PIOGLITAZONE HYDROCHLORIDE
Description
Pioglifazone an oral antidiabetic agent that acts primarily by increasing
insulin sensitivity. Pioglitazone is used in the management of type 2
diabetes mellitus (also known as non-insulin-dependent diabetes
mellitus (NIDDM) or adult-onset diabetes). Pharmacological studies
indicate that pioglitazone improves sensitivity to insulin in muscle
and adipose tissue and inhibits hepatic gluconeogenesis. It improves
glycaemic control while reducing circulating insulin levels.
Clinical Pharmacology
Mechanism of Action
Pioglitazone is a thiazolidinedione antidiabetic agent belongs to a
different chemical class and has a different pharmacological action
than the sulfonylureas, metformin, or the a-glucosidase inhibitors.
For its mechanism of action pioglitazone depends on the presence
of insulin. It decreases insulin resistance in the periphery and in the
liver resulting in increased insulin-dependent glucose disposal and
decreased hepatic glucose output.
Pioglitazone is a potent and highly selective agonist for peroxisome
proliferator-activated receptor-gamma (PPARg). PPAR receptors are
found in tissues important for insulin action such as adipose tissue,
skeletal muscle, and liver. Activation of PPARg nuclear receptors
modulates the transcription of a number of insulin responsive genes
involved in the control of glucose and lipid metabolism. In animal
models of diabetes,pioglitazone reduces the hyperglycaemia,
hyperinsulinaemia, and hypertriglyceridaemia characteristic of insulin-
resistant states such as type 2 diabetes. The metabolic changes
produced by pioglitazone result in increased responsiveness of insulin-
dependent tissues and are observed in numerous animal models of
insulin resistance.
Since pioglitazone enhances the effects of circulating insulin (by
decreasing insulin resistance), it does not lower blood glucose in
animal models that lack endogenous insulin.
Pharmacokinetics
Pioglitazone is well absorbed when taken orally, and food does not
alter the extent of 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.
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, two of the
pharmacologically active metabolites of pioglitazone, Metabolites III
(M-lll) and IV (M-IV), reach serum concentrations equal to or greater
than pioglitazone.
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.
Pioglitazone is extensively protein bound (>99%) in human serum,
principally to serum albumin. It also binds to other serum proteins,
but with lower affinity. Metabolites M-lll and M-IV also are extensively
metabolised by hydroxylation and oxidation; the metabolites also partly
convert to glucuronide or sulfate conjugates. The major cytochrome
P450 isoforms involved in the hepatic metabolism of pioglitazone are
CYP2C8 and CYP3A4 with contributions from a variety of other
isoforms including the mainly extrahepatic CYP1A1. Following oral
administration, approximately 15% to 30% of the pioglitazone dose
is recovered in the urine. Renal elimination of 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 liter/hr.
Hepatic Impairment:
Compared with normal controls, subjects with impaired hepatic
function have an approximate 45% reduction in pioglitazone and
total pioglitazone mean peak concentrations but no change in the
mean AUC values. Pioglitazone therapy should not be initiated if the
patient exhibits clinical evidence of active liver disease or serum
transaminase levels (ALT) exceed 2.5 times the upper limit of normal
Renal Impairment:
The serum elimination half-life of pioglitazone, M-lll, and M-IV remains
unchanged in patients with moderate (creatinine clearance 30 to 60
mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment
when compared to normal subjects.
Elderly: 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.
Indications :
Pioglit is indicated as monotherapy as an adjunct to diet and exercise
to improve glycaemic control in patients with type 2 diabetes mellitus.
pharmacokinetic profile
At steady state, maximum plasma drug concentrations (Cmax) were
0.7 and 1.2 mg/L, and times to Cmax (tmax) were 4.8 and 3.7 hours,
for pioglitazone 15 and 30 mg/day, respectively, in 11 healthy elderly
male volunteers (mean age 70.4 years) who were randomised to
receive either dosage of pioglitazone for 7 days. Respective Cmax
values for total active compound (unchanged pioglitazone plus active
metabolites Mil, Mill and MIV) were 1.4 and 2.5 mg/L.
