Zileuton

Zileuton belongs to the pharmacological class of 5-Lipoxygenase Inhibitor.

Zileuton has been approved for the treatment and maintenance of episodes of chronic asthma.

Zileuton is completely and rapidly absorbed. Zileuton achieved a mean volume of distribution of 1.2l/kg. The Zileuton is found to be undergo hepatic metabolism, and its N-dehydroxylated metabolite is found to be oxidatively metabolized by the cytochrome P450 isoenzymes such as 1A2, 2C9, and 3A4. Elimination is mainly in the form of metabolism with a mean terminal half-life of 2.5 hrs. The urinary excretion accounts for about o.2%of the dose.

The common side effects associated with Zileuton are headache, heartburn, muscle pain, diarrhea, throat pain, etc.

Zileuton is available in the form of an Immediate release and extended-release tablet.

Zileuton is available in the U.S., Canada, E.U.,and India.

Zileuton belongs to the pharmacological class of 5-Lipoxygenase Inhibitor. Zileuton relives the symptoms caused as a result of the inflammatory mediators through its selective inhibition of the 5-lipoxygenase enzyme. Specifically, Zileuton inhibits leukotriene LTB4, LTC4, LTD4, and LTE4 formation. This, in turn, reduces airway symptoms, decreases bronchial smooth muscle tone, and improves asthma.

Zileuton onset of action is within 2-4 hrs.

The mean Zileuton Cmax was found to be 4.98 µg/mL and Tmax to be 1.7hrs.

Zileuton is available in immediate-release and extended-release tablets and should be swallowed whole with water.

Zileuton can be used in the treatment of:

• Treatment and maintenance of episodes of chronic asthma

Zileuton can help to relieve symptoms and also for the treatment and maintenance of episodes of acute asthma.

Zileuton is approved for use in the following clinical indications:

• Treatment and maintenance of episodes of chronic asthma

Zileuton can be administered orally before/ after meals. The duration and dosage of treatment should be as per the clinical judgment of treating physician.

Immediate release: 600mg 4 times a day up to 2400 mg maximum dose limit

Extended-release: 1200mg 2 times a day morning and evening up to 2400 mg maximum dose limit.

Immediate Release Tablets, Extended Release tablets

• Dosage Adjustments in Hepatic Impairment Patients:

Active liver disease or persistent hepatic transaminase elevations which are found to be greater than or equal to 3 times the upper limit of normal (ULN): Contraindicated

• Dosage Adjustments in Pediatric Patients:

No dosage adjustments are needed for Pediatric Patients as it is not indicated in Pediatric Patients less than 12 years of age

Smoking cessation and maintaining health are a must.

Caffeine should be avoided or limited to use as it might lead to the risk of nausea, palpitations, nervousness, rapid heartbeat, etc.

Alcohol should be avoided in the patient, especially with an underlying liver disorder or liver dysfunction.

Diet containing food with a high glycemic index, saturated and trans fat food, red and processed meat, added sugar, salt, preservatives, refined and high energy-dense foods, low fiber, low antioxidants, and vitamins needs to be restricted.

The dietary restrictions are needed to be individualized as per the patient's requirements.

Zileuton may be contraindicated during the co-administration with the following drugs:

• Hypersensitivity to the ingredients of the medication
• Liver disease or persistent hepatic function enzyme elevations which is found to be more than or equal to three times the upper limit of normal (≥3×ULN)

The treating physician should closely monitor the patients and keep pharmacovigilance as follows:

Hepatotoxicity

An increase in one or more hepatic function enzymes and bilirubin might occur during Zileuton therapy. Such laboratory abnormalities may progress to clinically significant liver injury, which might remain unchanged, or resolve with a continued treatment regimen, usually within three weeks. If clinical signs and/or symptoms of liver dysfunction develop,such as right upper quadrant pain, nausea, fatigue, etc, or "flu-like" symptoms or transaminase elevations ≥5×Upper limit of normal occur, Zileuton should be discontinued, and hepatic function enzymes should be followed until normal. Since treatment with Zileuton might result in increased hepatic function enzymes and liver injury, hence Zileuton should be used with caution in patients who consume alcohol and/or have a past history of liver disease.

