Actos®
Pioglitazone HCl
Antidiabetic--Insulin Resistance Reducing Agent
Lilly
http://www.lilly.com/
Actos Monograph PDF download here.
Pharmacology
Actos (pioglitazone hydrochloride) is a
thiazolidinedione antidiabetic agent that depends on the presence of insulin
for its mechanism of action. Actos decreases insulin resistance in the
periphery and liver, resulting in increased insulin-dependent glucose disposal
and decreased hepatic glucose output respectively.
Actos improves glycemic
control while reducing circulating insulin levels. Unlike sulfonylureas, Actos
is not an insulin secretagogue. Actos is a potent and highly selective agonist
for peroxisome proliferator-activated receptor-gamma (PPARγ ). PPAR
receptors are found in tissues important for insulin action such as adipose
tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors
modulates the transcription of a number of insulin responsive genes involved in
the control of glucose and lipid metabolism, and in the maturation of
preadipocytes, predominantly of subcutaneous origin.
Insulin resistance is a
primary feature characterizing the pathogenesis of type 2 diabetes. Actos
results in increased responsiveness of insulin-dependent tissues. Actos
significantly improves hepatic and peripheral (muscle) tissue sensitivity to
insulin in patients with type 2 diabetes. Actos also results in significant
reductions in markers of beta cell hyperstimulation, such as fasting insulin
and fasting C-peptide. In short term clinical studies of 16 weeks duration,
Actos has also been shown to significantly improve biochemical markers of
pancreatic beta cell function.
In clinical studies in
patients with type 2 diabetes, Actos reduces the hyperglycemia and
hyperinsulinemia characteristic of insulin-resistant states, including type 2
diabetes.
Actos significantly
reduces hemoglobin A1c (HbA1c), a marker for long term
glycemic control), and fasting blood glucose (FBG) in patients with type 2
diabetes. Inadequately controlled hyperglycemia is associated with an increased
risk of diabetic complications, including cardiovascular disorders and diabetic
nephropathy, retinopathy and neuropathy.
Other risk factors for
diabetic complications in patients with type 2 diabetes include dyslipidemias
and hypertension. In addition, elevated microalbuminuria is an early indicator
of diabetic nephropathy.
Low HDL-C and elevated
triglycerides are common in patients with type 2 diabetes. Actos significantly
increases high density lipoprotein cholesterol (HDL-C) and reduces
triglycerides in patients with type 2 diabetes. It also increases the particle
size of low density lipoprotein.
Actos significantly
reduces carotid arterial intimal medial thickness. It also results in modest,
but significant, reductions in blood pressure. In addition, Actos significantly
decreases microalbuminuria in patients with type 2 diabetes. See also Warnings
and Precautions sections regarding use in patients with heart disease.
Since Actos enhances
the effects of circulating insulin (by decreasing insulin resistance), it does
not lower blood glucose in animal models that lack endogenous insulin.
Pharmacokinetics
Serum concentrations of total pioglitazone (pioglitazone
plus active metabolites) remain elevated 24 hours after once daily dosing.
Steady-state serum concentrations of both pioglitazone and total pioglitazone
are achieved within 7 days. At steady state, 2 of the pharmacologically active
metabolites of pioglitazone, Metabolites III (M-III) and IV (M-IV), reach serum
concentrations equal to or greater than pioglitazone. At steady state, in both
healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises
approximately 30% to 50% of the peak total pioglitazone serum concentrations
and 20% to 25% of the total area under the serum concentration-time curve
(AUC).
Maximum serum
concentration (Cmax), AUC, and trough serum concentrations (Cmin)
for both pioglitazone and total pioglitazone increase proportionally at doses
of 15 mg and 30 mg per day. There is a slightly less than proportional increase
for pioglitazone and total pioglitazone at a dose of 60 mg per day.
Absorption: Following oral administration, in
the fasting state, pioglitazone is first measurable in serum within 30 minutes,
with peak concentrations observed within 2 hours. Food slightly delays the time
to peak serum concentration to 3 to 4 hours, but does not alter the extent of
absorption.
