Comparative Efficacy and Safety of Lisdexamfetamine Dimesylate ...

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DISCUSSION This study is the first to qualitatively assess two long-acting, amphetamine-based stimulants, LDX and MAS XR, in adults. Using groups derived from registration trials that were matched on baseline severity of ADHD symptoms, duration of treatment, and approximately comparable amphetamine doses, a post hoc matched-group assessment was conducted. In these clinical trials, LDX and MAS XR had similar TEAEs. Common TEAEs ≥10% in the present analysis of both studies included dry mouth, decreased appetite, insomnia, and headache. The common differences of the percent incidence of all active treatment doses minus placebo TEAEs in both trials were decreased appetite, insomnia, and dry mouth. These are consistent with TEAEs observed with other long-acting stimulants in adults. 39,40 Although most TEAEs in both clini- TABLE 5 MEAN (SD) SBP, DBP, AND PULSE AT BASELINE AND AT ENDPOINT* Vital Sign, mean (SD) LDX 50 mg/day (n=117) Comparative Efficacy and Safety of LDX and MAS XR in Adults With ADHD cal trials were mild or moderate in severity, the incidence of severe TEAEs was twice as low in LDX-treated subjects than in MAS XR-treated subjects. As expected for stimulant therapies, LDX and MAS XR were associated with weight loss over a 4-week treatment period. The degree of weight loss was lower in LDX treatment groups versus MAS XR treatment groups when assessing groups with approximately equivalent amounts of amphetamine base. Within each trial, the degree of weight loss appeared to demonstrate a dose response. Although LDX and MAS XR were associated with increases in BP parameters and pulse, such changes were modest and not clinically meaningful. Given that the doses of LDX and MAS XR included in the present analysis have approximately equivalent amounts of amphetamine base, the mechanisms underlying the observed differences in cardiovascular effects are unclear. Subgroup post hoc analysis results for vital signs (SBP, DBP, LDX Trial MAS XR Trial LDX 70 mg/day (n=122) Placebo (n=62) MAS XR 20 mg/day (n=41) MAS XR 40 mg/day (n=42) Placebo (n=45) SBP, mm Hg Baseline 118.3 (9.8) 115.5 (10.0) 116.4 (10.3) 121.3 (10.8) 117.4 (13.5) 117.4 (10.7) Endpoint 118 (10.0) 117.3 (10.2) 116.0 (10.8) 122.8 (12.3) 120.0 (13.0) 116.6 (10.7) DBP, mm Hg Baseline 74.8 (8.3) 73.6 (8.1) 74.1 (8.2) 77.6 (8.7) 74.9 (9.8) 76.8 (8.4) Endpoint 75.7 (8.2) 75.5 (8.5) 75.2 (8.2) 80.6 (9.5) 79.2 (7.6) 79.8 (8.5) Pulse, bpm Baseline 72.4 (8.9) 69.8 (9.2) 70.9 (9.6) 73.1 (9.5) 73.6 (9.1) 71.8 (8.9) Endpoint 76.0 (11.5) 75.6 (10.4) 70.9 (8.1) 77.1 (11.1) 79.6 (9.8) 72.2 (9.5) *Endpoint=last valid postbaseline measurement. SD=standard deviation; SBP=systolic blood pressure; DBP=diastolic blood pressure; LDX=lisdexamfetamine dimesylate; MAS XR=mixed amphetamine salts extended release; bpm=beats per minute. Lasser R, Dirks B, Adeyi B, Babcock T. Primary Psychiatry. Vol 17, No 9. 2010. TABLE 6 OUTLIER CRITERIA MET BY PARTICIPANTS AT ENDPOINT* Outlier Criteria LDX 50 mg/day (n=117) LDX Trial MAS XR Trial LDX 70 mg/day (n=122) Placebo (n=62) MAS XR 20 mg/day (n=41) MAS XR 40 mg/day (n=42) Placebo (n=45) SBP ≥150 mm Hg 0 0 0 2 1 0 DBP ≥95 mm Hg 0 0 0 1 0 1 Pulse ≥mean + 2 SD bpm 3 4 3 6 4 3 QT interval >480 msec 0 0 0 0 0 0 QTcF >480 msec 0 0 0 0 0 0 *Endpoint=last valid postbaseline assessment. LDX=lisdexamfetamine dimesylate; MAS XR=mixed amphetamine salts extended release; SBP=systolic blood pressure; DBP=diastolic blood pressure; SD=standard deviation; bpm=beats per minute; QTcF=QT interval corrected using Fridericia’s formula. Lasser R, Dirks B, Adeyi B, Babcock T. Primary Psychiatry. Vol 17, No 9. 2010. Primary Psychiatry 51 © MBL Communications Inc. September 2010
R. Lasser, B. Dirks, B. Adeyi, T. Babcock and pulse) from the LDX and MAS XR analysis were consistent with what has been observed in their respective studies; the mean (SD) change from baseline at endpoint for both LDX and MAS XR were consistent with their respective primary study (data not shown). Another possibility for the difference was that this post hoc analysis of the selected groups may introduce some bias. A difference between these agents is the absence of l-amphetamine from LDX and its presence in MAS XR (both d- and l- isoforms), which may play an essential role in this slight cardiovascular difference between treatments. 41-43 Studies comparing the cardiovascular effects of d- and l-amphetamine have not yielded clear answers; however, many sources suggest that l-amphetamine may have greater peripheral and cardiovascular effects and that d-amphetamine is more potent as a central stimulant. 