Liraglutide / Citrulline Injection

Liraglutide

Liraglutide, is a glucagon-like peptide-1 (GLP-1) receptor agonist. The FDA initially approved Victoza®, a 1.8 mg daily subcutaneous injection of liraglutide, in 2010 as an additional therapy to diet and exercise for the management of type 2 diabetes. It is also sold under the brand name Saxenda® As a result of clinical study outcomes, liraglutide was also created as a weight-loss medication, and phase III clinical trials using its daily dose of 3.0 mg have produced positive results.

Liraglutide is a GLP-1 derivative that is 97% homologous to its parent molecule in terms of amino acid sequence. In reaction to nutrients in the lumen, the L cells of the digestive tract produce the polypeptide incretin hormone known as GLP-1. It results in a glucose-dependent stimulation of insulin secretion10, a decrease in plasma glucagon concentrations, a delay in stomach emptying, a suppression of hunger, an increase in heart rate, and a number of other effects including improvements in erectile function, testosterone production, sex hormone-binding globulin serum levels, and conventional sperm parameters in males.

The effects of GLP-1  on weight loss are assumed to be due to appetite suppression and delayed stomach emptying. However, the therapeutic potential of GLP-1 in its natural form has been severely constrained by its pharmacokinetic profile. Native GLP-1 has a half-life of less than 2 minutes once it enters the bloodstream due to its fast degradation by the enzymes neutral endopeptidases (NEP) and dipeptidyl peptidase IV (DPP IV).

In order to increase the pharmacokinetic effects, arginine was substituted for lysine at position 34 in the GLP-1 peptide and a palmitic acid chain with a glutamic acid spacer was added on the lysine residue at position 26. The result was liraglutide.

Peak absorption of liraglutide occurs 11 hours after subcutaneous injection, and absolute bioavailability is 55%. Due to the fatty acid chain, liraglutide has a high protein binding percentage (98%) and a wide volume of distribution. Its 13-hour half-life in both healthy people and people with type 2 diabetes permits once-daily subcutaneous administration. It is believed to be removed by the liver and kidneys as tiny peptides and does not affect the cytochrome P450 system.

L-Citrulline

L-citrulline is a conditional, non-essential amino acid, naturally found in abundance in watermelon. L-Citrulline bypasses the hepatic metabolism and inhibits the arginase effect to increase L-arginine synthesis. Citrulline is recycled into arginine via argininosuccinate synthetase (ASS) to increase arginine availability in most of the tissues producing nitric oxide.

• Cardiovascular health
• Vasodilation (blood flow)
• Erectile function
• General health and longevity

All amino acids are separated into three categories: essential, nonessential, and conditional.

Essential Amino Acids: Essential amino acids are the amino acids that are present in foods – since the body cannot produce them endogenously.

Nine out of the twenty amino acids necessary for health are essential, but adults need get only eight of them from dietary sources: valine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine and tryptophan. The 9^th amino acid is histidine and it is only essential in infants. The body cannot store amino acids, so a regular daily supply of these essential building blocks of protein is needed.

Non-essential and Conditional Amino Acids: Nonessential is a misnomer because these amino acids do fill essential roles. They are considered non-essential because the body can synthesize them, not because they are not essential to health.

Of these eleven non-essential amino acids, eight are referred to as conditional amino acids because when the body is ill or under stress, it may not be capable of producing enough of these amino acids to meet its needs.

The conditional amino acids include; arginine, ornithine, glutamine, tyrosine, cysteine, glycine, proline, and serine.

Amino acids can be used by the body to produce energy, but their primary function is to build proteins. Certain amino acids may also fill non-protein-building functions; such as in the formation of neurotransmitters or hormones.

Each of the body’s twenty amino acids has a unique chemical structure that dictates how they’ll be utilized. A protein will consist of fifty to two-thousand different amino acids that are linked together in a particular sequence according to specific (genetic) instructions.

Liraglutide

An incretin mimetic and glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide shares amino acid sequence homology of 97% with endogenous GLP-1. Approximately 20% of the total circulating endogenous GLP-1 is GLP-1. It binds and activates the GLP-1 (cell-surface) receptor which is coupled to adenylyl cyclase activation through the stimulatory G-protein, Gs in pancreatic beta cells.

In reaction to nutrients in the lumen, the L cells of the digestive tract produce the polypeptide incretin hormone known as GLP-1. It results in a glucose-dependent stimulation of insulin secretio, a decrease in plasma glucagon concentrations.

When blood glucose levels are raised, liraglutide raises intracellular cyclic AMP (cAMP), which triggers the release of insulin.

