New Drug Approvals

The Pharmacology and Toxicology of Nateglinide

 

Michael Levine [1, 2]
Michael J. Burns, MD [2]

Int J Med Toxicol 2001; 4(4): 25


Author Affiliation

  1. Finch University/The Chicago Medical School, North Chicago, Il 60064

  2. Department of Emergency Medicine
    Division of Medical Toxicology
    Beth Israel Deaconess Medical Center

Address for Correspondence

Michael J. Burns, MD
Division of Medical Toxicology
Beth Israel Deaconess Medical Center
330 Brookline Avenue
Boston, MA 02215
Phone: (617) 754-2326
Fax: (617) 754-2350
E-mail: mburns@caregroup.harvard.edu

Case report

Financial source:

None

There are no financial, litigational, or other relationships that may lead to a conflict of interest in the preparation of this manuscript.

INTRODUCTION

Type II diabetes mellitus is a progressive disease that results from both impaired insulin secretion and peripheral resistance to insulin. The disease affects approximately 15.7 million people in the United States.1 Traditionally, the focus of treatment for type II diabetes has been to lower fasting plasma glucose concentrations. Recently, however, it has been shown that the postprandial glucose concentration is a more accurate predictor of glycemic control, and is associated with lower plasma levels of glycosylated hemoglobin (HbA1c).2 Thus, a new direction in the treatment of type II diabetes mellitus is to more tightly control postprandial plasma glucose concentrations. This control is particularly important since reductions in HbA1c are associated with a reduction in microvascular complications, one of the major contributors to premature death in diabetic patients.3

Postprandial insulin secretion occurs in two stages. The first stage, which is lost in patients with type II diabetes, involves an early, rapid secretion of insulin in response to a meal. The second phase of insulin secretion is related to the duration of the hyperglycemic stimulus.4 This second phase is maintained in type II diabetics.

The sulfonylureas do not appreciably control postprandial plasma glucose concentrations.5 In addition, they are associated with many side effects, most notably, hypoglycemia.6 Nateglinide (StarlixÔ) is a novel drug designed for the treatment of type II diabetes. Like repaglinide (PrandinÔ), nateglinide belongs to the meglitinide class of oral hypoglycemic agents. The results of several small-scale studies demonstrate that nateglinide restores the first phase of insulin secretion in type II diabetics. In addition, nateglinide is well-tolerated, and appears to have a significantly lower likelihood of inducing hypoglycemia than sulfonylureas. In pre-marketing trials, the incidence of nateglinide-induced hypoglycemia ranged from 0 to 1.8% of patients.4-5, 7-11 The following is a description of the pharmacology, pharmacokinetics, and anticipated toxicology of nateglinide.

STRUCTURE AND PHARMACOLOGY

Nateglinide (StarlixÔ) is a derivative of the amino acid, D-phenylalanine (Figure 1). Nateglinide is internationally marketed by Novartis Pharmaceutical Corporation. In August 1999, nateglinide received first approval for use in type II diabetics in Japan, where it is marketed under the names Starsis and Fastic. In December 2000, the United States Food and Drug Administration (FDA) approved nateglinide for use as monotherapy or in combination with metformin in type II diabetic patients whose blood sugar is not controlled with diet and exercise. It is currently available in 24 countries throughout Europe, Asia, and North and South America.

Like repaglinide and many of the sulfonylureas, nateglinide causes insulin secretion via inhibition of the ATP-sensitive potassium channels in the pancreatic beta cells.5 Nateglinide causes a reduction in potassium efflux via these ATP-sensitive potassium channels which results in membrane depolarization and a subsequent influx of calcium through voltage-sensitive calcium channels. The entry of the calcium leads to the eventual exocytosis of insulin. Unlike other oral hypoglycemic agents, nateglinide principally stimulates the first phase of insulin release. This preferential stimulation results in a rapid onset and short duration of action. The latter effect decreases the incidence of sustained hypoglycemia.12

Insulin secretion from nateglinide is dose-dependent. In addition, there is a direct correlation between the plasma glucose concentration and the amount of nateglinide-induced insulin secretion.10 Conversely, when plasma glucose concentrations are normal or low, drug-induced insulin release is decreased.5, 7 While ATP-sensitive potassium channels are also in heart and skeletal muscle, nateglinide has a high in vitro specificity for the ATP-sensitive potassium channels in the pancreatic beta cells, and does not appear to alter cardiovascular or skeletal muscle function.13