After 7 days treatment, elimination half-lives (t Vz p ) were 4.9 and
4 hours and areas under plasma drug concentration versus time
curves over 24 drug concentration versus time curves over 24 hours
after administration (AUC,,) were 6 and 10.2 mg/Lxh for pioglitazone
15 and 30 mg/day, respectively (parent compound only).
Corresponding AUC24 values for total active compound (parent drug
plus active metabolites) were 23.3 and 39.7 mg/Lxh.
In 12 healthy young adults ( mean age 23 years) who received
pioglitazone 15 or 30 mg/day for 8 days, steady-state Cmax values
were0.7 and 1.7 mg/L and t 2.5 and 3 hours with pioglitazone 15
and 30 mg/day, respectively.
Steady-state t 72 13 values in young volunteers for parent drug only
were 3.3 and 4.9 hours, and AUG,, values were 4.8 and 15.3 mg/
Lxh for pioglitazone15 and 30 mg/day, respectively, t Vz p for total
pioglitazone is reported to be 16 to 24 hours.
Ninety-six hours after the final dose in elderly volunteers, 28.7% of
the total dose in the 15 mg/day recipients and 23.3% in the 30 mg/
day receipients had been excreted in the urine as conjugated (MI+MIV)
or unconjugated (MV) metabolites.
Pioglitazone undergoes extensive hepatic metabolism, predominantly
via the cytochrome P450 (CYP) 2C8 system. Secondary pathways
include CYP3A4, and CYP1A1/2.
A study in 21 individuals with severe [creatinine clearance) (CL,,) <
1.8 L/h] or moderate (CL,, 1.8to 3.6 Uh) renal impairment and 6
healthy volunteers showed AUC values for pioglitazone (single and
multiole dailv doses of 45 ma) and its maior metabolites Mill and
MIV to decrease with increasing impairment of renal function. This
suggests increased hepatic clearance of pioglitazone secondary to
reduced protein binding in plasma, with no net change in free plasma
drug concentrations, inpatients with renal impairment who receive the drug.
Effects on Glucose and Lipid Metabolism
Animal Studies
Pioglitazone has been shown to decrease plasma glucose, insulin
and/or triglyceride levels in various diabetic and insulin-resistant
animal models including Wistar fatty rats, fa/fa Zucker rats. KKAy
diabetic mice and insulin-resistant rhesus monkeys.
Relative to untreated controls, pioglitazone 20 mg/kg/day administered
for 4 days reduced plasma glucose and insulin levels by 44 and 60%
respectively, in KKAy diabetic mice (p<0.005).
After 10 days treatment pioglitazone 3 mg/kg/day reduced fasting
plasma glucose, serum insulin and serum triglyceride levels by 19.64
and 44%, respectively, in obese, insulin-resistant rhesus monkeys
(all p<0.05 vs pretreatment placebo phase). These changes were
accompanied by statistically significant falls in systolic and mean
arterial pressures.
Markedly improved insulin action and glucose utilisation were
accompanied by weight gain after 28 days treatment with pioglitazone
10 mg/kg/day in fa/fa Zucker rats. Glucose utilisation (measured by
the 2 - deoxyglucose technique) was increased 3- to 4-fold in adipose
tissue depots (p<0.001 vs. untreated controls) and 1.7-told in soleus
muscle (p<0.05 vs controls). The mean body weight gain in treated
rats was 1.7 times that in untreated controls over the study period
(p<0.05).
Pioglitazone 20 mg/kg/day for 1 month significantly decreased fasting
plasma glucose and insulin levels in fa/fa Zucker rats but not in lean
rats, and increase net energy intake in both types of rat (all p<0.05
vs controls). Basal metabolic rates were unchanged. Relative to
controls, weekly growth rates increased with pioglitazone treatment
(by 32 and 67% in lean and obese rats, respectively). Analysis of
fat and lean body masses indicated that protein accumulation was
preferentially stimulated by pioglitazone in lean, insulin-responsive
rats, whereas tipid accumulation predominated in obese animals.
