbidity and mortality
vary directly with the level of total- C and LDL- C and inversely
with the level of HDL- C.
In patients with hypercholesterolemia,
BAYCOL (cerivastatin sodium
tablets) has been shown to reduce
plasma total cholesterol,
LDL-C, and apolipoprotein B. In
addition, it also reduces plasma
triglycerides
and increases plasma HDL-C. The agent
has no consistent effect
on plasma Lp( a). The
effect of BAYCOL on cardiovascular
morbidity and mortality
has not been determined.
Mechanism of Action
Cerivastatin is a competitive inhibitor
of HMG-CoA reductase, which is responsible for the conversion
of 3- hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) to mevalonate,
a precursor of sterols,
including cholesterol. The inhibition
of cholesterol biosynthesis
by cerivastatin reduces the level of cholesterol
in hepatic cells, which
stimulates the synthesis
of LDL receptors, thereby increasing the uptake
of cellular LDL
particles. The end result
of these biochemical
processes is a reduction
of the plasma cholesterol concentration.
Pharmacokinetics
Absorption: BAYCOL (cerivastatin sodium
tablets) is administered orally in the active form. The mean
absolute bioavailability
of cerivastatin following a 0.2-mg tablet
oral dose
is 60% (range 39 - 101% ). In
general, the coefficient
of variation (based
on the inter-subject variability
for both systemic exposure
(area under the curve, UC) and 1 Cmax is in the 20% to
40% range. The bioavailability
of cerivastatin sodium tablets is equivalent
to that of a solution
of cerivastatin sodium. No unchanged cerivastatin is excreted in
feces. Cerivastatin exhibits linear kinetics over the dose
range of 0.05 to 0.3 mg
daily. Mean maximum
concentrations (Cmax) following evening cerivastatin
tablet doses of 0.05,
0.1, 0.2, and 0.3 mg are
0.6, 1.3, 2.4, and 3.8 mg/L,
respectively. AUC values
are also dose-proportional over this dose
range and the mean time
to maximum concentration
tmax) is approximately 2.5 hours for all dose
strengths. ollowing oral
administration, the terminal
elimination half-life (tl/2) for cerivastatin is 2 to
3 hours. Steady-state plasma concentrations show
no evidence
of cerivastatin accumulation following administration of up to 0.40
mg daily.
Results from an overnight pharmacokinetic evaluation
following single- dose administration
of cerivastatin with the evening meal
or 4 hours after the evening meal
showed that administration
of cerivastatin with the evening meal did not significantly alter
either AUC or Cmax compared
to dosing the drug 4 hours
after the evening meal. In
patients given 0.2 mg cerivastatin
sodium once daily for 4 weeks, either at mealtime or at bedtime,
there were no differences
in the lipid-lowering effects of cerivastatin. Both regimens of
0.2 mg once daily were slightly
more efficacious than 0.1 mg twice daily.
Distribution: The volume
of distribution
(VDss) is calculated to be 0.3 L/kg. More than 99% of the circulating
drug is bound
to plasma proteins (80% to albumin). Binding is reversible
and independent of drug concentration up to 100 mg/L.
Metabolism: Biotransformation pathways for cerivastatin
in humans include the following: demethylation of the benzylic methyl
ether to form Ml and hydroxylation
of the methyl group
in the 6’- isopropyl moiety to form
M23. The combination of both reactions leads to formation
of metabolite M24. The major circulating blood
components are cerivastatin and the pharmacologically active Ml
and M23 metabolites. The relative potencies of metabolites Ml and
M23 are approximately 50% and 80% of the parent
compound, respectively.
Following a 0.3- mg dose
of cerivastatin to 6 healthy
volunteers, mean Cmax values for cerivastatin, Ml, and M23 were
3.0,0.2, and 0.5 mg/L,
respectively. Therefore, the cholesterol- lowering effect
is due primarily to the parent
compound, cerivastatin.
