Azstarys
Azstarys Uses, Dosage, Side Effects, Food Interaction and all others data.
Dexmethylphenidate is the dextrorotary form of methylphenidate introduced in 2002. It is a norepinephrine-dopamine reuptake inhibitor (NDRI) and thus a psychostimulant. It is used for treatment of Attention Deficit Hyperactivity Disorder (ADHD). The d-isomer is thought to have greater effect with fewer side effects than the l-isomer or the racemic mixture.
Dexmethylphenidate is the d-enantiomer of methylphenidate. This enantiomer is more pharmacologically active than the racemic mixture and may block norepinephrine and dopamine reuptake in synapses.
Attention Deficit Hyperactivity Disorder (ADHD) is an early-onset neurodevelopmental disorder that often extends into adulthood and is characterized by developmentally inappropriate and impaired attention, impulsivity, and motor hyperactivity. The underlying cause of ADHD is unclear but likely involves dysfunction in dopaminergic and noradrenergic neurotransmission, as evidenced by the clear beneficial effect of CNS stimulants such as methylphenidate and amphetamine that increase extracellular dopamine and norepinephrine levels. Serdexmethylphenidate is a prodrug of the CNS stimulant dexmethylphenidate, a common first-line treatment for ADHD, that is combined with dexmethylphenidate to provide extended plasma concentrations and therapeutic benefit with once-daily dosing.
Serdexmethylphenidate was granted FDA approval on March 2, 2021, and is currently marketed as a combination capsule with dexmethylphenidate under the trademark AZSTARYS™ by KemPharm, Inc.
Serdexmethylphenidate is a prodrug of the CNS stimulant dexmethylphenidate, which increases extracellular levels of dopamine and norepinephrine in the CNS, leading to altered neurotransmission. As a CNS stimulant, serdexmethylphenidate carries a risk of abuse, misuse, and dependence, which should be monitored. Also, CNS stimulants are associated with increased blood pressure, heart rate, and risk of serious cardiovascular reactions, including stroke, myocardial infarction, and sudden death; patients should be assessed before starting therapy and monitored for cardiovascular abnormalities. Similarly, CNS stimulants may also result in peripheral vasculopathy, including Raynaud's phenomenon. Due to its ability to alter neurological function, serdexmethylphenidate may exacerbate pre-existing psychoses, induce manic episodes in patients with bipolar disorder, or result in newly diagnosable manic or psychotic symptoms. Frequent, sustained, and painful erections, which may require medical attention, have been observed in patients who have been treated for some time with serdexmethylphenidate, often associated with a dose increase. Finally, like other CNS stimulants, serdexmethylphenidate has been associated with weight loss and growth retardation, which may require treatment interruption in serious cases.
| Trade Name | Azstarys |
| Generic | Dexmethylphenidate + serdexmethylphenidate |
| Type | Capsules |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Dexmethylphenidate is a norepinephrine-dopamine reuptake inhibitor used in the treatment of ADHD in conjunction with other therapies.
Dexmethylphenidate is used as a treatment for ADHD, ideally in conjunction with psychological, educational, behavioral or other forms of treatment.
Serdexmethylphenidate is a prodrug of the CNS stimulant dexmethylphenidate used as a first-line treatment for Attention Deficit Hyperactivity Disorder (ADHD).
Serdexmethylphenidate is a prodrug of dexmethylphenidate that is indicated in combination with dexmethylphenidate for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients aged six years and older.
Azstarys is also used to associated treatment for these conditions: Attention Deficit Hyperactivity Disorder (ADHD)Attention Deficit Hyperactivity Disorder (ADHD)
How Azstarys works
Methylphenidate inhibits dopamine and norepinephrine reuptake transporters in synapses, especially in the thalamus and striatum. One study shows no detectable difference in the caudal prefrontal cortex of treated or untreated monkeys, though multiple rat studies show activity on the prefrontal cortex. Imaging of human brains after administration of methylphenidate shows changes to blood flow of various regions of the brain including the striatum, supplementary motor area, and posterior parietal cortex.
Attention Deficit Hyperactivity Disorder (ADHD) is an early-onset neurodevelopmental disorder that often extends into adulthood and is characterized by developmentally inappropriate and impaired attention, impulsivity, and motor hyperactivity. Proper diagnosis is hindered by a lack of biological markers (based on symptoms alone), a spectrum of severity, and frequent comorbidities such as autism spectrum disorder, reading disabilities, developmental coordination disorders, and tic disorders. Although the underlying cause(s) is unclear, dopaminergic, noradrenergic, serotonergic, cholinergic, glutaminergic, and opioid neurotransmission likely plays a role.
Serdexmethylphenidate is a prodrug of the CNS stimulant dexmethylphenidate(MPH), a common first-line treatment for ADHD. The main effect of MPH is to increase the extracellular levels of dopamine and norepinephrine, which has numerous potential downstream effects. This occurs mainly due to MPH's ability to inhibit the corresponding dopamine and norepinephrine monoamine transporters. Other studies have suggested additional possible MPH functions, including serotonin 5-HT1A receptor agonism, redistribution of vesicular monoamine transporter-2 (VMAT-2), and either direct or indirect activation of α2-adrenergic receptors. Overall, imaging studies reveal that MPH acts to alter brain activity in relevant regions associated with executive function, emotional regulation, reward processing, and working memory.
