Analyte Names and Structures:
Lisdexamfetamine dimesylate

Synonyms:
VyvanseTM
Lisdexamfetamine_dimesylate.jpg
Relevant Physicochemical Data:
The chemical designation is (2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide dimethanesulfonate.
The molecular formula is C15H25N3O• (CH4O3S)2, which corresponds to a molecular weight of 455.60.

It is a white to off-white powder that is soluble in water (792 mg/L)
It is suggested to store the drug at room temperature, 59 to 89º F (15 - 30ºC) and to protect it from light. [5]


General Relevancy:
Lisdexamfetamine is a central nervous system stimulant. It is a controlled substance (Schedule II) and only available by prescription. It is a pro-drug of dextroamphetamine and is used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). It is available as 30, 50 and 70 mg capsules. It was developed to provide an extended duration of effect that is consistent throughout the day with a reduced potential for abuse, overdose toxicity and drug tampering. It may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. After oral administration, it is rapidly absorbed from the gastrointestinal tract and converted by first-pass intestinal and/or hepatic metabolism (not via the P450 enzymes) to dextroamphetamine, which is responsible for the drug’s activity, and L-lysine, which is a naturally occurring essential amino acid. Amphetamines are non-catecholamine sympathomimetic amine with CNS stimulant activity and are thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamine neurotransmitters into the extraneuronal space. Lisdexamfetamine, the parent drug, does not bind to the sites responsible for the reuptake of norepinephrine and dopamine in vitro. [5]

Following oral administration of 70 mg dose, approximately 96% of the dose was recovered in the urine compared to 0.3% in the feces over 120 hours (5 days). In the urine, 42% of the dose was related to amphetamine, 25% hippuric acid and 2% of intact lisdexamfetamine. Plasma concentrations of unconverted lisdexamfetamine are low and transient usually becoming non-quantifiable by 8 hours post-administration. The plasma elimination half-life of lisdexamfetamine generally averages less than one hour. [5]

In pediatric patients (6 – 12 years) orally administered a single dose of 30 mg, 50 mg, or 70 mg lisdexamfetamine after an 8-hour overnight fast, the observed Tmax of dextro-amphetamine was approximately 3.5 hours. The Tmax of the lisdexamfetamine was approximately 1 hour. Linear pharmacokinetics was established over the dosage range of 30 to 70 mg in children aged 6 to 12 years. The pharmacokinetics of d-amphetamine was similar in pediatric (6 – 12 years) and adolescent (13 – 17 years) ADHD patients, and in health adult volunteers. Any difference in kinetics after oral administration was a result of difference in mg/kg dosing. [3]

In a steady state study of healthy adults where fasting subjects were administered a 70 mg dose daily, steady state concentrations were likely to have occurred in all subjects by Day 5, but presumed to be achieved within approximately 2 days. Intact lisdexamfetamine was eliminated within 6 hours of last dose and 95% of amphetamine was eliminated within 48 hours. [3]

There was no accumulation of d-amphetamine at steady state in health adults and no accumulation of lisdexamfetamine after once daily dosing for 7 consecutive days. [5]

Food does not affect the observed AUC and Cmax of d-amphetamine in adults following a single oral dose, but prolongs the Tmax by about 1 hour when compared to a fasting state. [5]

The recommended dosing regimen for children starting treatment for the first time or switching from another medication is 30 mg daily in the morning, with adjustments made in 20 mg/day increments at approximately weekly intervals. The maximum recommended daily dose is 70 mg. [2]

The most commonly reported adverse effects were decreased appetite, trouble falling asleep, stomach ache and irritability. [1]


Pharmacokinetics (TDM):



Proper Specimen Types:
The proper specimen to test (i.e. blood versus urine) for amphetamine would depend on the purpose of the testing performed. Therapeutic drug monitoring is usually performed on the blood/plasma sample, while compliance or abuse detection may be determined via the urine sample. The whole blood/plasma concentration ratio for amphetamine was determined to be 0.6 at a blood level of 500 nanog/mL and 1.0 at 5000 nanog/mL. [4]

