Ocular Gene Therapy in a Patient with Dystrophic Epidermolysis Bullosa.

Dystrophic epidermolysis bullosa is a rare genetic disease caused by damaging variants in COL7A1, which encodes type VII collagen. Blistering and scarring of the ocular surface develop, potentially leading to blindness. Beremagene geperpavec (B-VEC) is a replication-deficient herpes simplex virus type 1-based gene therapy engineered to deliver functional human type VII collagen. Here, we report the case of a patient with cicatrizing conjunctivitis in both eyes caused by dystrophic epidermolysis bullosa who received ophthalmic administration of B-VEC, which was associated with improved visual acuity after surgery.

Trial of Beremagene Geperpavec (B-VEC) for Dystrophic Epidermolysis Bullosa.

BACKGROUND: Dystrophic epidermolysis bullosa is a rare genetic blistering skin disease caused by mutations in COL7A1, which encodes type VII collagen (C7). Beremagene geperpavec (B-VEC) is a topical investigational herpes simplex virus type 1 (HSV-1)-based gene therapy designed to restore C7 protein by delivering COL7A1. METHODS: We conducted a phase 3, double-blind, intrapatient randomized, placebo-controlled trial involving patients 6 months of age or older with genetically confirmed dystrophic epidermolysis bullosa. For each patient, a primary wound pair was selected, with the wounds matched according to size, region, and appearance. The wounds within each pair were randomly assigned in a 1:1 ratio to receive weekly application of either B-VEC or placebo for 26 weeks. The primary end point was complete wound healing of treated as compared with untreated wounds at 6 months. Secondary end points included complete wound healing at 3 months and the change from baseline to weeks 22, 24, and 26 in pain severity during changes in wound dressing, assessed with the use of a visual analogue scale (scores range from 0 to 10, with higher scores indicating greater pain). RESULTS: Primary wound pairs were exposed to B-VEC and placebo in 31 patients. At 6 months, complete wound healing occurred in 67% of the wounds exposed to B-VEC as compared with 22% of those exposed to placebo (difference, 46 percentage points; 95% confidence interval [CI], 24 to 68; P = 0.002). Complete wound healing at 3 months occurred in 71% of the wounds exposed to B-VEC as compared with 20% of those exposed to placebo (difference, 51 percentage points; 95% CI, 29 to 73; P<0.001). The mean change from baseline to week 22 in pain severity during wound-dressing changes was -0.88 with B-VEC and -0.71 with placebo (adjusted least-squares mean difference, -0.61; 95% CI, -1.10 to -0.13); similar mean changes were observed at weeks 24 and 26. Adverse events with B-VEC and placebo included pruritus and chills. CONCLUSIONS: Complete wound healing at 3 and 6 months in patients with dystrophic epidermolysis bullosa was more likely with topical administration of B-VEC than with placebo. Pruritus and mild systemic side effects were observed in patients treated with B-VEC. Longer and larger trials are warranted to determine the durability and side effects of B-VEC for this disease. (Funded by Krystal Biotech; GEM-3 ClinicalTrials.gov number, NCT04491604.).

In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a phase 1 and 2 trial.

Recessive dystrophic epidermolysis bullosa (RDEB) is a lifelong genodermatosis associated with blistering, wounding, and scarring caused by mutations in COL7A1, the gene encoding the anchoring fibril component, collagen VII (C7). Here, we evaluated beremagene geperpavec (B-VEC), an engineered, non-replicating COL7A1 containing herpes simplex virus type 1 (HSV-1) vector, to treat RDEB skin. B-VEC restored C7 expression in RDEB keratinocytes, fibroblasts, RDEB mice and human RDEB xenografts. Subsequently, a randomized, placebo-controlled, phase 1 and 2 clinical trial (NCT03536143) evaluated matched wounds from nine RDEB patients receiving topical B-VEC or placebo repeatedly over 12 weeks. No grade 2 or above B-VEC-related adverse events or vector shedding or tissue-bound skin immunoreactants were noted. HSV-1 and C7 antibodies sometimes presented at baseline or increased after B-VEC treatment without an apparent impact on safety or efficacy. Primary and secondary objectives of C7 expression, anchoring fibril assembly, wound surface area reduction, duration of wound closure, and time to wound closure following B-VEC treatment were met. A patient-reported pain-severity secondary outcome was not assessed given the small proportion of wounds treated. A global assessment secondary endpoint was not pursued due to redundancy with regard to other endpoints. These studies show that B-VEC is an easily administered, safely tolerated, topical molecular corrective therapy promoting wound healing in patients with RDEB.