Excretion: Cerivastatin itself is not found in either
urine or feces; Ml and M23 are the major metabolites excreted by
these routes. Following an oral
dose of 0.4 mg
14C-cerivastatin to healthy
volunteers, excretion of radioactivity
is about 24% in the urine
and 70% in the feces. The parent
compound, cerivastatin,
accounts for less than 2% of the total radioactivity excreted. The
plasma clearance
for cerivastatin in humans after intravenous
dosing is 12 to 13 liters per
hour.
| SPECIAL POPULATIONS |
| Geriatric: |
Plasma concentrations
of cerivastatin are similar in healthy
elderly male subjects
(> 65 years) and in young males (< 40 years). |
| Gender: |
Plasma concentrations
of cerivastatin in females are slightly higher than in males
approximately 12% higher for Cmax and 6% higher
for AUC) |
| Pediatric: |
Cerivastatin pharmacokinetics
have not been studied in pediatric
patients. |
| Race: |
Cerivastatin pharmacokinetics
were compared across studies in Caucasian, Japanese and Black
subjects. No significant
differences in A.C.
Cmax, tmax and t1/2 were
found. |
| Renal: |
Steady- state plasma
concentrations of cerivastatin are similar in healthy
volunteers (Clcr> 90 mL/min/ l.73m*) and in patients with
mild renal impairment
(Clcr 61- 90 mLmin/ l. 73m2). In
patients with moderate (Clcr 31- 60 mLmin/ .73m2)
or severe (Clcr £ 30 mLmin/
.73m2) renal
impairment,
AUC is up to 60% higher,
Cmax up to 23% higher, and t1/2 up to
47% longer compared to subjects with normal
renal function.
|
| Hemodialysis: |
While studies have
not been conducted in patients with end- stage
renal disease,
hemodialysis is not expected to signifi-cantly enhance clearance
of cerivastatin since the drug
is extensively bound
to plasma proteins. |
| Hepatic: |
Cerivastatin has
not been studied in patients with active liver
disease (see CONTRAINDICATIONS)
Caution should be exercised when BAYCOL (ceriva-statin sodium
tablets) is administered to patients with a history
of liver disease
or heavy alcohol ingestion (see WARNINGS). |
Clinical Studies
BAYCOL (cerivastatin sodium
tablets) has been studied in controlled trials in North America,
Europe, Israel, and South Africa and has been shown to be effective
in reducing plasma total
cholesterol (Total-C)
and LDL cholesterol
(LDL-C) in heterozygous
familial and non-familial
forms of hypercholesterolemia
and in mixed hyperlipidemia.
Over 2,800 patients with Type IIa and IIb hypercholesterolemia
were treated in trials of 4 to 104 weeks duration. In
a 24= week, randomized, double- b.i.d.
placebo-controlled US trial in 934 patients with primary
hypercholesterolemia,
BAYCOL (cerivastatin sodium tablets) 0.05 to 0.3 mg
once daily produced dose-related reductions in plasma
LDL-C and Total-C. Significant reductions in mean
total-C and LDL-C were evident after one week, peaked at four weeks,
and were maintained for the duration
of the trial. Reductions in plasma
triglycerides
(TG) and increases in HDL-C were also observed. The results from
this study in patients treated with the marketed doses of cerivastatin
are summarized in Table 1.
Table1
|
Response in Patients with Primary Hypercholestemlemia
Mean Percent Change from Baseline after
24 Weeks
|
| Dosage |
n
|
Total-C
|
LDL-C
|
LDL-C
|
TG
|
Apo- 8
|
| Placebo |
137’
|
+ 1.7
|
+ 1.8
|
+ 3.1
|
+ 1.1
|
+ 3.2
|
| BAYCOL |
| 0.2 mg
qd" |
143t
|
-1 7 .4
|
m- 25.3
|
+10.4
|
10.7
|
18.7
|
| 0.3 mg
qd* . |
135
|
-1 9 .4
|
-28.2
|
t10.3
|
-12.7
|
-20.5
|
| ' 137 patients
were evaluated for all parameters except LDL-C which had 136
patients
t 143 patients were evaluated for Total-C, HDL-C
and TG. For LDL-C and Apo-B there were 140 and 141 patients
evaluated, respectively.
135 patients were evaluated for all parameters except LDL-C
which had 134 patients.
.' qd = once daily
|
In a separate dose-scheduling study, BAYCOL (cerivastatin sodium
tablets) was given as either a 0.2- mg
dose once daily with dinner
or at bedtime or as a 0.1= mg
dose twice daily (morning
and evening), Mean LDL-C reduction in response
to BAYCOL dosed once with dinner or at bedtime was about 4% greater
than the mean reduction
in response to twice
daily (divided) dosing (p< 0.05).
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