Neuropsychiatric Events

Neuropsychiatric events have been reported in adults and adolescent patients taking Zileuton and Zileuton immediate-release tablets. Post-marketing reports with Zileuton include sleep disorders and some behavior changes have been observed. The clinical details of some post-marketing reports which involve Zileuton appears consistent with a drug-induced effect. Patients and prescribers should be alerted for neuropsychiatric events. Patients are be instructed to notify their physician if such changes occur. Physicians should be carefully evaluating the benefits and risks of continuing treatment with Zileuton if such events occur.

Avoid alcohol usage while on Zileuton medication, as alcohol can worsen the effects of any underlying disease condition, including conditions such as dizziness, blurred vision, etc.

Zileuton and/or its metabolites are found to be excreted in rat milk. It is not known whether Zileuton is excreted in human milk. Because many drugs are found to be excreted in human milk, and because of the potential for tumorigenicity caused by Zileuton which has been shown in animal studies. Hence, a decision should be made whether to discontinue or continue the drug, taking into account the importance of the Zileuton to the mother.

Teratogenic Effects

Pregnancy Category C:

Developmental studies indicated adverse effects such as increased skeletal variations and reduced body weight in rats at an oral dose of about 300 mg/kg/day. Zileuton or its metabolites cross the placental barrier of rats. Three out of 118 rabbit fetuses had developed skeletal variations an oral dose of about 150 mg/kg/ day which is equivalent to the maximum recommended human daily oral dose on an mg/m2 basis. There were found to be no adequate and well-controlled studies on pregnant women. Zileuton should be used during pregnancy only when the potential benefits outweighs the potential risk to the fetus.

No sufficient scientific evidence is traceable regarding the use and safety of Zileuton in concurrent use with any particular food.

The adverse reactions related to Zileuton can be categorized as follows:

Common

• Stuffy or runny nose
• Tightness of the chest or wheezing
• Troubled breathing
• Upset stomach
• Cough
• Fever
• Headache
• Nausea

Less common

• Weakness
• Abdominal or stomach pain
• Sore throat

Rare

• Right upper stomach pain
• Unusual tiredness or weakness
• Yellow eyes or skin
• Flu-like symptoms
• Itching

The clinically relevant drug interactions of Zileuton are briefly summarized here:

Theophylline: In a drug-interaction study involving 16 healthy subjects, co-administration with multiple doses of zileuton immediate-release tablets i.e.800 mg every 12 hours and theophylline i.e.200 mg every 6 hours for five days resulted in a significant decrease which is approximately 50% in the steady-state clearance of theophylline, which is found to be an approximate doubling of theophylline AUC, and an increase in theophylline Cmax by 73%. The elimination half-life of theophylline was also increased by 24%. Also, during co-administration, theophylline-related adverse reactions had been observed more frequently than after theophylline alone. Upon initiation of Zileuton in patients who receive theophylline, the theophylline dose should be reduced by approximately one-half, and plasma theophylline concentrations should be closely monitored. Similarly, after initiating therapy with theophylline in a patient receiving Zileuton, the maintenance dose or dosing interval of theophylline should be adjusted accordingly and determined by the serum theophylline determinations.

Warfarin: A concomitant administration of multiple doses of zileuton immediate-release tablets, i.e. 600 mg every 6 hours and warfarin in 30 healthy subjects resulted in around 15% decrease in R-warfarin clearance and an increase in AUC by about 22%. These pharmacokinetic changes have been accompanied by a clinically significant increase in time of prothrombin. Monitoring of the prothrombin time, or of other suitable coagulation tests, with the appropriate dose titration of warfarin, is recommended in patients who recieve concomitant Zileuton and warfarin therapy.

Propranolol: Co-administration of Zileuton immediate-release tablets with propranolol resulted in a significant increase in propranolol concentrations. Administration of a single dose of 80 mg propranolol in 16 healthy male subjects who have received zileuton immediate-release tablets of about 600 mg every 6 hours for 5 days had resulted in a 42% decrease in propranolol clearance. This has resulted in an increase in propranolol Cmax, AUC, and elimination half-life by about 52%, 104%, and 25%, respectively. There was found to be an increase in β-blockade, which caused decrease in heart rate associated with the co-administration of these drugs. Patients who are concomitantly on Zileuton and propranolol medications should be closely monitored, and the dose of propranolol must be reduced as necessary. No drug-drug interaction studies have been conducted between Zileuton and other beta-adrenergic blocking agents. Hence , it is reasonable to employ appropriate clinical monitoring when these drugs are co-administered with Zileuton.