This insulin release decreases as blood glucose levels rise and get closer to euglycemia. Additionally, liraglutide reduces glucagon secretion in a way that is glucose-dependent. A further component of the blood-glucose-lowering mechanism is a postponement of stomach emptying. Due to the ubiquitous endogenous enzymes dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidases, GLP-1(7-37) has a half-life of 1.5 to 2 minutes (NEP).

Liraglutide’s once-daily dosage is appropriate because of its pharmacokinetic profile, which includes self-association that slows absorption, plasma protein binding, and stability against metabolic breakdown by DPP-4 and NEP.

GLP-1 is a physiological regulator of appetite and calorie intake, and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation. In animal studies, peripheral administration of liraglutide resulted in the presence of liraglutide in specific brain regions regulating appetite, including the hypothalamus. Although liraglutide activated neurons in brain regions known to regulate appetite, specific brain regions mediating the effects of liraglutide on appetite were not identified in rats.

L-Citrulline

Citrulline is involved in the urea cycle, eliminating waste products by excreting them in urine.  Converted into arginine, it produces nitric oxide, a substance that relaxes blood vessels and improves blood flow.

Liraglutide

Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice. Malignant thyroid C-cell carcinomas were detected in rats and mice. A statistically significant increase in cancer was observed in rats receiving liraglutide at 8 times clinical exposure compared to controls. It is unknown whether liraglutide will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors could not be determined by clinical or nonclinical studies.

In the clinical trials, there have been 4 reported cases of thyroid C-cell hyperplasia among Victoza-treated patients and 1 case in a comparator-treated patient (1.3 vs. 0.6 cases per 1000 patient-years). One additional case of thyroid C-cell hyperplasia in a Victoza-treated patient and 1 case of MTC in a comparator-treated patient have subsequently been reported. This comparator-treated patient with MTC had pre-treatment serum calcitonin concentrations >1000 ng/L suggesting pre-existing disease. All of these cases were diagnosed after thyroidectomy, which was prompted by abnormal results on routine, protocol-specified measurements of serum calcitonin. Four of the five liraglutide-treated patients had elevated calcitonin concentrations at baseline and throughout the trial. One liraglutide and one nonliraglutide-treated patient developed elevated calcitonin concentrations while on treatment. Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. The serum calcitonin assay used in the Victoza clinical trials had a lower limit of quantification (LLOQ) of 0.7 ng/L and the upper limit of the reference range was 5.0 ng/L for women and 8.4 ng/L for men. At Weeks 26 and 52 in the clinical trials, adjusted mean serum calcitonin concentrations were higher in Liraglutide-treated patients compared to placebo-treated patients but not compared to patients receiving active comparator. At these timepoints, the adjusted mean serum calcitonin values (~ 1.0 ng/L) were just above the LLOQ with between-group differences in adjusted mean serum calcitonin values of approximately 0.1 ng/L or less. Among patients with pre-treatment serum calcitonin below the upper limit of the reference range, shifts to above the upper limit of the reference range which persisted in subsequent measurements occurred most frequently among patients treated with Victoza 1.8 mg/day. In trials with on-treatment serum calcitonin measurements out to 5-6 months, 1.9% of patients treated with liraglutide 1.8 mg/day developed new and persistent calcitonin elevations above the upper limit of the reference range compared to 0.8-1.1% of patients treated with control medication or the 0.6 and 1.2 mg doses of liraglutide.

In trials with on-treatment serum calcitonin measurements out to 12 months, 1.3% of patients treated with liraglutide 1.8 mg/day had new and persistent elevations of calcitonin from below or within the reference range to above the upper limit of the reference range, compared to 0.6%, 0% and 1.0% of patients treated with liraglutide 1.2 mg, placebo and active control, respectively. Otherwise, liraglutide did not produce consistent dose-dependent or time-dependent increases in serum calcitonin. Patients with MTC usually have calcitonin values >50 ng/L.

In clinical trials, among patients with pre-treatment serum calcitonin <50 ng/L, one liraglutide-treated patient and no comparator-treated patients developed serum calcitonin >50 ng/L. The liraglutide-treated patient who developed serum calcitonin >50 ng/L had an elevated pre-treatment serum calcitonin of 10.7 ng/L that increased to 30.7 ng/L at Week 12 and 53.5 ng/L at the end of the 6-month trial. Follow-up serum calcitonin was 22.3 ng/L more than 2.5 years after the last dose of liraglutide. The largest increase in serum calcitonin in a comparator-treated patient was seen with glimepiride in a patient whose serum calcitonin increased from 19.3 ng/L at baseline to 44.8 ng/L at Week 65 and 38.1 ng/L at Week 104. Among patients who began with serum calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of liraglutide-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients, with an incidence of 1.1% among patients treated with 1.8 mg/day of Victoza. The clinical significance of these findings is unknown.

