Mechanism of Action
ACTOS 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
in the liver resulting in increased insulin-dependent glucose disposal and
decreased hepatic glucose output. Unlike sulfonylureas, pioglitazone is not
an insulin secretagogue.
Pioglitazone is a potent and highly selective agonist for peroxisome proliferator
activated receptor-gamma (PPAR?). PPAR receptors are found in tissues important
for
insulin action such as adipose tissue, skeletal muscle, and liver. Activation
of PPAR?
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 hyperglycemia, hyperinsulinemia,
and hypertriglyceridemia characteristic of insulin-resistant states such as
type 2 dia-
betes. 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 and Drug Metabolism
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-III)
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. 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. At steady-state, in both healthy volunteers
and in pa-
tients with type 2 diabetes, pioglitazone comprises approximately 30% to 50%
of the
total peak serum concentrations and 20% to 25% of the total AUC.
In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism
of
pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and to a lesser
de-
gree CYP3A4 with additional contributions from a variety of other isoforms
including the
mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination
with P450
inhibitors and substrates have been performed (see Drug Interactions).
Excretion and Elimination: 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 L/hr.