Preclinical Evaluation of a Modified Herpes Simplex Virus Type 1 Vector Encoding Human TGM1 for the Treatment of Autosomal Recessive Congenital Ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) is a diverse group of cornification diseases associated with severe clinical complications and decreased quality of life. Germline mutations in the TGM1 gene, which encodes the enzyme TGM1, are the predominant cause of ARCI. These TGM1 mutations trigger the abnormal epidermal differentiation and impaired cutaneous barrier function observed in patients with ARCI. Unfortunately, current ARCI therapies focus solely on symptomatic relief. Thus, there is a significant unmet need for therapeutic strategies aimed at correcting the TGM1 deficiency underlying ARCI. In this study, we investigated the ability of KB105, a gene therapy vector encoding full-length human TGM1, to deliver functional human TGM1 to keratinocytes. In vitro, KB105 efficiently infected TGM1-deficient human keratinocytes, produced TGM1 protein, and rescued transglutaminase enzyme function. In vivo studies demonstrated that both single and repeated topical KB105 administration induced TGM1 protein expression in the target epidermal layer without triggering fibrosis, necrosis, or acute inflammation. Toxicity and biodistribution assessments on repeat dosing indicated that KB105 was well-tolerated and restricted to the dose site. Overall, our results demonstrate that rescuing TGM1 deficiency in patients with ARCI through topical KB105 application represents a promising strategy for safely and noninvasively treating this debilitating disease.

Thrombospondin-1 Is a Major Activator of TGF-ß Signaling in Recessive Dystrophic Epidermolysis Bullosa Fibroblasts.

Mutations in the gene encoding collagen VII cause the devastating blistering disease recessive dystrophic epidermolysis bullosa (RDEB). RDEB is characterized by severe skin fragility and nonhealing wounds aggravated by scarring and fibrosis. We previously showed that TSP1 is increased in RDEB fibroblasts. Because transforming growth factor-ß (TGF-ß) signaling is also increased in RDEB, and TSP1 is known to activate TGF-ß, we investigated the role of TSP1 in TGF-ß signaling in RDEB patient cells. Knockdown of TSP1 reduced phosphorylation of smad3 (a downstream target of TGF-ß signaling) in RDEB primary fibroblasts, whereas overexpression of collagen VII reduced phosphorylation of smad3. Furthermore, inhibition of TSP1 binding to the LAP/TGF-ß complex decreased fibrosis in engineered extracellular matrix formed by RDEB fibroblasts, as evaluated by picrosirius red staining and analyses of birefringent collagen fibrillar deposits. We show that collagen VII binds TSP1, which could potentially limit TSP1-LAP association and subsequent TGF-ß activation. Our study suggests a previously unreported mechanism for increased TGF-ß signaling in the absence of collagen VII in RDEB patient skin. Moreover, these data identify TSP1 as a possible target for reducing fibrosis in the tumor-promoting dermal microenvironment of RDEB patients.

Pharmacokinetics of lisdexamfetamine dimesylate and its active metabolite, d-amphetamine, with increasing oral doses of lisdexamfetamine dimesylate in children with attention-deficit/hyperactivity disorder: a single-dose, randomized, open-label, crossover study.

BACKGROUND: Lisdexamfetamine dimesylate (LDX) is a long-acting oral prodrug stimulant indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children 6 to 12 years old and in adults. Information on the pharmacokinetic profile of LDX in children with ADHD is lacking. OBJECTIVE: The aim of this study was to assess the pharmacokinetic properties of d-amphetamine delivery from LDX, and intact LDX with increasing doses of LDX administered in children with ADHD. METHODS: This single-dose, randomized, open-label, 3-period crossover study was conducted in children aged 6 to 12 years with ADHD symptoms that adversely affected school performance and required a medication switch. Eligible patients had prior stimulant experience, with good tolerability. Patients were administered a single oral dose of LDX 30, 50, or 70 mg in a randomized sequence. Each study period was separated by a 6-day washout. The pharmacokinetic properties of d-amphetamine and intact LDX were calculated over 48 hours. Adverse events (AEs) were assessed using physical examination, including vital sign measurements, and ECG. RESULTS: The study enrolled 18 children (mean [SD] age, 9.6 [1.9] years [range, 6-12 years]; 56% boys; weight, 36.0 [7.6] kg; 44% white, 44% black). Mean (%CV) C(max) values of d-amphetamine postdose were 53.2 (18.1), 93.3 (19.5), and 134.0 (19.4) ng/mL with LDX 30, 50, and 70 mg, respectively (T(max), approximately 3.5 hours). These findings suggest that the overall AUC for d-amphetamine was dose proportional. The intact LDX AUC was 10% to 20% higher in girls than in boys, and for d-amphetamine was <10% higher. The most commonly reported AEs, of 17 total cases, with 30-, 50-, and 70-mg LDX were anorexia (4 [22%], 7 [41%], and 8 [47%], respectively), elevated blood pressure (2 [11%], 1 [6%], and 3 [18%]), and abdominal pain (2 [11%], 2 [12%], and 2 [12%]). All AEs were mild or moderate. No serious AEs were reported. One child was withdrawn from the analysis because of pharyngitis considered to be unrelated to LDX use. CONCLUSION: The findings from this study in a small, select population of children with ADHD suggest that the concentrations of d-amphetamine, the active metabolite of LDX, after single-dose administration of LDX at increasing doses appeared to be dose proportional and had low interpatient variability.

