Various stimulant drug formulations, such as methylphenidate (Ritalin®, Concerta®, and others) and amphetamine (Dexedrine®, Adderall®, and others) products, are the most commonly prescribed medications for attention-deficit/hyperactivity disorder (ADHD) (Findling, 2008). In this article, I review the unique prodrug stimulant lisdexamfetamine dimesylate (LDX, Vyvanse®), which is a U.S. Food and Drug Administration (FDA)-approved treatment for ADHD in children and adults.
What Is Lisdexamfetamine?
Prodrugs are pharmacologically inactive compounds, designed to maximize the amount of the active component of the prodrug that ultimately reaches its site of action (Hardman, Limbird, Molinoff, Ruddon, & Gilman, 1996). Inactive prodrugs work therapeutically when they are converted to biologically active metabolites. LDX is an inactive prodrug in which d-amphetamine (dextroamphetamine or DEX, Dexedrine®) is chemically bonded to l-lysine, an essential amino acid (Krishnan & Montcrief, 2007a). After oral ingestion, the bond is metabolically cleaved, LDX is converted to l-lysine and to the pharmacologically active DEX, and unconverted LDX serum concentrations are very low.
When LDX is administered parenterally, minimal amounts of DEX are released. Although the LDX conversion enzyme(s) are unknown, this confirms that the biotransformation occurs in the gastrointestinal tract. Compared with orally ingested DEX, exposure to LDX-released DEX is decreased and delayed after intravenous or intranasal LDX administration and with very high oral LDX dosages (above therapeutic amounts). Pharmacokinetic studies show that DEX is released from LDX in an extended-release pattern, suggesting that the metabolic conversion of LDX is a rate-limited process (Krishnan & Stark, 2008).
In February 2007, the FDA approved LDX for ADHD in children ages 6 to 12 on the basis of two controlled studies. A two-phase study involving 52 patients (ages 6 to 12) compared three LDX dosages (30, 50, and 70 mg per day), three mixed amphetamine salts extended release (MAS-XR, Adderall XR®) dosages (10, 20, and 30 mg per day), and placebo (Biederman, Boellner, et al., 2007). During the first 3-week dosage-titration phase, all participants received open-label MAS-XR to determine their optimal dosage (10, 20, or 30 mg per day). On the basis of this MAS-XR dosage, patients were assigned to one of three groups: cohort A (MAS-XR 10 mg per day, LDX 30 mg per day, placebo), cohort B (MAS-XR 20 mg per day, LDX 50 mg per day, placebo), or cohort C (MAS-XR 30 mg per day, LDX 70 mg per day, placebo).
The patients in each group then entered into a 3-week randomized, double-blind, placebo-controlled, crossover phase. During this phase, patients received placebo, MAS-XR, and LDX (for 1 week each in random order) at dosages depending on their cohort assignment. All dosages of LDX and MAS-XR were significantly more efficacious compared with placebo. The overall rate of treatment-emergent adverse events (TEAEs) was similar for placebo (15%), LDX (16%), and MAS-XR (18%). The most common TEAEs for LDX were insomnia, decreased appetite, and anorexia. The most common TEAEs for MAS-XR were decreased appetite, abdominal pain, insomnia, and vomiting. Neither drug had significant adverse effects on vital signs, cardiac function, or laboratory studies.
A second randomized, double-blind, 4-week study involving 290 patients (ages 6 to 12) compared three LDX dosages (30, 50, or 70 mg per day) with placebo (Biederman, Krishnan, Zhang, McGough, & Findling, 2007). The LDX 30 mg group took 30 mg per day for 4 weeks. The 50 mg group took 30 mg per day for 1 week and 50 mg per day for 3 weeks. The 70 mg group took 30 mg per day for 1 week, 50 mg per day for 1 week, and 70 mg per day for 2 weeks.
All LDX dosages were significantly more efficacious than placebo. There was a nonsignificant trend toward greater improvement with higher LDX dosages. Overall, TEAEs were significantly less common with placebo (47%) than with LDX 30 mg (72%), LDX 50 mg (68%), or LDX 70 mg (84%). Drop-out rates due to TEAEs were nonsignificantly lower for placebo (1%) compared with LDX 30 mg (8%), LDX 50 mg (5%), and LDX 70 mg (14%). Drop-out rates due to lack of efficacy were nonsignificantly higher for placebo (17%) compared with LDX 30 mg (1%), LDX 50 mg (0%), and LDX 70 mg (1%). Compared with placebo, LDX was more commonly associated with decreased appetite, insomnia, upper abdominal pain, headache, irritability, vomiting, weight decrease, and nausea. LDX had no significant adverse effect on vital signs, cardiac function, or laboratory studies.