Distribution: The mean apparent volume of
distribution (Vd/F) of pioglitazone following single-dose administration is
0.63±0.41 (mean±SD) L/kg of body weight. Pioglitazone is extensively protein
bound (>99%) in human serum, principally to serum albumin. Pioglitazone also
binds to other serum proteins, but with lower affinity. Metabolites M-III and
M-IV also are extensively bound (>98%) to serum albumin.
Metabolism: Pioglitazone is extensively
metabolized by hydroxylation and oxidation; the metabolites also partly convert
to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy
derivatives of pioglitazone) and M-III (keto derivative of pioglitazone) are
pharmacologically active in animal models of type 2 diabetes. In addition to
pioglitazone, M-III and M-IV are the principal drug-related species found in
human serum following multiple dosing.
Pioglitazone incubated
with expressed human P450 or human liver microsomes results in the formation of
M-IV and to a much lesser degree, M-II. The major cytochrome P450 isoforms involved
in the hepatic metabolism of pioglitazone are CYP2C8 and CYP3A4 (>50% of
metabolism) with contributions from a variety of other isoforms including the
mainly extrahepatic CYP1A1. Ketoconazole inhibited up to 85% of hepatic
pioglitazone metabolism in vitro at an equimolar concentration to pioglitazone.
At higher than the therapeutic concentrations, pioglitazone had no effect on
the reactions mediated by human liver microsomes expressing cytochrome P450
isoforms including CYP2C8 and CYP3A4. In vivo human studies have not been
performed to investigate any induction of CYP3A4 by pioglitazone.
Excretion and Elimination: Following oral
administration, approximately 15% to 30% of the pioglitazone dose is recovered
in the urine as metabolites. Renal elimination of unchanged pioglitazone is
negligible, and the drug is excreted primarily as metabolites and their
conjugates. It is presumed that most of the oral dose is excreted into the bile
either unchanged or as metabolites and eliminated in the feces.
The mean serum
half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and
16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F,
calculated to be 5 to 7 L/hr.
Special Populations
Renal Insufficiency: The serum elimination
half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with
moderate (creatinine clearance 0.5 to 1.0 mL/s [30 to 60 mL/min]) to severe
(creatinine clearance <0.5 mL/s [30 mL/min]) renal impairment when compared
to normal subjects. No dose adjustment in patients with renal dysfunction is
recommended.
Hepatic Insufficiency: A single-dose, open-label
study was conducted to investigate the effects of impaired hepatic function on
pioglitazone. A group of 24 subjects was enrolled; 12 with normal hepatic
function and 12 with abnormal hepatic function classified as Childs-Pugh Class
B or C. Subjects received a 30 mg pioglitazone tablet 10 minutes after a
diet-controlled meal, and changes in the serum pharmacokinetic profile and
urinary excretion of pioglitazone and its metabolites were then studied.
Compared with controls, subjects with impaired hepatic function have a 45%
reduction in pioglitazone and total (pioglitazone plus active metabolites) mean
peak concentrations but no change in the mean AUC values. The findings of this
study showed that the extent of pioglitazone absorption, as indicated by AUC0–24,
was similar in both normal subjects and individuals with impaired hepatic
function. No adverse events attributable to pioglitazone were reported in
either group, and no clinically significant changes in baseline laboratory
tests, including liver function tests, were observed.
Although no adverse
events attributed to drug were noted in any group, Actos should be used with
caution in patients with hepatic disease (see Warnings, Hepatic Disease and
Precautions, Hepatic Insufficiency).
Geriatrics
In healthy elderly subjects, peak serum
concentrations of pioglitazone and total pioglitazone are not significantly
different, but AUC values are slightly higher and the terminal half-life values
slightly longer than for younger subjects. These changes were not of a
magnitude that would be considered clinically relevant.
Children
Pharmacokinetic data in the pediatric population
are not available. Actos is not recommended for patients under 18 years of age.
Gender
Actos improved glycemic control in both males
and females. In controlled clinical trials the mean Cmax and AUC
values were increased 20% to 60% in females. HbA1c decreases from
baseline were generally greater for females than for males (average mean
absolute difference in HbA1c 0.005). Since therapy should be
individualized for each patient to achieve glycemic control, no dose adjustment
is recommended based on gender alone.
