Pioglitazone

Pioglitazone is an Antidiabetic Agent belonging to pharmacology class of Thiazolidinedione

Pioglitazone can be used in the treatment of Diabetes mellitus, type 2, treatment.

Following oral administration of pioglitazone, Tmax of pioglitazone was within two hours. Food delays the Tmax to three to four hours but does not alter the extent of absorption (AUC). 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. M-III and M-IV are also extensively bound (>98%) to serum albumin.Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-III and M-IV are the major circulating active metabolites in humans.. 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 (t1/2) of pioglitazone and its metabolites (M-III and M-IV) range from three to seven hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be five to seven L/hr.

The common side effects associated with Pioglitazone include Decreased Hb or hematocrit, hypoglycemia (if combined with other antidiabetic agents or insulin), macular oedema with decreased visual acuity, weight gain; increased risk of bladder carcinoma, bone fracture (higher risk in women), and cardiac failure.

Pioglitazone is available in the form of Tablets.

The molecule is available in India, USA, Japan, Germany.

Pioglitazone is a potent and selective agonist for peroxisome proliferator-activated receptor-gamma (PPARgamma). Activation of nuclear PPARgamma receptors influences the production of a number of gene products involved in glucose and lipid metabolism. PPARgamma is abundant in the cells within the renal collecting tubules; fluid retention results from stimulation by thiazolidinediones which increases sodium reabsorption.

Pioglitazone is available in tablets.

Pioglitazone can be used in the treatment of Diabetes mellitus, type 2, treatment. It is also used to treat Nonalcoholic steatohepatitis.

Pioglitazone is an 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.

Pioglitazone is approved for use in the following clinical indications

Diabetes mellitus, type 2, treatment: As an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus.

Although not approved there have been certain off labelled uses documented for pioglitazone which includes:

Nonalcoholic steatohepatitis.

Diabetes mellitus, type 2, treatment:

Note: May be used as an adjunctive agent or alternative monotherapy for patients in whom initial therapy with lifestyle intervention and metformin failed or who cannot take metformin; may be preferred when avoidance of hypoglycemia is desirable. Use has been associated with an increased risk of heart failure, and risk is increased with concomitant insulin use . Avoid use in patients with preexisting heart failure

Oral: Initial: 15 to 30 mg once daily.

Dosage adjustment: May increase in 15 mg/day increments every 4 to 12 weeks if needed to achieve glycemic goals (maximum: 45 mg/day) . Discontinue use if signs or symptoms of heart failure develop.

Nonalcoholic steatohepatitis (off-label use):

Note: May consider use in patients with biopsy-confirmed nonalcoholic steatohepatitis who also have type 2 diabetes mellitus; treatment may also be considered in patients with prediabetes, though risks may more closely match benefits.

Oral: 30 mg once daily for 2 months, then increase dose to 45 mg once daily . Consider limiting dose to ≤30 mg/day if worsening heart failure is a concern ; patients with cardiovascular disease were excluded from clinical trials.

Tablets

15 mg, 30 mg, 45 mg.

Tablets

Dose Adjustment in Kidney impairment patient:

Altered kidney function: Mild to severe impairment: No dosage adjustment necessary.

Hemodialysis, intermittent (thrice weekly): Unlikely to be dialyzed; no supplemental dose or dosage adjustment necessary.

Peritoneal dialysis: Unlikely to be dialyzed due to high protein binding (expert opinion); no dosage adjustment necessary.

CRRT: No dosage adjustment necessary.

PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary

Dose Adjustment in Hepatic Patient:

Hepatic impairment prior to initiation:

Patients without cirrhosis: No dosage adjustment necessary; use with caution if baseline liver tests are abnormal; some studies involving patients with nonalcoholic steatohepatitis (NASH) excluded patients with baseline LFTs (eg, AST, ALT) that were ≥2.5 to 3 times ULN . Once initiated, repeat LFTs periodically (eg, every 2 to 3 months). Note: Studies in patients with NASH, with or without type 2 diabetes mellitus, excluded patients with other causes of liver disease (eg, hepatitis C, alcohol-associated fatty liver disease).

Patients with cirrhosis: Use in patients with cirrhosis is not recommended ; studies in patients with NASH, with or without type 2 diabetes mellitus, excluded patients with cirrhosis .

Hepatic impairment during therapy: Drug-induced liver injury associated with pioglitazone is rare. If liver injury is suspected (eg, fatigue, jaundice, dark urine), interrupt therapy, measure serum liver tests, and investigate possible etiologies:

If an alternative etiology is not identified and ALT >3 times ULN: Do not reinitiate therapy.