Other Concomitant Drug Therapy: Drug-drug interaction studies was conducted in healthy subjects between Ethinyl estradiol and prednisone and zileuton immediate-release tablets . The drugs known to be metabolized by the CYP3A4 isoenzyme, hadshown no significant interaction. However, no formal drug-drug interaction studies have been conducted between Zileuton and CYP3A4 inhibitors, such as ketoconazole.Drug-drug interaction studies in healthy subjects with zileuton immediate-release tablets and sulfasalazine, naproxen,digoxin, and phenytoin, have been conducted. There found to be no significant interaction between any of the above mentioned drugs and Zileuton.

The common side effects of Zileuton include the following:

• Muscle pain
• Nose and throat irritation
• Pain or fullness in the face
• Headache
• Heartburn
• Diarrhea

Pregnancy Category C:

Developmental studies indicated adverse effects such as increased skeletal variations and reduced body weight in rats at an oral dose of about 300 mg/kg/day. Zileuton or its metabolites cross the placental barrier of rats. Three out of 118 rabbit fetuses had developed cleft palates at an oral dose of about 150 mg/kg/ day which is equivalent to the maximum recommended human daily oral dose administered on an mg/m2 basis. There were found to be no adequate and well-controlled studies on pregnant women. Zileuton should be used during pregnancy only when the potential benefits outweighs the potential risk to the fetus.

Nursing Mothers

Zileuton and/or its metabolites are found to be excreted in rat milk. It is not known whether Zileuton is excreted in human milk. Because many drugs are found to be excreted in the human milk, and because of the potential for tumorigenicity which has been shown by Zileuton in animal studies. Hence, a decision should be made whether to continue or discontinue the drug.

Pediatric Use

Zileuton is not indicated for use in children aged less than 12 years . The safety and efficacy of pediatric patients have not been established.

Geriatric Use

A subgroup analysis of a controlled and open-label clinical studies with zileuton immediate-release tablets suggested that females aged ≥65 years appeared to be at increased risk of Alanine Aminotransferase elevations. In Zileuton placebo-controlled studies, there were found to be no discernable trends in Alanine Aminotransferase elevations noted in subset analyses for patients aged ≥65 years , although the database might not have been sufficiently large to detect a trend.

The physician should be knowledgeable and vigilant about the treatment pertaining to the identification and treatment of the overdose of Zileuton.

The human experience of acute overdose with Zileuton is found to be limited. A patient in a clinical study was administered between 6.6 and 9.0 g of zileuton immediate-release tablets in a single dose adminitration. Vomiting had been induced, and the patient was recovered without sequelae. Zileuton is not removed by dialysis. In case of overdosage, the patient should be treated with symptomatic and supportive measures. If indicated, elimination of unabsorbed drugs should be achieved by emesis or by gastric lavage. The usual precautions should be observed to maintain the airway.

Pharmacodynamics

Zileuton is said to be an oral active inhibitor of ex vivo LTB4 formation in humans. The inhibition of formation of LTB4 in whole blood is found to be directly related to Zileuton plasma levels. In patients suffering from asthma, the IC50 is estimated to be around 0.46 µg/mL, and a maximum inhibition of ≥80% was found to be reached at a zileuton concentration of about 2 µg/mL. In patients who are suffering asthma receiving zileuton immediate-release tablets of dose 600 mg 4 times daily, peak plasma levels averaging upto 5.9 µg/mL were found to be associated with inhibition of a mean LTB4 which is about 98%. Zileuton is found to inhibit the synthesis of cysteinyl leukotrienes, as determined by reduced urinary LTE4 levels.

Pharmacokinetics

• Absorption

A three-way crossover study had been conducted in healthy male and female subjects where n=23 with a mean age of 33 range 20-55, following a single dose of 1200 mg i.e.2 × 600 mg Zileuton tablets under fasted and fed conditions, and 2 doses of 600 mg zileuton immediate-release tablets for every 6 hours under fasted conditions. Food increased the peak mean plasma concentrations i.e.Cmax and the mean extent of absorption i.e.AUC of Zileuton by 18 and 34%, respectively, and prolonged Tmax from 2.1 hours to around 4.3 hours.