Toxicity
There is no difference in effect across genders. The difference in effect across racial groups, patients under 6 years, renal impairment, hepatic impairment, pregnancy, lactation, and geriatric patients has not been well studied. Patients with renal impairment are not expected to need dose adjustment as the drug is not mainly cleared renally. Animal studies in pregnant and lactating rats showed delayed fetal skeletal ossification, and reduced weight gain in male offspring. Due to these studies, caution must be exercised and the benefits and risks of taking this drug must be weighed. It is unlikely that dexmethylphenidate is carcinogenic but B6C3F1 mice, which are sensitive to the development of hepatic tumours, developed hepatoblastomas at 2 times the maximum recommended human dose. Methylpheidate was not found to be mutagenic but is weakly clastogenic in Chinese Hamster Ovary cells. Methylphenidate does not impair fertility in animal studies.
Serdexmethylphenidate/dexmethylphenidate overdose results in symptoms consistent with CNS overstimulation, including gastrointestinal complaints such as nausea and vomiting, neurological effects including anxiety, euphoria, confusion, and hallucinations/delirium, cardiovascular effects such as arrhythmias, hypertension/hypotension, and tachycardia, general effects such as agitation, restlessness, twitching, convulsions, sweating, flushing, mucous membrane dryness, tachypnea, mydriasis, and serious effects such as rhabdomyolysis, loss of consciousness, coma, and death. Overdose treatment should consist of appropriate symptomatic and supportive care.
Volume of Distribution
2.65L/kg when administered intravenously.
Serdexmethylphenidate has a mean apparent volume of distribution of 29.3 L/kg following serdexmethylphenidate/dexmethylphenidate administration. Serdexmethylphenidate/dexmethylphenidate (28/6 or 56/12 mg) administered orally in patients aged between six and 17 years of age produced an apparent volume of distribution of dexmethylphenidate of between 37.6 and 66 L/kg.
Elimination Route
Taking dexmethylphenidate with or without food does not affect patients in a clinically relevant way. 90% of an oral dose is absorbed but as a result of hepatic first pass metabolism, oral bioavailability of dexmethylphenidate is 23% compared to l-methylphenidate with an oral bioavailability of 5% . Maximum concentration is generally reached in 1-1.5 hours.
Following a single dose of serdexmethylphenidate/dexmethylphenidate (52.3/10.4 mg) compared to extended-release dexmethylphenidate (40 mg) capsules in healthy volunteers under fasted conditions, the Cmax and AUC of dexmethylphenidate were 14.0 ng/mL and 186 ng*h/mL and 28.2 ng/mL and 248 ng*h/mL, respectively. The kinetics are approximately linear over a range of concentrations, with steady-state being reached after the third once-daily dose. Serdexmethylphenidate has a low oral bioavailability of 3%. The Tmax for both serdexmethylphenidate and dexmethylphenidate is approximately two hours under fasted conditions when coadministered. When serdexmethylphenidate is administered as a single entity, the dexmethylphenidate Tmax is approximately eight hours.
Different ratios of serdexmethylphenidate to dexmethylphenidate, 64/8, 56/12, and 48/16 mg, each equivalent to 40 mg of dexmethylphenidate, were tested in healthy adult volunteers under fasted conditions. In each case, dexmethylphenidate reached peak plasma concentrations in roughly two hours (mean between 1.6-1.8 hours), which gradually decreased over 24 hours. The Cmax varied from 15.5 ± 3.7 to 23.8 ± 5.7 ng/mL while the AUC0-24h varied from 187.0 ± 41.0 to 207 ± 54.4 ng*h/mL. Another study investigated the pharmacokinetics of serdexmethylphenidate/dexmethylphenidate (28/6 or 56/12 mg) in patients aged between six and 17 years of age. In general, the Cmax and AUC varied between cohorts and dose but were roughly equivalent when normalized for both dose and body weight.
Half Life
The mean terminal half life is approximately 2.2 hours. However other studies have shown 3.8-3.9 hours, or 5.96 hours after intravenous administration and 5.69 hours following an oral dose.
Following a single oral dose of 52.3 mg/10.4 mg serdexmethylphenidate/dexmethylphenidate, the mean plasma terminal elimination half-lives of each component were roughly 5.7 and 11.7 hours, respectively. At steady-state in healthy adults under fasted conditions, serdexmethylphenidate/dexmethylphenidate at 64/8, 56/12, and 48/16 mg resulted in a dexmethylphenidate half-life of between 8.5 ± 2.3 and 9.2 ± 3.5 hours.
Clearance
0.40L/hr/kg following an intravenous dose and a renal clearance of 0.005L/hr/kg.
Serdexmethylphenidate has a mean apparent clearance of about 3.6 L/h/kg following oral serdexmethylphenidate/dexmethylphenidate administration. In patients aged 6-17 years following oral administration of 28/6 or 56/12 mg serdexmethylphenidate/dexmethylphenidate, dexmethylphenidate has a mean apparent clearance of between 2.5 and 3.4 L/h/kg when normalized for dose.
Elimination Route
Dexmethylphenidate is mainly eliminated renally. After 48 hours, 90% of the dose is collected in the urine and 3.3% is collected from feces.
Following oral serdexmethylphenidate dosing in humans, roughly 62% and 37% of the initial dose was recovered in the urine and feces, of which about 0.4% and 11% of the initial dose was recovered unchanged, respectively. Ritalinic acid accounted for approximately 63% of the recovered dose. When methylphenidate was administered orally as a racemate, about 90% of the dose was recovered in urine, of which racemic acid accounted for approximately 80% of the dose.
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