In April 2008, the FDA approved LDX for ADHD in adults age 18 and older on the basis of a randomized, double-blind, 4-week study of 414 patients (ages 18 to 55) comparing three LDX dosages (30, 50, and 70 mg per day) with placebo (Adler et al., 2008). The dosage-titration schedule for LDX was similar to the study by Biederman, Krishnan, et al. (2007). All LDX dosages were significantly more efficacious than placebo. Overall, TEAEs were less common with placebo (58%) compared with LDX (72% for all dosage groups pooled together). Drop-out rates among the four study groups were not significantly different. Compared with placebo, LDX was more commonly associated with decreased appetite, dry mouth, insomnia, nausea, diarrhea, and anxiety. LDX did not have significant adverse effects on vital signs, cardiac function, or laboratory studies.
The long-term effectiveness of LDX has not been well studied in children or adults. An interim analysis of data from a 1-year, open-label study of LDX in children has been reported (Goodman, 2007). In this study, 272 patients (ages 6 to 12) were treated openly with LDX 30 mg per day to 70 mg per day for up to 1 year. At the time of the report, 201 patients (74%) had taken LDX for at least 6 months, and 146 patients (54%) had taken LDX for 1 year. There was no evidence that therapeutic tolerance (loss of effect) occurred over time. TEAEs were reported in 78% of patients, but these were mostly mild to moderate in severity and typically occurred early in treatment. The most common TEAEs were decreased appetite, weight decrease, headache, insomnia, upper abdominal pain, and irritability. After the initial 2 months, decreased appetite and weight were the only TEAEs reported in more than 5% of patients. Overall, 25 patients (9%) discontinued treatment because of TEAEs.
The abuse liability of LDX has been investigated in two controlled studies (Blick & Keating, 2007). A double-blind, placebo-controlled, 6-day crossover study involving 36 adults without ADHD but with a history of stimulant abuse (within the past 28 days) compared three LDX dosages (50, 100, and 150 mg per day), DEX 40 mg per day, diethylpropion (DEP, Tenuate®) 200 mg per day, and placebo. The primary measure of subjective response was the “Liking” score on the Drug Rating Questionnaire-Subject Liking Scale. The mean maximum post-dosage Liking score was significantly greater for DEX compared with placebo and with the two lower dosages of LDX; it was significantly greater for DEX, DEP, and LDX 150 mg compared with placebo; and it was significantly greater for LDX 150 mg compared with the two lower dosages of LDX. No significant difference was found between DEX and LDX 150 mg, nor between DEP and any dosage of LDX, nor between placebo and the two lower dosages of LDX. The mean maximum Liking score also peaked significantly later for all dosages of LDX compared with DEX and DEP, indicating a delayed effect for LDX.
A second double-blind, placebo-controlled, 2-day crossover study involving 9 adults without ADHD but with a history of stimulant abuse compared intravenous LDX 50 mg, intravenous DEX 20 mg, and placebo. The subjective and behavioral effects of DEX were significantly greater than those of LDX and placebo (both of which were not significantly different), and these effects occurred significantly more rapidly with DEX (i.e., within 15 minutes).
LDX is available in 20, 30, 40, 50, 60, and 70 mg capsules. The recommended starting dosage is 30 mg per day, with a maximum recommended dosage of 70 mg per day. Some patients may require higher dosages to achieve an optimal response, but the effectiveness of dosages greater than 70 mg per day has not been systematically studied. Moreover, the finite capacity of the LDX converting enzyme(s) will become saturated with escalating dosages. At some point, then, higher LDX dosages will not necessarily result in greater DEX concentrations or better clinical benefits.
Administration in the morning should provide an adequate therapeutic benefit throughout the day and minimize insomnia. It is possible that individual patients might have a shorter duration of action and might benefit from divided dosing. LDX can be taken with or without food (Krishnan & Zhang, 2008). The capsule contents can be mixed with liquids, which might be useful for children. Typical side effects include insomnia, decreased appetite, nausea, vomiting, upper abdominal pain, weight loss, dry mouth, and irritability. Rare adverse effects reported with other amphetamine products could also occur with LDX (e.g., psychosis, dysphoria, restlessness, tics, agitation, seizures). Tachycardia, increased blood pressure, and other cardiovascular effects are possible, although the LDX clinical studies did not demonstrate significant adverse cardiac effects. However, on the basis of concerns about the risk of amphetamines in patients with known cardiac abnormalities, LDX should not be used in these patients.