Administration of pioglitazone 1 mg/kg/day for 14 days decreased
plasma glucose and triglyceride levels (to 57 and 59%, respectively,
of levels in untreated control animals), but did not affect plasma
insulin levels or skeletal muscle glycogen content in male Wistar fatty
rats. Pioglitazone monotherapy was also associated with increased
food intake and gains in bodyweight. Addition of metformin 300 mg/
kg/day reduced plasma insulin levels (to 70% of control levels) and
suppressed food intake increases and bodyweight gains.56
Studies in Humans
Piogiltazone 30 mg/day for a mean 87 days was associated with
significant increases in insulin stimulated glucose disposal (from 5.5
to 8.3 mg/kg/min; p < 0.001 vs baseline) under euglycaemic,
hyperinsulinaemic clamp conditions in 20 patients with type 2 dibetes
mellitus. Recruited patients were not obese, with a mean body mass
index (BMI) of 23.9 kg/m2; diabetes was controlled by diet alone in
3 patients and by diet plus sulphonylurea treatment in 17.
Pioglitazone significantly (p<0.01 vs baseline) reduced fasting plasma
glucose (from 11.0 to 8.9 mmol/L), fasting serum insulin (from 83 to
66 pmol/L), serum free fatty acid (from 1.3 to 0.8 mEq/L) and serum
triglyceride levels (from 1.9 to1.3 mmol/L). Serum levels of high
density lipoprotein (HDL)-cholesterol increased from 1.2 to 1.5 mmol/
L (p<0.01), but BMI did not change significantly after pioglitazone
treatment.
Pioglitazone 30 mg/day enhanced splanchnic glucose uptake under
euglycaemic hyperinsulinaemic clamp conditions in patients with type
2 diabetes mellitus controlled by diet alone or diet and sulphonylurea
treatment in a randomised, placebo-controlled double-blind trial. After
12 weeks' treatment in 21 patients, the mean glucose infusion rate
before an oral glucose load increased from 8.2 to 9.2 mg/kg/min (p
= 0.003 vs baseline), and splanchnic glucose uptake (expressed as
a proportion of oral glucose load) increased from 28.5 to 59.4 %
(p=0.01 vs baseline and p = 0.042 vs placebo). Placebo treatment
in 9 patients produced no significant changes in either of these
parameters.56
Cardiovascular Effects :
Pioglitazone 20 mg/kg/day for 7 weeks prevented the development of
hypertension and reduced plasma insulin levels (by 70 and 37%,
respectively, relative to untreated controls) in rats fed diets with high
fat or glucose content. The same dosage of pioglitazone for 4 weeks
significantly (p<0.001 vs untreated controls) reduced fasting and
postprandial plasma insulin levels and systolic and mean blood
pressure in spontaneously hypertensive rats.
Pioglitazone has been shown to possess direct, insulin-independent
vasorelaxant properties. Addition of the drug at a rate of 0.1 mg/
g to feed given to spontaneously hypertensive rats for 6 weeks
decreased mean systolic blood pressure (by 23%; p< 0.001 vs
untreated controls ) and significantly (p<0.05 vs controls) attenuated
contractile responses of mesenteric arterial and aortic tissue to
arginine vasopressin and noradrenaline (norepinephrine).
At a daily dosage of approximately 22mg/kg, pioglitazone prevented
increases in blood pressure seen in rats given a normal or high-
fructose diet. In vitro data showed attenuation by pioglitazone 20 mg/
L of the contractile effects of noradrenaline 25 to 150 nmol/L,
potassium chloride 28 mmol/L or arginine vasopressin 0.66 nmol/L
in rat aortic rings.
In a vehicle-controlled study, pioglitazone 3 mg/kg/day for 13 weeks
significantly lowered systolic blood pressure, decreased proteinuria,
improved histological renal injury scores with respect to
glomerulosclerosis and renal arteriosclerosis, and attenuated aortic
medial wall thickening in genetically obese Wistar fatty rats with
insulin resistance.