Pharmacodynamics and Clinical Effects
Clinical studies demonstrate that Actos improves
insulin sensitivity in insulin-resistant patients. Actos enhances cellular
responsiveness to insulin, increases insulin-dependent glucose disposal,
improves hepatic sensitivity to insulin, and improves dysfunctional glucose
homeostasis. In patients with type 2 diabetes, the decreased insulin resistance
produced by Actos results in significantly lower blood glucose concentrations,
lower plasma insulin levels, and lower HbA1c values. Based on results
from an open-label extension studies, the glucose lowering effects of Actos are
sustained for more than 1 year, but some patients require titration to higher
doses to maintain the response. The effect of Actos occurs in the absence of
weight loss.
Actos exerts its
antihyperglycemic effect in the presence of insulin. Because Actos does not
stimulate insulin secretion, hypoglycemia would not be expected in patients
treated with Actos alone.
In pharmacodynamic
studies of both monotherapy and combination therapy, treatment with Actos was
associated with decreases in free fatty acids.
In a 26-week,
placebo-controlled, dose-ranging study, mean triglyceride levels decreased in
the 15 mg, 30 mg, and 45 mg Actos dose groups compared to a mean increase
in the placebo group. Mean HDL-C levels increased to a greater extent in the
Actos-treated patients than in the placebo-treated patients. There were no
consistent differences for low density lipoprotein cholesterol (LDL-C) and
total cholesterol in Actos-treated patients compared to placebo (see Table 1).
CPS:Actos_t1Click here for Table 1
Table 1: Actos
Lipids in a 26-week, Multicentre,
Placebo-controlled Dose-ranging Study
|
|
Placebo
|
Actos 15 mg Once Daily
|
Actos 30 mg Once Daily
|
Actos 45 mg Once Daily
|
|
Triglycerides (mmol/L)
|
N=79
|
N=79
|
N=84
|
N=77
|
|
Baseline (mean)
|
2.97
|
3.20
|
2.95
|
2.93
|
|
Percent change from baseline (mean)
|
4.8%
|
-9.0%
|
-9.6%
|
-9.3%
|
|
HDL Cholesterol (mmol/L)
|
N=79
|
N=79
|
N=83
|
N=77
|
|
Baseline (mean)
|
1.08
|
1.04
|
1.06
|
1.05
|
|
Percent change from baseline (mean)
|
8.1%
|
14.1%
|
12.2%
|
19.1%
|
|
LDL Cholesterol (mmol/L)
|
N=65
|
N=63
|
N=74
|
N=62
|
|
Baseline (mean)
|
3.59
|
3.41
|
3.51
|
3.28
|
|
Percent change from baseline (mean)
|
4.8%
|
7.2%
|
5.2%
|
6.0%
|
|
Total Cholesterol (mmol/L)
|
N=79
|
N=79
|
N=84
|
N=77
|
|
Baseline (mean)
|
5.81
|
5.69
|
5.76
|
5.53
|
|
Percent change from baseline (mean)
|
4.4%
|
4.6%
|
3.3%
|
6.4%
|
In two other
monotherapy studies (study duration 24 weeks and 16 weeks), the results were
generally consistent with the data above. For Actos-treated patients, the
placebo-corrected mean changes from baseline decreased by 21 to 23% for
triglycerides, and increased by 5 to 13% for HDL-C.
Statistically
significant increases in HDL-C and reductions in triglycerides were also
observed with Actos in 2 controlled, combination therapy studies (each 16 weeks
duration), in which patients with type 2 diabetes who were receiving therapy
with a sulfonylurea or metformin were randomized to placebo or combination
therapy with Actos.
Patients taking statins
were not excluded from clinical trials. In these patients, the mean increases
in HDL-C and reductions of triglycerides with Actos were observed in addition
to the effects of the statin.
Actos is also
associated with weight gain (see Precautions and Adverse Effects). However, the
weight gain observed in clinical studies with Actos was consistently associated
with improved glycemic control. In addition, Actos significantly decreases
visceral (abdominal) fat stores while increasing extra-abdominal fat. The
reduction in visceral fat correlates with improved hepatic and peripheral
tissue insulin sensitivity. Abdominal obesity is a risk factor for
cardiovascular disorders.