If an alternative etiology is identified and ALT elevated (but <3 times ULN) or total bilirubin elevated (but <2 times ULN): May reinitiate with caution.

Pioglitazone may be contraindicated in the following conditions:-

History or current heart failure (NYHA stages I-IV); diabetic ketoacidosis, active or history of bladder cancer; uninvestigated macroscopic haematuria, hepatic impairment.

Congestive Heart Failure

• Pigolitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when Pigolitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of Pigolitazone must be considered.

Hypoglycemia

• Patients receiving Pigolitazone in combination with insulin or other antidiabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia. A reduction in the dose of the concomitant antidiabetic medication may be necessary to reduce the risk of hypoglycemia.

Hepatic Effects

• There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking Pigolitazone, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the Pigolitazone controlled clinical trial database to date.
• Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) and assessing the patient is recommended before initiating Pigolitazone therapy. In patients with abnormal liver tests, Pigolitazone should be initiated with caution.
• Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than 3 times the upper limit of the reference range), Pigolitazone treatment should be interrupted and investigation done to establish the probable cause. Pigolitazone should not be restarted in these patients without another explanation for the liver test abnormalities.
• Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury, and should not be restarted on Pigolitazone. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with Pigolitazone can be used with caution.

Urinary Bladder Tumors

• Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study. In two 3-year trials in which Pigolitazone was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking Pigolitazone compared to 5/3679 (0.14%) in patients not taking Pigolitazone. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on Pigolitazone and two (0.05%) cases on placebo.
• A five-year interim report of an ongoing 10-year observational cohort study found a non-significant increase in the risk for bladder cancer in subjects ever exposed to Pigolitazone, compared to subjects never exposed to Pigolitazone (HR 1.2 [95% CI 0.9 –1.5]). Compared to never exposure, a duration of Pigolitazone therapy longer than 12 months was associated with an increase in risk (HR 1.4 [95% CI 0.9 –2.1]), which reached statistical significance after more than 24 months of Pigolitazone use (HR 1.4 [95% CI 1.03 –2.0]). Interim results from this study suggested that taking Pigolitazone longer than 12 months increased the relative risk of developing bladder cancer in any given year by 40% which equates to an absolute increase of three cases in 10,000 (from approximately seven in 10,000 [without Pigolitazone] to approximately 10 in 10,000 [with Pigolitazone]).
  
• There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, Pigolitazone should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with Pigolitazone should be considered in patients with a prior history of bladder cancer.

Edema

• In controlled clinical trials, edema was reported more frequently in patients treated with Pigolitazone than in placebo-treated patients and is dose-related. In postmarketing experience, reports of new onset or worsening edema have been received.
• Pigolitazone should be used with caution in patients with edema. Because thiazolidinediones, including Pigolitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, Pigolitazone should be used with caution in patients at risk for congestive heart failure. Patients treated with Pigolitazone should be monitored for signs and symptoms of congestive heart failure.

Fractures

• In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to Pigolitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for Pigolitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and persisted during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in the incidence of fracture was observed in men treated with Pigolitazone (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with Pigolitazone and attention should be given to assessing and maintaining bone health according to current standards of care.

Macular Edema

• Macular edema has been reported in postmarketing experience in diabetic patients who were taking Pigolitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination.
• Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of the thiazolidinedione.
• Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings.

Ovulation

• Therapy with Pigolitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking Pigolitazone. This effect has not been investigated in clinical trials, so the frequency of this occurrence is not known. Adequate contraception in all premenopausal women treated with Pigolitazone is recommended.

Macrovascular Outcomes

• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Pigolitazone or any other antidiabetic drug.

There is no sufficient scientific evidence traceable regarding use and safety of Pioglitazone in concurrent use with alcohol.

It is not known if Pioglitazone is present in breast milk.

Pregnancy Category C

There are no adequate and well-controlled studies of Pigolitazone in pregnant women. Animal studies show increased rates of post-implantation loss, delayed development, reduced fetal weights, and delayed parturition at doses 10 to 40 times the maximum recommended human dose. Pigolitazone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations

Abnormal blood glucose concentrations during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality. Most experts recommend the use of insulin during pregnancy to maintain blood glucose concentrations as close to normal as possible for patients with diabetes.

The adverse reactions related to Pioglitazone can be categorized as

Common Adverse effects:

Decreased Hb or haematocrit, hypoglycemia (if combined with other antidiabetic agents or insulin), macular oedema with decreased visual acuity, weight gain; increased risk of bladder carcinoma, bone fracture (higher risk in women), and cardiac failure

Less Common Adverse effects:

fluid retention;, resumption of ovulation ,Anemia.

Rare Adverse Effects:

Upper respiratory tract infection; dyspnea, bronchitis.