In vitro, pioglitazone at conentrations of 0.01 and 1 mg/L inhibited
the proliferation induced by basic fibroblast growth factor of mouse
aortic endothelial cells, but not that induced by insulin. In addition,
pioglitazone 10 mg/kg/day inhibited balloon catheterisation-induced
intimal thickening in carotid arteries of male Wistar fatty and lean
rats. This effect was enhanced in the presence of diabetes.
Pioglitazone 3 mg/kg/day also reduced injury induced neointims
thickening in common carotid arteries of Wistar rats and attenuate*
uptake of bromodeoxyuridine (a marker of DNA synthesis in neointima
in mesenteric arterial tissue from spontaneously hypertensive rats
Overall, these results show vasculoprotective effects of pioglitazoni
in both diabetic and nondiabetic animal models that are thought t"
be related to inhibition of proliferation of vascular smooth muscli
cells.
Pioglitazone (300 parts per million added to 200 g/day of feed
markedly decreased lipid deposition in the aortas of rabbits fed witi
diets containing 0.5% cholesterol for 10 weeks (lipid deposition are.
15% with pioglitazone vs 57% in controls). The drug had no significar
effect on serum levels of total and HDL-cholesterol or triglyceride
but was associated with tendencies towards decreased blood pressun
and lipid peroxide levels. These results indicate overall inhibition c
atherosclerosis by pioglitazone.
Other Effects :
In addition to reducing hyperglycaemia, hyperlipidaemia ane
hyperinsulinaemia, pioglitazone 3 mg/kg/day attenuated th
development of microalbuminuria and the histological change
associated with diabetic nephropathy when administered to Wisto
fatty rats from 71015 weeks of age.
When given in feed for 48 hours after growth hormone treatmer
(200 mg/day subcutaneously for 3 days), pioglitazone 20 mg/kg/da
ameliorated the hyperglycaemic, hyperinsulinaemic effects of th
hormone without interfering with its growth-stimulating activity in femal
aeneticallv obese (ob/ob) mice.
Side effects
Pioglitazone has been generally well tolerated in human studies. The
side-effects reported with pioglitazone as monotherapy are upper
respiratory tract infection, myalgia, injury, tooth disorder, headache,
back pain, hyperglycaemia, fatigue, sinusitis and pharyngitis. A small
number of patients had adverse events of anaemia and oedema.
Overall, these events were generally mild to moderate in severity and
usually did not require discontinuation of treatment.
The side-effects reported with pioglitazone when used in combination
with sulfonylureas, metformin or insulin were generally similar to those
reported during pioglitazone monotherapy with the exception of an
increase in the occurrence of oedema in the insulin combination
study. Mild to moderate hypoglycemia was reported during
combination therapy with sulfonylurea or insulin. Hypoglycemia was
reported when pioglitazone was used in combination with a
sulfonylurea. Anaemia and oedema were reported during combination
therapy with insulin.
Overdosage
Limited data are available with regard to overdosage in humans.
Pioglitazone had been taken by a male patient i.e. 120 mg per day
for four days, and then 180 mg per day for seven days. The patient
denied any clinical symptoms during this period. In the event of an
overdosage supportive treatment should be initiated as directed by
the patient's clinical status.
Dosage and Administration
The management of antidiabetic therapy should be individualized.
Pioglitazone should be taken once daily without regard to meals.
Monotherapy
Pioglitazone monotherapy in patients not adequately controlled with
diet and exercise may be initiated at 15 mg or 30 mg once daily. For
patients who respond inadequately to the dose of pioglitazone
following 12 weeks of treatment as determined by reduction in FPG,
the dose may be increased to 45 mg once daily. For patients not
responding adequately to monotherapy, combination therapy should
be considered.
No dosage adjustments are required for the elderly.
No dosage adjustment is necessary when pioglitazone is used as
monotherapy in patients with renal impairment.