41,44 In a small clinical trial in children with ADHD, Arnold and colleagues 44 found no significant differences in effects on BP and heart rate, but it was also assessed at the third week of treatment. Unlike changes in BP parameters, increases in pulse were very similar between equivalent (ie, similar total amphetamine base) doses of LDX and MAS XR with only minimally higher rates observed with MAS XR. In neither study did treatment result in clinically significant changes in QT interval. Both LDX and MAS XR were associated with significant reductions (versus placebo) in ADHD core symptoms as assessed by ADHD-RS-IV total scores. Significant improvements were also observed on clinician ratings of global improvement as assessed by CGI score. At approximately equivalent amphetamine doses, LDX resulted in numerically greater improvements in ADHD-RS-IV and CGI than MAS XR. The ADHD-RS-IV treatment effect size and CGI-I/CGI- C was larger for both LDX doses when compared qualitatively with approximately equivalent doses of MAS XR. The ADHD- RS-IV total score effect sizes suggest that both LDX doses demonstrated effect sizes that are considered large; effects sizes for MAS XR were medium. The CGI effect sizes for LDX were medium and large for both LDX doses (50 and 70 mg/day), respectively, and medium for both doses of MAS XR (20 and 40 mg/day). These differences in effect sizes may be due to the relative sample sizes of LDX groups that were almost twice as large as the MAS XR group as well as relative placebo responses across both studies. When comparing placebo-adjusted comparisons (eg, effect size) for each stimulant, the reader is reminded that the placebo cohort used for comparison differed in each study. While no direct comparisons of these placebo groups were performed, the placebo effect appears greater in the LDX trial. This was indicated by the greater decrease in ADHD-RS-IV total score change from baseline at endpoint for the placebo cohort in the LDX trial. Overall, a qualitative assessment would imply a slightly better improvement with LDX versus MAS XR when compared with placebo. The present analysis suggests that, at approximately comparable doses, LDX was more efficacious than MAS XR and had lower incidence of the differences (all active treatment doses [for either trial] minus placebo) in the percent of AEs and any percent differences of AEs versus MAS XR, although prospective and quantitative comparison studies are required to confirm these results. The results of this analysis are consistent with short-term controlled clinical trials evaluating the safety and efficacy of LDX and MAS XR in children and adolescents with ADHD that also demonstrated significant improvements versus placebo in both ADHD-RS-IV total score and CGI ratings. 28,45 Furthermore, although the present analysis used data from a pair of short-term trials, the effectiveness of both LDX and MAS XR for the treatment of ADHD in adults has been demonstrated in long-term trials. 46,47 Other considerations in terms of assessing potential differences between both treatment regimens should be noted. The mode of therapeutic action for amphetamines in the treatment of ADHD is thought to be due to the block of reuptake of norepinephrine and dopamine into the presynaptic neuron and their increased release into the extraneuronal space. LDX, the parent drug, does not bind to the sites responsible for the reuptake of the neurotransmitters. 48 Thus, although there are similarities between LDX and MAS XR, they are different in terms of mechanism of action (prodrug versus mechanical release) and their pharmacokinetic profiles (LDX has a more predictable pharmacokinetic profile). Although pharmacokinetic studies of MAS XR in adults indicated consistency in terms of bioavailability, 49-51 the prodrug mechanism of LDX may provide a more consistent pharmacokinetic profile. In a clinical trial in healthy adults, LDX demonstrated low inter- and intrasubject variability, offering consistent time to maximum d-amphetamine concentration. 52 With prodrug LDX administration, d-amphetamine plasma concentrations increased linearly and in a dose-dependent manner, with no indication of enzyme saturation in healthy adults and showed reliable delivery over a wide range of doses. 52 The prodrug mechanism requires intrinsic enzymatic cleavage of intact LDX to active d-amphetamine and is independent of exogenous formulation/drug-release delivery systems such as MAS XR. 53 Mechanically formulated delayed-release beads can be crushed, so they are more easily susceptible to abuse 9 ; enteric-coated beads can be affected by gastric pH, since they have a pH-sensitive, release-delaying polymer layer and overcoating. 54 Variations in pH did not affect the solubility profile of LDX, and increases in pH beyond this range only slightly reduced solubility. 55 Hence, the absorption of LDX versus MAS XR is not readily altered or converted by enzymes that simulated conditions of the gastrointestinal tract and is consistent with intact LDX absorption. 20 It has also been suggested that LDX is absorbed intact by active transport in the small intestine. 20 Although, changes in urinary pH alter the elimination of either drug, with urinary alkalinization decreasing excretion and acidification increasing excretion, 23,48 d-amphetamine is not available until after metabolism Primary Psychiatry 52 © MBL Communications Inc. September 2010
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