Figure 1 plots the
change in body weight for patients who had completed 48 weeks of treatment with
pioglitazone in an open-label trial.
Figure 1:
Actos
Mean Change from Baseline for Body Weight by
Visit for Patients who Completed 48 Weeks of Open-label Treatment
As indicated in Figure
1, at Week 48 the mean change from baseline in body weight was 5.55 kg for the
de novo group, 6.34 kg for the roll-over placebo group, and 5.36 kg for the
roll-over pioglitazone group. For the total patient group, the mean change from
baseline in body weight was 5.56 kg. The maximum and minimum weight changes
observed up to Week 48 from time of entry into this open-label trial for the
total patient group were 21.77 kg and − 19.86 kg, respectively (median
weight change: 4.54 kg).
Two patients were
withdrawn from the study due to reported weight increases of 15.6 kg and 20.8
kg, respectively. For the first patient, the investigator believed the weight
gain was due to edema, and for the second, a dose of 60 mg of pioglitazone was
used, and the patient had dietary factors that could have also contributed to
the weight gain. Any abnormally large weight gain experienced by some patients
may be due to fluid retention (see Warnings, Edema).
During three
placebo-controlled, 16 week, combination therapy studies the mean weight
increased for all Actos treatment groups: for the sulfonulyrea combination
therapy study the mean increase with Actos 15 mg and 30 mg was 1.9 and 2.9 kg,
respectively; for the metformin study, the mean increase with Actos 30 mg was
0.95 kg and for the insulin study, the mean increase with Actos 15 and 30 mg
was 2.3 and 3.7 kg, respectively.
However, the individual
weight change was highly variable. The range of weight changes during the study
is shown in Table 2 (see Precautions, Weight Gain).
CPS:Actos_t2Click here for Table 2
Table 2: Actos
Change In Weight During Double-Blind,
Combination Therapy Studies
|
Combination Therapy:
|
Sulfonylurea
|
Metformin
|
Insulin
|
|
Placebo
|
Actos
15 mg
|
Actos
30 mg
|
Placebo
|
Actos
30 mg
|
Placebo
|
Actos
15 mg
|
Actos
30 mg
|
|
|
N
|
160 (%)
|
157 (%)
|
168 (%)
|
112 (%)
|
137 (%)
|
162 (%)
|
165 (%)
|
174 (%)
|
|
|
>10 kg loss
|
1 (0.6)
|
-
|
-
|
-
|
1 (0.6)
|
1 (0.6)
|
-
|
-
|
|
|
≥ 5 to 10 kg loss
|
13 (8.1)
|
2 (1.3)
|
4 (2.4)
|
15 (13.4)
|
9 (6.6)
|
9 (5.6)
|
6 (3.6)
|
3 (1.7)
|
|
|
0 to <5 kg loss
|
76 (47.5)
|
23 (14.6)
|
16 (9.5)
|
54 (48.2)
|
21 (15.3)
|
59 (36.4)
|
19 (11.5)
|
13 (7.5)
|
|
|
0 kg
|
19 (11.9)
|
5 (3.2)
|
4 (2.4)
|
9 (8.0)
|
10 (7.3)
|
11 (6.3)
|
9 (5.5)
|
6 (3.4)
|
|
|
0 to ≤ 5 kg gain
|
49 (30.6)
|
110 (70.0)
|
106 (63.1)
|
33 (29.5)
|
81 (59.1)
|
78 (48.1)
|
100 (60.6)
|
96 (55.2)
|
|
|
>5 to 10 kg gain
|
2 (1.3)
|
16 (10.2)
|
36 (21.4)
|
1 (0.9)
|
15 (10.9)
|
4 (2.5)
|
30 (18.2)
|
49 (28.2)
|
|
|
>10 kg gain
|
-
|
1 (0.6)
|
2 (1.2)
|
-
|
-
|
-
|
1 (0.6)
|
7 (4.0)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
In patients receiving
long-term combination therapy with sulfonylurea or metformin, median weight
gain (5.40 kg after at least 60 weeks Actos therapy) was similar to that with
Actos monotherapy (median weight gain 4.54 kg after 48 weeks).