The clinically relevant drug interactions ofPioglitazone is briefly summarized here

Strong CYP2C8 Inhibitors

• An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the serum concentration-time curve or AUC) and half-life (t1/2) of pioglitazone. Therefore, the maximum recommended dose of Pigolitazone is 15 mg daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors.

CYP2C8 Inducers

• An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with Pigolitazone, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of 45 mg for Pigolitazone.

The most common side effects of Pioglitazone includes: Decreased Hb or haematocrit, hypoglycemia (if combined with other antidiabetic agents or insulin), macular oedema with decreased visual acuity, weight gain; increased risk of bladder carcinoma, bone fracture (higher risk in women), and cardiac failure.

Pregnancy Category C

• There are no adequate and well-controlled studies of Pigolitazone in pregnant women. Animal studies show increased rates of post-implantation loss, delayed development, reduced fetal weights, and delayed parturition at doses 10 to 40 times the maximum recommended human dose. Pigolitazone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations

• Abnormal blood glucose concentrations during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality. Most experts recommend the use of insulin during pregnancy to maintain blood glucose concentrations as close to normal as possible for patients with diabetes.

Animal Data

• In animal reproductive studies, pregnant rats and rabbits received pioglitazone at doses up to approximately 17 (rat) and 40 (rabbit) times the maximum recommended human oral dose (MRHD) based on body surface area (mg/m2); no teratogenicity was observed. Increases in embryotoxicity (increased postimplantation losses, delayed development, reduced fetal weights, and delayed parturition) occurred in rats that received oral doses approximately 10 or more times the MRHD (mg/m2 basis). No functional or behavioral toxicity was observed in rat offspring. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in rat offspring at oral maternal doses approximately two or more times the MRHD (mg/m2 basis). In rabbits, embryotoxicity occurred at oral doses approximately 40 times the MRHD (mg/m2 basis).

• Labor and Delivery

There is no FDA guidance on use of Pioglitazone during labor and delivery.

• Nursing Mothers

• It is not known whether Pigolitazone is secreted in human milk. Pioglitazone is secreted in the milk of lactating rats. Because many drugs are excreted in human milk, and because of the potential for Pigolitazone to cause serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or discontinue Pigolitazone, taking into account the importance of Pigolitazone to the mother.

Pediatric Use

• Safety and effectiveness of Pigolitazone in pediatric patients have not been established.
• Pigolitazone is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors.

Geriatic Use

• A total of 92 patients (15.2%) treated with Pigolitazone in the three pooled 16- to 26-week double-blind, placebo-controlled, monotherapy trials were ≥65 years old and two patients (0.3%) were ≥75 years old. In the two pooled 16- to 24-week add-on to sulfonylurea trials, 201 patients (18.7%) treated with Pigolitazone were ≥65 years old and 19 (1.8%) were ≥75 years old. In the two pooled 16- to 24-week add-on to metformin trials, 155 patients (15.5%) treated with Pigolitazone were ≥65 years old and 19 (1.9%) were ≥75 years old. In the two pooled 16- to 24-week add-on to insulin trials, 272 patients (25.4%) treated with Pigolitazone were ≥65 years old and 22 (2.1%) were ≥75 years old.
• In PROactive, 1068 patients (41.0%) treated with Pigolitazone were ≥65 years old and 42 (1.6%) were ≥75 years old.
• In pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients.
• Although clinical experiences have not identified differences in effectiveness and safety between the elderly (≥65 years) and younger patients, these conclusions are limited by small sample sizes for patients ≥75 years old.

Gender

There is no FDA guidance on the use of Pioglitazone with respect to specific gender populations.

Race

There is no FDA guidance on the use of Pioglitazone with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Pioglitazone in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Pioglitazone in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Pioglitazone in women of reproductive potentials and males.

Signs and Symptoms

During controlled clinical trials, one case of overdose with Pigolitazone was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period.

Management

In the event of overdosage, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.

Pharmacodynamics:

Pioglitazone is an 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.

Pharmacokinetics:

Absorption

Following oral administration of pioglitazone, Tmax of pioglitazone was within two hours. Food delays the Tmax to three to four hours but does not alter the extent of absorption (AUC).

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. M-III and M-IV are also 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-III and M-IV are the major circulating active metabolites in humans.

In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone, which include CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo study of pioglitazone in combination with gemfibrozil, a strong CYP2C8 inhibitor, showed that pioglitazone is a CYP2C8 substrate. Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with Pigolitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer.

Excretion

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 (t1/2) of pioglitazone and its metabolites (M-III and M-IV) range from three to seven hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be five to seven L/hr.

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