Therapy with pioglitazone should not be initiated if the patient exhibits
clinical evidence of active liver disease or increased serum
transaminase levels (ALT greater than 2.5 times the upper limit of
normal at the start of therapy (See WARNINGS & PRECAUTIONS).
There are no data on the use of pioglitazone in patients under 18
years of age; therefore, use of pioglitazone in paediatric patients is
not recommended.
Combination Therapy
Pioglitazone in combination with a sulfonylurea or metformin or insulin
may be initiated at 15 mg or 30 mg once daily. The current sulfonylurea
dose or metformin dose or insulin dose can be continued upon
initiation of pioglitazone therapy. If patients report hypoglycemia, the
dose of the sulfonylurea or metformin or insulin should be decreased.
Maximum Recommended Dose:
The dose of pioglitazone should not exceed 45 mg once daily.
Dose adjustment in patients with renal insufficiency is not
recommended.
Therapy with pioglitazone should not be initiated if the patient exhibits
clinical evidence of active liver disease or increased serum
transaminase levels (ALT greater than 2.5 times the upper limit of
normal) at the start of therapy. Liver enzyme monitoring is
recommended in all patients prior to initiation of therapy with
pioglitazone and periodically thereafter.
Pioglit is also indicated for use in combination with a sulfonylurea,
metformin or insulin when diet and exercise plus the single agent
does not result in adequate glycaemic control in patients with type
2 diabetes.
Contra-indications :
Pioglit is contraindicated in patients who are hypersensitive to any
component of this drug.
Warnings and Precautions
Due to its mechanism of action, pioglitazone exerts its hypoglycaemic
effect only in the presence of insulin. Therefore, pioglitazone should
not be used in patients with type 1 diabetes or for the treatment of
diabetic ketoacidosis.
Because of concern that hepatic toxicity may be a class effect of
thiazolidinediones, measurement of serum alanine transaminase (ALT)
before beginning treatment, every two months for one year and
periodically thereafter is recommended. Values more than 2.5 times
higher than the upper limit of normal preclude starting treatment, and
those more than three times higher call for stopping the drug.
Hypoglycaemia :
Patients receiving pioglitazone in combination with insulin or oral
hypoglycaemic agents may be at risk for hypoglycaemia, and a
reduction in the dose of concomitant may be necessary.
Ovulation:
Pioglitazone, like other thiazolidinediones, may result in resumption
of ovulation in premenopausal, anovulatory women with insulin
resistance. As a consequence of their improved insulin sensitivity,
these patients may be at risk for pregnancy if adequate contraception
is not used.
Haematologic :
Pioglitazone may cause decreases in haemoglobin and haemotocrit.
The changes occurred primarily during the first 4 to 12 weeks of
therapy and remained relatively constant thereafter.
Oedema :
Pioglitazone should be used with caution in patients with oedema.
Pregnancy & Lactation
There are no adequate and well-controlled studies in pregnant women.
Pioglitazone should not be used during pregnancy unless the potential
benefit justifies the potential risk to the foetus.
It is not known whether pioglitazone is excreted in human milk, but
pioglitazone or some metabolite of pioglitazone is excreted at low
concentration in the milk of lactating rats. Because many drugs are
excreted in human milk, pioglitazone should not be administered to
a nursing woman.
Drug interactions
Administration of another thiazolidinedione with an oral contraceptive
containing ethinyl estradiol and norethindrone reduced the plasma
concentrations of both hormones by approximately 30%, which could
result in loss of contraception. The pharmacokinetics of
coadministration of pioglitazone and oral contraceptives have not
been evaluated in patients receiving pioglitazone and an oral
contraceptive. Therefore, additional caution regarding contraception
should be exercised in patients receiving pioglitazone and an oral
contraceptive.
Concurrent administration of pioglitazone with glipiride or digoxin or
metformin in healthy volunteers had no effect on the steady-state
Dharmacokinetics of either aliDiride, diaoxin, or metformin.