PHARMACOKINETICS

Nateglinide is available in both 60 mg and 120 mg tablets. Following ingestion, nateglinide has a bioavailability of 73%.14 Gastrointestinal absorption of nateglinide is rapid, with a maximum plasma concentration occurring within one-half to two hours (tmax, 1.5 ± 1.1 hours).9 Maximal insulin concentration (peak drug effect) is reached at two hours.9, 10, 14 The manufacturer reports that absorption of nateglinide is delayed if ingested following a meal as compared to on an empty stomach.15 Following absorption, the drug is highly protein-bound (98%), primarily to albumin.16 The extent of serum protein binding is independent of drug concentration up to 10 mg/ml;16 it is unknown whether protein binding is altered when serum drug concentrations are well above the therapeutic range. The steady state volume of distribution is 10 L in healthy adults16. The peak plasma concentration of nateglinide (Cmax) ranges from 5.6 to 6.1 mg/ml.9, 14, 17

Nateglinide has a rapid onset of action, as evidenced by the return of plasma glucose levels to baseline within four hours following consumption of nateglinide.7 Nateglinide has a short half-life (mean 1-1.25 hours).7, 15 The pharmacokinetic parameters of nateglinide are compared with those of the related drug, repaglinide, in Table 1.

Nateglinide is extensively metabolized in the liver, primarily via the cytochrome P-450 isoenzymes CYP2C9 (70%) and CYP3A4 (30%).16, 18 Excretion of hepatic metabolites occurs primarily by the kidney; eight metabolites have been identified in urine and two in bile.19 Some of the metabolites retain pharmacologic activity.19-20

Nateglinide should be taken one to 30 minutes prior to meals. The recommended starting and maintenance dose is 120-mg, three times a day before meals.

Special populations:

There are no gender or age differences in the pharmacokinetics of nateglinide.16 In addition, there is no difference in the pharmacokinetics of nateglinide between caucasians and African Americans.16 No significant difference in renal clearance of nateglinide is observed when comparing healthy patients to those patients with mild hepatic cirrhosis. Thus, adjusting the dosage of nateglinide in patients with mild cirrhosis is not likely necessary.1, 17 However, the data regarding dosing of nateglinide in patients with moderate to severe hepatic cirrhosis is unknown. Dosage adjustment is also not necessary in patients with mild to severe renal insufficiency, including those patients with renal failure on hemodialysis.16 Data on nateglinide in lactating women and in children is not available. The drug manufacturer recommends that nateglinide should not be used in pregnant women. As with other diabetic medications, malnourished patients and those who drink alcohol, engage in strenuous physical exercise, or have adrenal insufficiency, may be more susceptible to hypoglycemia with nateglinide.

CLINICAL EFFICACY

In numerous double-blind studies, nateglinide has demonstrated superior efficacy when compared to placebo or other oral hypoglycemic agents.4-5, 7-10, 12, 15 The efficacy of nateglinide is further enhanced when given in combination with metformin.21-22 Nateglinide restores phase I insulin secretion in type II diabetics. In all clinical efficacy studies, nateglinide has been well-tolerated with minimal adverse effects.4-5, 7-10, 12, 15, 21-22

TOXICOLOGY

Animal toxicity data has not been published and is not available from the manufacturer (personal communication with Novartis Pharmaceuticals).

In healthy human volunteers, nateglinide produced no significant changes in vital signs or in the electrocardiogram when compared to baseline measurements.9 The most common adverse reactions were dizziness, headache, and somnolence. In addition, there was one patient who developed an asymptomatic elevation of serum transaminases.9 The transaminase abnormality resolved following cessation of nateglinide therapy.