Analyte(s) to be Determined:
Dextro-amphetamine

Methods of Analysis:

There are several methods for the determination of amphetamine including immunoassay, gas chromatography, liquid chromatography and thin layer chromatography. The method of analysis would depend on the sample submitted and purpose of testing. As of this report, NMS Labs is using immunoassay, and gas chromatography and gas chromatography with mass spectrometry detection for amphetamine determination, and gas chromatography/mass spectrometry for d- and l- isomer differentiation.

Measurable Range (Upper/Lower Detection Limits):


Critical Concentrations:
In children aged 6 – 12 years of age the following mean plasma concentrations were found for d-amphetamine: [3]
Lisdexamfetamine_dimesylate_chart1.jpg
In healthy adults [3]

Lisdexamfetamine_dimesylate_chart2.jpg

Steady state in healthy adults given 70 mg once daily for 7 days: Mean (SD) [3]
Lisdexamfetamine_dimesylate_chart3.jpg
Postmortem amphetamine blood concentrations have ranged from 500 to 41,000 nanog/mL in reported deaths cases due to amphetamine. [4]

Potential Interfering Compounds:


Stability Data:
The package literature indicates to store the drug at room temperature 59 to 89º F (15 - 30ºC) and to protect from light. Although when I spoke with Paula Ang, Pharm D., Medical Affairs Associate from Shire Pharmaceuticals in Wayne, PA, on 6/21/07, she had no information on the stability of the drug in biological specimens. My concern is the in vitro transformation of lisdextramine, the pro-drug, to amphetamine resulting in a falsely elevated amphetamine finding. This concern should be evaluated through in-house stability studies.

Interpretative Comment(s):
In children, the mean plasma d-Amphetamine concentrations at approximately 3.5 hours following 30 mg, 50 mg and 70 mg of Lisdexamfetamine were 53 nanog/mL, 93 nanog/mL and 134 nanog/mL, respectively.

In healthy adults, the mean (±SD) steady state plasma concentrations of d-Amphetamine following 70 mg given once daily ranged from 18±14 to 90±30 nanog/mL

Other sources of d-amphetamine (such as Adderall® and Dexedrine®) may contribute to this finding.


(NOTE
: It is suggested that an additional statement be added to the current reference comments for amphetamine test codes indicating lisdexamfetamine as a source of the amphetamine).


References:

1) FDA Approvals: Cuymbalta, Vyvanse, Kadian CME. Medscape Medical News. www.medscape.com/viewarticle/553314_print. June 20, 2007.

2) Lisdeamfetamine dimesylate. DrugPoint® Summary and Drugdex® Evaluations. Micromedex® Healthcase Series. 2007.

3) Personal communication (letter) from Dr. Paula Ang, Medical Affairs Associate, Shire Pharmaceuticals, Inc. June 21, 2007.

4) R. Baselt. Amphetamine in Disposition of Toxic Drugs and Chemicals in Man. 7th Ed. Biomedical Publications, Foster City, CA. 2004.


5) VyvanseTM (Lisdexamfetamine dimesylate). Product Information from New River Pharmaceuticals, Inc. (Blacksberg VA 24060; distributed by Shire US, Inc. Wayne, PA 19087). 2007.


General Questions:
1.
What is the application of the test?
Therapeutic drug monitoring, compliance testing and/or abuse testing

2.
Who would use this application and why?
Generally, physicians would use this test to monitor for therapy, compliance and potential abuse of this substance.

3. Is testing currently available / new to the industry by some other means?
The testing for amphetamine is not new to the industry.

4. What are the features / benefits of this test to the user?
To monitor for lisdexamfetamine (d-amphetamine) therapy and compliance.

5. What is the scientific significance of this test?

To evaluate patient use of lisdexamfetamine.