Counsel patients regarding the risk for MTC and the symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate the potential risk of MTC, and such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Patients with thyroid nodules noted on physical examination or neck imaging obtained for other reasons should be referred to an endocrinologist for further evaluation. Although routine monitoring of serum calcitonin is of uncertain value in patients treated with liraglutide, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation.

Pancreatitis

In clinical trials of liraglutide, there were 7 cases of pancreatitis among liraglutide-treated patients and 1 case among comparator-treated patients (2.2 vs. 0.6 cases per 1000 patient-years). Five cases with liraglutide were reported as acute pancreatitis and two cases with liraglutide were reported as chronic pancreatitis. In one case in a liraglutide-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established. One additional case of pancreatitis has subsequently been reported in a liraglutide-treated patient. Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. There are no conclusive data establishing a risk of pancreatitis with liraglutide treatment. After initiation of liraglutide, and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, liraglutide and other potentially suspect medications should be discontinued promptly, confirmatory tests should be performed and appropriate management should be initiated. If pancreatitis is confirmed, liraglutide should not be restarted. Use with caution in patients with a history of pancreatitis.

Use with Medications Known to Cause Hypoglycemia

Patients receiving liraglutide in combination with an insulin secretagogue (e.g., sulfonylurea) may have an increased risk of hypoglycemia. In the clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 7 liraglutide-treated patients and in no comparator-treated patients. Six of these 7 patients treated with liraglutide were also taking a sulfonylurea. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea or other insulin secretagogues.

Macrovascular Outcomes

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

L-Citrulline

L-Citrulline may affect how certain drugs work in the body. Don’t take this medication if you are using nitrates to treat heart disease, any type of medicine for hypertension or ED drugs like sildenafil, tadalafil or vardenafil.The combination of L-Citrulline with these drugs could result in a dangerous drop in blood pressure.

Liraglutide

Use is not advised. There is no evidence to support a drug’s association with a risk for severe birth abnormalities and miscarriage. According to research on animal reproduction, the fetus throughout pregnancy could be at risk.

L-Citrulline

L-Citrulline is contraindicated in pregnancy.

Liraglutide

In tests on animals, this medication was excreted into rat milk at levels that were roughly 50% of maternal plasma levels. Rats given this medication during pregnancy and lactation saw less postnatal weight gain. This observation might be explained by decreased maternal food intake. Use is not advised, and a choice should be made about whether to stop nursing or stop the medication after considering its significance to the mother. Liraglutide has not been studied in pediatric patients.

L-Citrulline

L-Citrulline is contraindicated in breastfeeding.

Liraglutide

In vitro assessment of drug−drug interactions

Liraglutide has low potential for pharmacokinetic drug-drug interactions related to cytochrome P450 (CYP) and plasma protein binding.

In vivo assessment of drug−drug interactions 

The drug-drug interaction studies were performed at steady state with liraglutide 1.8 mg/day. The effect on rate of gastric emptying was equivalent between liraglutide 1.8 mg and 3 mg (acetaminophen AUC0-300min). Administration of the interacting drugs was timed so that Cmax of liraglutide (8-12 h) would coincide with the absorption peak of the co-administered drugs.

Oral Contraceptives

A single dose of an oral contraceptive combination product containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel was administered under fed conditions and 7 hours after the dose of liraglutide at steady state. Liraglutide lowered ethinylestradiol and levonorgestrel Cmax by 12% and 13%, respectively. There was no effect of liraglutide on the overall exposure (AUC) of ethinylestradiol. Liraglutide increased the levonorgestrel AUC0-∞ by 18%.

Liraglutide delayed Tmax for both ethinylestradiol and levonorgestrel by 1.5 h. Digoxin: A single dose of digoxin 1 mg was administered 7 hours after the dose of liraglutide at steady state. The concomitant administration with liraglutide resulted in a reduction of digoxin AUC by 16%; Cmax decreased by 31%. Digoxin median time to maximal concentration (Tmax) was delayed from 1 h to 1.5 h.

Lisinopril
A single dose of lisinopril 20 mg was administered 5 minutes after the dose of liraglutide at steady state. The co-administration with liraglutide resulted in a reduction of lisinopril AUC by 15%. Cmax decreased by 27%. Lisinopril median Tmax was delayed from 6 h to 8 h with liraglutide.

Atorvastatin
Liraglutide did not change the overall exposure (AUC) of atorvastatin following a single dose of atorvastatin 40 mg, administered 5 hours after the dose of liraglutide at steady state. Cmax was decreased by 38% and median Tmax was delayed from 1 h to 3 h with liraglutide.