Following both short-term and long-term treatment, nateglinide is well-tolerated. In many studies, the overall incidence of adverse effects for patients treated with nateglinide was similar to placebo. In type II diabetics, common adverse effects that occurred with greater frequency than placebo included headache, gastrointestinal symptoms (primarily nausea and diarrhea), symptoms associated with hypoglycemia (e.g., sweating, tremor, dizziness, and asthenia), mild elevations in serum transaminases, and an increased frequency of upper respiratory infections.7, 10, 16, 21-22 The laboratory abnormalities were not found in all studies.5, 10 In many of the patients with symptoms commonly associated with hypoglycemia, there were no numerical decreases in plasma glucose concentrations. These symptoms were considered to be from relative hypoglycemia, rather than true hypoglycemia.7, 10 Confirmed hypoglycemia (blood glucose < 3.3mmol/L, < 60 mg/dl) was observed in 1.3 to 2.4% of patients.1,16 In one study, a single patient on nateglinide suffered a myocardial infarction and died.7 However, the authors of the study attributed this death to the patient’s underlying chronic coronary artery disease, and not to nateglinide.

To date, no human overdose data is clinically available. In pre-marketing studies, no overdoses of nateglinide were reported to Novartis Pharmaceuticals.16 It is expected that clinical toxicity would result from exaggerated pharmacologic activity. Thus, it is anticipated that overdose with nateglinide will result in hypoglycemia. Drug effect may be blunted in those who take an overdose with food or soon after a meal. The incidence and duration of hypoglycemia for patients who overdose with nateglinide is unknown. Since nateglinide has a high specificity for the ATP-sensitive potassium channels in the pancreatic beta cells as compared to those channels in myocardial cells, it is unlikely that an overdose will produce direct cardiovascular effects.

DRUG INTERACTIONS

Since nateglinide is metabolized by both CYP3A4 and CYP2C9 isoenzymes, there is potential for interaction with other drugs that are substrates or inhibitors of these isoenzymes. In addition, nateglinide itself is an inhibitor of CYP2C9 but not CYP3A4.16 Warfarin is a substrate of both CYP3A4 and CYP2C9, diclofenac is a substrate for CYP2C9, and troglitazone is a CYP3A4 inducer.16 Co-administration of nateglinide with each of these drugs, however, yields no significant alterations in the pharamcokinetic properties of these drugs.16 Co-administration of nateglinide with other substrates or inhibitors of CYP3A4 or CYP2C9 may increase plasma concentrations of nateglinide and increase the risk for hypoglycemia. For example, the co-administration of erythromycin or fluconazole, known CYP3A4 inhibitors, may potentiate the hypoglycemic effects from nateglinide. Experience to date is insufficient to know if clinically significant interactions exist.

Nateglinide prevents the metabolism of tolbutamide and will potentiate the hypoglycemic actions of this drug.16 Co-administration of nateglinide and metformin results in better control of postprandial plasma glucose concentrations than administration of either of these drugs alone.21-22 Nateglinide should not be used in combination with an insulin secretagogue or in place of an insulin secretagogue.16

Table 2 lists other drugs that have known pharmacodynamic interactions with nateglinide.

There are no known nateglinide interactions with food, although as stated previously nateglinide absorption is greatly reduced when there is food in the stomach.

OVERDOSE MANAGEMENT

Diagnosis of nateglinide overdose is based primarily on a history of ingestion in combination with suggestive physical and laboratory findings. Nateglinide can be detected in human serum and urine via high performance liquid chromatography (HPLC) with an ultraviolet detection at 210 nm.23 The correlation between serum nateglinide concentration and toxic effects are unknown, although the nateglinide concentration is directly related to the amount of insulin secreted, and is therefore inversely related to plasma glucose concentration.

While there are no data on nateglinide overdose in the literature, management of overdose should focus on monitoring closely for hypoglycemia and reversing it, should it occur. Initially, symptomatic hypoglycemia should be treated with a concentrated (25 to 50%) intravenous dextrose solution. If hypoglycemia is recurrent or persistent, an intravenous infusion of 10% dextrose in water is recommended and titrated to maintain blood glucose concentrations in the normal range. The long-acting synthetic analogue of somatostatin, octreotide (SandostatinÔ, Novartis Pharmaceuticals), may be an effective adjunct therapy for the treatment of hypoglycemia. Octreotide is a potent inhibitor of insulin, glucagon, and other gastrointestinal and pancreatic hormone secretion. Octreotide binds to the somatostatin receptor on the beta cell plasma membrane and reduces calcium influx through the voltage-dependent calcium channel via a G-protein mechanism. This results in an inhibition of insulin release. Thus, octreotide may inhibit the insulin secretory action of nateglinide. Octreotide is well-tolerated and has a rapid onset of action. Octreotide may be given at a dose of 1 mcg/kg (50 to 100 mcg in adults) intravenously every 8 to 12 hours. Despite a small volume of distribution (<1 L/kg), nateglinide is not likely to be effectively removed by hemodialysis due to its high degree of plasma protein binding. The effectiveness of removal by hemoperfusion has not been studied.