• Distribution

An apparent volume of distribution of Zileuton is found to be approximately 1.2 L/kg. Zileuton is 93% bound to plasma proteins,which is primarily to albumin, with minor binding to α1–acid glycoprotein.

• Metabolism

The in-vitro studies using human liver microsomes has shown that Zileuton and its N-dehydroxylated metabolite can be metabolized oxidatively by enzymes such as CYP1A2, CYP2C9, and CYP3A4. Many zileuton metabolites have been identified in human plasma and urine which include two diastereomeric O-glucuronide conjugates as major metabolites and an N-dehydroxylated metabolite . The urinary excretion of the inactive the A-66193 metabolite and unchanged Zileuton each accounted for around less than 0.5% of the single radiolabeled dose of Zileuton. Multiple doses of 1200 mg Zileuton two times a day had resulted in a peak plasma levels of 4.9 µg/mL of the inactive metabolite A-66193 which achieved AUC of around 93 µg·hr/ mL, showing a large inter-subject variability. This inactive metabolite A-66193 , has been shown to be formed by the gastrointestinal microflora before the absorption of the Zileuton, its formation increases the absorption of zileuton and its absorption gets delayed.

• Elimination

An elimination of Zileuton predominantly occurs via metabolism with a mean terminal half-life of around 3.2 hours. Apparent oral clearance of Zileuton is 669 mL/min. Zileuton activity is primarily due to the presence of the parent drug. Studies with the radiolabeled drug Zileuton have demonstrated that orally administered Zileuton is found to be well absorbed into the systemic circulation with about 94.5% and 2.2% of the radiolabeled dose, and it was recovered in urine and feces, respectively.

• De Chandt MT, Cairns CB, et al.: Zileuton: The clinical implications of 5-Lipoxygenase inhibition in severe airway disease. 2007 Apr;61(4):663-76.
• Westcott JY, Repine JE, et al.: Intrinsic 5-lipoxygenase activity is required for neutrophil responsivity. 1994 Aug 16;91(17):8156-9.
• Kamada AK, et al. : Zileuton : The first 5-lipoxygenase inhibitor for the treatment of asthma.1996 Jul-Aug;30(7-8):858-64.
• Tanaka R: 5-lipoxygenase inhibitors in asthma therapy. 1996 Nov;54(11):3040-4.
• Request FG,et.al: The Tolerability of leukotriene modifiers in asthma: a review of clinical experience. BioDrugs. 1999 Jun;11(6):385-94.
• Su LT, Yue L, Runnels LW, et al.: The Blockade of TRPM7 channel activity and cell death by inhibitors of 5-lipoxygenase. 2010 Jun 17;5(6):e11161.
• Wenzel SE: The Leukotriene receptor antagonists and related compounds. 1999 Mar-Apr;6(2):189-93.
• Yang K,et.al: The Prostaglandins and leukotriene B4 are potent inhibitors of 11beta-hydroxysteroid dehydrogenase type 2 activity in human choriocarcinoma JEG-3 cells. 1999 Jul;61(1):40-5.
• Kushihara M, Hirasawa N, et al.: The Inhibition by troglitazone of the antigen-induced production of leukotrienes in immunoglobulin E-sensitized RBL-2H3 cells.2000 Jan;129(2):367-73.
• Libertine-Garahan L,et.al: The Anti-inflammatory activities of LDP-392, a dual PAF receptor antagonist and 5-lipoxygenase inhibitor. 2001 Sep;44(3):213-20.
• Peters-Golden M,et.al: The Peroxynitrite-induced nitrotyrosination of proteins is blocked by direct 5-lipoxygenase inhibitor zileuton. 2001 Oct;299(1):198-203.
• Chen YZ: TTD,et.al: The Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5.
• Zouboulis CC: Zileuton, a new efficient and a safe systemic anti-acne drug. 2009 May;1(3):188-92.
• Seltmann H, Alestas T,et.al: The Zileuton prevents the activation of the leukotriene pathway and also reduces sebaceous lipogenesis. 2010 Feb;19(2):148-50.