As with Actos monotherapy
studies, weight gain in patients treated with Actos in combination with a
sulfonylurea, metformin or insulin was associated with improved glycemic
control.
Clinical Studies
Monotherapy: Three randomized, double-blind,
placebo-controlled trials with durations from 16 to 26 weeks were conducted to
evaluate the use of Actos as monotherapy in patients with type 2 diabetes.
These studies examined Actos at doses up to 45 mg or placebo once daily in
865 patients. All 3 studies included patients previously treated with
another oral antidiabetic agent (sulfonylureas, n=524; metformin, n=170;
acarbose, n=19) and patients who were previously untreated (n=268).
In a 26-week
dose-ranging study, 408 patients with type 2 diabetes were randomized to
receive 7.5 mg, 15 mg, 30 mg, or 45 mg of Actos, or placebo once daily. Therapy
with any previous antidiabetic agent was discontinued 8 weeks prior to the
double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of Actos produced
statistically significant improvements in HbA1c and fasting blood
glucose (FBG) at endpoint compared to placebo (see Figure 2 and Table 3).
Figure 2 shows the
time course for changes in FBG and HbA1c for the entire study
population in this 26-week study.
Table 3 shows HbA1c
and FBG values for the entire study population.
The study population
included patients not previously treated with antidiabetic medication (naive;
31%) and patients who were receiving antidiabetic medication at the time of
study enrollment (previously treated; 69%). The data for the naive and
previously treated patient subsets are shown in Table 4. All patients entered
an 8-week washout/run-in period prior to double-blind treatment. This run-in
period was associated with little change in HbA1c and FBG values
from screening to baseline for the naive patients; however, for the
previously-treated group, washout from previous anti-diabetic medication
resulted in deterioration of glycemic control and increases in HbA1c
and FBG.
In a 24-week study, 260
patients with type 2 diabetes were randomized to 1 of 2 forced-titration Actos
treatment groups or a mock titration placebo group. Therapy with any previous
antidiabetic agent was discontinued 6 weeks prior to the double-blind period.
In one Actos treatment group, patients received an initial dose of 7.5 mg once
daily. After 4 weeks, the dose was increased to 15 mg once daily and after
another 4 weeks, the dose was increased to 30 mg once daily for the remainder
of the study (16 weeks). In the second Actos treatment group, patients received
an initial dose of 15 mg once daily and were titrated to 30 mg once daily and
45 mg once daily in a similar manner. Treatment with Actos, as described,
produced statistically significant improvements in HbA1c and FBG at endpoint
compared to placebo (see Table 5).
Figure 2:
Actos
Mean Change from Baseline for FBG and HbA1c
in a 26-week Placebo-controlled Dose-ranging Study
CPS:Actos_t3Click here for Table 3
Table 3: Actos
Glycemic Parameters in a 26-week
Placebo-controlled Dose-ranging Study
|
|
Placebo
|
Actos 15 mg Once Daily
|
Actos 30 mg Once Daily
|
Actos 45 mg Once Daily
|
|
|
Total Population
|
|
HbA1c
|
N=79
|
N=79
|
N=85
|
N=76
|
|
|
Baseline (mean)
|
0.104
|
0.102
|
0.102
|
0.103
|
|
|
Change from Baseline (adjusted meana
)
|
0.007
|
-0.003
|
-0.003
|
-0.009
|
|
|
Difference from Placebob (adjusted
meana )
|
|
-0.01
|
-0.01
|
-0.016
|
|
|
FBG (mmol/L)
|
N=79
|
N=79
|
N=84
|
N=77
|
|
|
Baseline (mean)
|
14.9
|
14.8
|
14.9
|
15.3
|
|
|
Change from Baseline (adjusted meana
)
|
0.5
|
-1.7
|
-1.8
|
-3.1
|
|
|
Difference from Placebob (adjusted
meana )
|
|
-2.2
|
-2.3
|
-3.6</ |