LDX is not metabolized in the liver and does not affect liver metabolic enzymes (Krishnan & Montcrief, 2007a). DEX is partially metabolized in the liver, and DEX and its metabolites are excreted through the kidneys. Therefore, the use of LDX in patients with impaired liver or kidney function should be monitored closely. Potential drug-drug interactions involving LDX will be similar to those expected for DEX. Although LDX has not been specifically studied in adolescent patients (ages 13 to 17), the drug’s effectiveness should not be different than in children or adults. There are no specific data on the safety of LDX during pregnancy, but precautions are similar to those for other amphetamine products.
Clinical Implications and Conclusion
The unique characteristics of LDX have several potentially important clinical implications. Compared with oral DEX, dosage-related side effects may tend to plateau with higher LDX dosages. For the same reason, though, using high LDX dosages beyond the maximum recommended may have limited therapeutic benefits for most patients. In addition, deliberate ingestion of high LDX dosages (e.g., in a suicide attempt or to get “high”) may be less toxic (Krishnan & Montcrief, 2007b) and less likely to induce euphoria (Blick & Keating, 2007) compared with similar oral high-dosage DEX ingestions. Intravenous or intranasal abuse may be less likely with LDX than with DEX. Substance abuse precautions still apply to LDX. Finally, there is a relatively longer and more predictable duration of action with LDX compared with short-acting amphetamine products (Dextrostat®, Dexedrine®, Adderall®), as well as decreased variability of LDX-released DEX serum concentrations compared with long-acting amphetamine products (Dexedrine Spansules®, Adderall XR®) (Findling, 2008).
Nurses should understand the unique pharmacology of LDX that distinguishes it from other amphetamine products. Although its efficacy is not significantly different from that of other stimulants, LDX may be different with respect to potential toxicity and abuse liability.
- Adler, L, Goodman, DW, Kollins, SH, Weisler, R, Krishnan, S & Zhang, Y et al. 2008, May. Efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder. Abstract presented at the 161st annual meeting of the American Psychiatric Association. , Washington, DC. .
- Biederman, J, Boellner, SW, Childress, A, Lopez, FA, Krishnan, S & Zhang, Y2007. Lisdexamfetamine dimesylate and mixed amphetamine salts extended-release in children with ADHD: A double-blind placebo-controlled crossover analog classroom study. Biological Psychiatry, 62, 970–976. doi:10.1016/j.biopsych.2007.04.015 [CrossRef]
- Biederman, J, Krishnan, S, Zhang, Y, McGough, JJ & Findling, RL2007. Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with attention-deficit/hyperactivity disorder: A phase III multicenter randomized double-blind forced-dose parallel-group study. Clinical Therapeutics, 29, 450–463. doi:10.1016/S0149-2918(07)80083-X [CrossRef]
- Blick, SK & Keating, GM2007. Lisdexamfetamine. Paediatric Drugs, 9, 129–135. doi:10.2165/00148581-200709020-00007 [CrossRef]
- Findling, RL2008. Evolution of the treatment of attention-deficit/hyperactivity disorder in children: A review. Clinical Therapeutics, 30, 942–957. doi:10.1016/j.clinthera.2008.05.006 [CrossRef]
- Goodman, DW2007. Lisdexamfetamine dimesylate: The first prodrug stimulant. Psychiatry, 4. Retrieved July 9, 2008, from http://www.psychiatrymmc.com/lisdexamfetamine-dimesylate-the-first-prodrug-stimulant/
- Hardman, JG, Limbird, LE, Molinoff, PB, Ruddon, RW & Gilman, AG (Eds.). 1996. Goodman & Gilman’s the pharmacological basis of therapeutics (9th ed.). New York: McGraw-Hill.
- Krishnan, S & Montcrief, S2007a. An evaluation of the cytochrome P450 inhibition potential of lisdexamfetamine in human liver microsomes. Drug Metabolism and Disposition, 351, 180–184. doi:10.1124/dmd.106.011973 [CrossRef]
- Krishnan, S & Montcrief, S2007b. Toxicity profile of lisdexamfetamine dimesylate in three independent rat toxicology studies. Basic & Clinical Pharmacology & Toxicology, 101, 231–240. doi:10.1111/j.1742-7843.2007.00093.x [CrossRef]
- Krishnan, S & Zhang, Y2008. Relative bioavailability of lisdexamfetamine 70-mg capsules in fasted and fed healthy adult volunteers and in solution: A single-dose crossover pharmacokinetic study. Journal of Clinical Pharmacology, 48, 293–302. doi:10.1177/0091270007310381 [CrossRef]
- Krishnan, SM & Stark, JG2008. Multiple daily-dose pharmacokinetics of lisdexamfetamine dimesylate in healthy adult volunteers. Current Medical Research and Opinions, 24, 33–40. doi:10.1185/030079907X242737 [CrossRef]