Because of the rapid absorption of nateglinide, it is unlikely that orogastric lavage would prove beneficial following an overdose of nateglinide. For the majority of patients, gastrointestinal decontamination by the administration of a single dose of activated charcoal is the preferred method of decontamination.

Sulfonylurea overdoses often necessitate a 24-hour period of hospital observation due to the delayed, recurrent, and protracted risk of hypoglycemia following an overdose, even when the patient is asymptomatic and euglycemic at presentation to the ED.25 Due to the shorter duration of action of nateglinide, however, it is possible that a prolonged period of hospital observation is not required and patients could be discharged following a period of observation of only 4 to 6 hours. Until there is significant clinical experience with nateglinide overdose, however, it is recommended that any patient with a known or suspected intentional nateglinide overdose be admitted to the hospital for a minimum of 24 hours for serial monitoring of the plasma glucose concentration. Similarly, any patient that develops symptomatic hypoglycemia following therapeutic dosing with nateglinide should be admitted and observed for 24 hours due to the theoretical risk of recurrent hypoglycemia. When acute accidental ingestion of a small number of nateglinide pills may have occurred (as with a child that is unable to provide an accurate history), a shorter period of observation is likely safe since the onset of hypoglycemia should occur rapidly in this setting. If these patients remain asymptomatic during an 8-hour period of observation, they may be safely discharged provided that they did not receive intravenous dextrose while being observed. Any patient that develops symptomatic hypoglycemia, however, should be treated, admitted and observed for 24 hours.

Currently, the medical toxicology community has differences of opinion with respect to a safe period of observation following accidental sulfonylurea ingestion (recommendations range from 8 to 24 hours).26-30 Whether this difference of opinion should extend to accidental nateglinide ingestion is unknown. The initial overdose experience with this drug should clarify this issue and help guide future treatment decisions.

Because of the lack of well-controlled studies involving pregnant women, it is unclear if nateglinide will cross the placental barrier (personal communications with Novartis Pharmaceuticals), and if an overdose in a pregnant woman would adversely affect the fetus.

CONCLUSION

Nateglinide is a novel oral hypoglycemic agent for the management of type II diabetes. The drug has a rapid onset of action, short half-life, and short duration of action. When administered prior to a meal, nateglinide restores phase I insulin secretion, which is lost in type II diabetics. While there are no reported cases of nateglinide overdose, overdose is likely to result in hypoglycemia. The principal goal of treatment following nateglinide overdose should maintain euglycemia, likely through a combination of supplemental dextrose administration and octreotide therapy.

Figure 1. The structure of nateglinide.

Figure 1. The structure of nateglinide.

Table 1. Pharmacokinetic parameters of nateglinide and repaglinide.

NATEGLINIDE

REPAGLINIDE

Class Meglitinide Meglitinide
Cmax (ng/ml) 5600-6060 20.6
Tmax (hours) 1.5 1.0
AUC (ug ° h/ml) 13.4 ± 3.2 47.5 ± 34.3 (given 10 min preprandal)
Serum protein binding (%) 98 >98
Volume of distribution (L) 10 31
Metabolized Liver Primarily liver
Excreted Primarily urine Primarily feces
Half life (hours) 1.25 1.0
Bioavailability 73% 56%
Pregnancy Class C Class C

References for nateglinide cited in text. References for repaglinide are 9, 24.

Table 2. Pharmacodynamic Interactions of Nateglinide.16

Augment hypoglycemic action of nateglinide

Reduce hypoglycemic action of nateglinide

NSAIDS Thiazides
Salicylates Corticosteroids
MAOIs Thyroid products
Non-selective beta adrenergic blockers Sympathomimetics

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