Acetaminophen
Liraglutide did not change the overall exposure (AUC) of acetaminophen following a single dose of acetaminophen 1000 mg, administered 8 hours after the dose of liraglutide at steady state. Cmax was decreased by 31% and median Tmax was delayed up to 15 minutes.

Griseofulvin
Liraglutide did not change the overall exposure (AUC) of griseofulvin following co-administration of a single dose of griseofulvin 500 mg with liraglutide at steady state. Griseofulvin Cmax increased by 37% while median Tmax did not change.

Insulin Detemir 
No pharmacokinetic interaction was observed between liraglutide and insulin detemir when separate subcutaneous injections of insulin detemir 0.5 Unit/kg (single-dose) and liraglutide 1.8 mg (steady state) were administered to patients with type 2 diabetes mellitus.

Specific Populations

Elderly
Age had no effect on the pharmacokinetics of liraglutide based on a pharmacokinetic study in healthy elderly subjects (65 to 83 years) and population pharmacokinetic analyses of patients 18 to 80 years of age.

Gender 
Based on the results of population pharmacokinetic analyses, females have 34% lower weight-adjusted clearance of liraglutide compared to males. Based on the exposure-response data, no dose adjustment is necessary based on gender.

Race and Ethnicity 
Race and ethnicity had no effect on the pharmacokinetics of liraglutide based on the results of population pharmacokinetic analyses that included Caucasian, Black, Asian and Hispanic/NonHispanic subjects. Body weight significantly affects the pharmacokinetics of liraglutide based on results of population pharmacokinetic analyses. The exposure of liraglutide decreases with an increase in baseline body weight. However, the 1.2 mg and 1.8 mg daily doses of liraglutide provided adequate systemic exposures over the body weight range of 40 – 160 kg evaluated in the clinical trials. Liraglutide was not studied in patients with body weight >160 kg.

Pediatric
Liraglutide has not been studied in pediatric patients.

Renal Impairment
The single-dose pharmacokinetics of liraglutide were evaluated in subjects with varying degrees of renal impairment. Subjects with mild (estimated creatinine clearance 50-80 mL/min) to severe (estimated creatinine clearance 9) hepatic impairment were included in the trial. Compared to healthy subjects, liraglutide AUC in subjects with mild, moderate and severe hepatic impairment was on average 11%, 14% and 42% lower, respectively.

Hepatic Impairment
The single-dose pharmacokinetics of liraglutide were evaluated in subjects with varying degrees of hepatic impairment. Subjects with mild (Child Pugh score 5-6) to severe (Child Pugh score > 9) hepatic impairment were included in the trial. Compared to healthy subjects, liraglutide AUC in subjects with mild, moderate and severe hepatic impairment was on average 11%, 14% and 42% lower, respectively.

L-Citrulline

L-Citrulline may affect how certain drugs work in the body. Don’t take this medication if you are using nitrates to treat heart disease, any type of medicine for hypertension or ED drugs like sildenafil, tadalafil or vardenafil. The combination of L-Citrulline with these drugs could result in a dangerous drop in blood pressure.

Liraglutide

Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Liraglutide is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate the human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors.

The most common adverse reactions, reported in ≥5% of patients treated with liraglutide and more commonly than in patients treated with placebo, are headache, nausea, diarrhea, and anti-liraglutide antibody formation.

Immunogenicity-related events, including urticaria, were more common among liraglutide-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials.

Do not use liraglutide if:
•    you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC)
•    you have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
•    you have had a serious allergic reaction to liraglutide

Symptoms of a serious allergic reaction include:
•    swelling of your face, lips, tongue, or throat
•    problems breathing or swallowing
•    severe rash or itching
•    fainting or feeling dizzy
•    very rapid heartbeat

Thyroid C-cell tumors in animals: Human relevance unknown. Counsel patients regarding the risk of medullary thyroid carcinoma and the symptoms of thyroid tumors.

Pancreatitis: In clinical trials, there were more cases of pancreatitis among liraglutide-treated patients than among comparator-treated patients. If pancreatitis is suspected, liraglutide and other potentially suspect drugs should be discontinued. Liraglutide should not be restarted if pancreatitis is confirmed. Use with caution in patients with a history of pancreatitis.

Serious hypoglycemia: Can occur when liraglutide is used with an insulin secretagogue (e.g. a sulfonylurea). Consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia.

Macrovascular outcomes: There have been no studies establishing conclusive evidence of macrovascular risk reduction with liraglutide or any other antidiabetic drug.

L-Citrulline

L-Citrulline may affect how certain drugs work in the body. Don’t take this medication if you are using nitrates to treat heart disease, any type of medicine for hypertension or ED drugs like sildenafil, tadalafil or vardenafil.The combination of L-Citrulline with these drugs could result in a dangerous drop in blood pressure.

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

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