Double-blind, placebo-controlled study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the efficacy and safety of 30, 50, and 70 mg/day lisdexamfetamine dimesylate compared with placebo in adults with attention-deficit/hyperactivity disorder (ADHD). METHOD: Following a 7- to 28-day washout, 420 adults aged 18 to 55 years with moderate to severe ADHD (DSM-IV-TR criteria) were treated with 30, 50, or 70 mg/day lisdexamfetamine or placebo, respectively, for 4 weeks (N = 119, 117, 122, and 62, respectively). The 50- and 70- mg/day groups underwent forced-dose titration. The primary efficacy measure was the clinician-determined ADHD Rating Scale (ADHD-RS) total score. The study was conducted from May 2006 to November 2006. RESULTS: Treatment groups were well matched at baseline, including in ADHD-RS scores. At endpoint, changes in ADHD-RS scores were significantly greater for each lisdexamfetamine dose than for placebo (placebo = -8.2, 30 mg/day lisdexamfetamine = -16.2, 50 mg/day lisdexamfetamine = -17.4, 70 mg/day lisdexamfetamine = -18.6; all p < .0001 vs. placebo), with no differences between doses. Significant differences relative to placebo were observed in each lisdexamfetamine group, beginning at week 1 and for each week throughout. The percentage of subjects who improved (Clinical Global Impressions-Improvement scale rating < or = 2) was significantly greater for each lisdexamfetamine dose than for placebo at each week and at endpoint (placebo = 29%, 30 mg/day lisdexamfetamine = 57%, 50 mg/day lisdexamfetamine = 62%, 70 mg/day lisdexamfetamine = 61%; all p < .01). Adverse events were generally mild and included dry mouth, decreased appetite, and insomnia. CONCLUSION: All 3 lisdexamfetamine doses were significantly more effective than placebo in the treatment of adults with ADHD, with improvements noted within 1 week. Lisdexamfetamine was generally well tolerated by these patients.

Metabolism, distribution and elimination of lisdexamfetamine dimesylate: open-label, single-centre, phase I study in healthy adult volunteers.

BACKGROUND AND OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) in children often persists into adulthood and is potentially associated with significant social and occupational impairments. It is important to understand the effects of pharmacological treatments of ADHD in adults. This study aimed to assess the absorption, metabolism and elimination of lisdexamfetamine dimesylate in normal, healthy adult subjects following a single oral dose. A secondary objective was to assess the safety and tolerability of treatment. METHODS: In an open-label, single-centre study, six healthy adult volunteers aged 22-52 years received a single oral 70 mg dose of (14)C-radiolabelled lisdexamfetamine dimesylate in solution following a 10-hour fast. Blood samples drawn pre-dose and at time points up to 120 hours post-dose were used for plasma pharmacokinetic analysis of the active d-amphetamine and the intact parent compound lisdexamfetamine dimesylate. Recovery of radioactivity was determined by liquid scintillation counting of blood samples (whole blood and plasma), urine samples and faecal samples collected pre-dose and at designated time points up to 120 hours post-dose. Urine samples were also analysed for the presence of amphetamine-derived metabolites. Safety was assessed by adverse event reporting, changes in physical findings, vital sign measurements, ECG measurements, and clinical laboratory test results. RESULTS: For intact lisdexamfetamine dimesylate, the median time to reach maximum plasma drug concentration (t(max)) was 1.00 hour, and the mean maximum plasma drug concentration (C(max)) was 58.2 +/- 28.1 ng/mL. Intact lisdexamfetamine dimesylate exhibited modest systemic exposure (area under the drug concentration-time curve from time 0 to infinity [AUC(infinity)] 67.04 +/- 18.94 ng . h/mL), and rapid elimination (mean apparent terminal elimination half-life [t((1/2)beta)] 0.47 hours). For d-amphetamine, the median t(max) was 3.00 hours, and the mean C(max) was 80.3 +/- 11.8 ng/mL. The AUC(infinity) of d-amphetamine was 1342 +/- 216.9 ng . h/mL, and elimination occurred as a first-order process. The t((1/2)beta) of d-amphetamine was 10.39 hours. Peaks consistent with amphetamine and hippuric acid were identified in urine samples by high-performance liquid chromatography radioactive profiling. Relative to dose administered, 41.5% was recovered in urine as d-amphetamine, 24.8% as hippuric acid and 2.2% as intact lisdexamfetamine dimesylate. Less than 0.3% of the administered dose was recovered in the faeces. During the 0- to 48-hour urine samples, no unexpected adverse events or clinically significant laboratory, ECG or physical examination findings related to the study medication were observed. CONCLUSIONS: Following a single 70 mg oral dose, lisdexamfetamine dimesylate was quickly absorbed, extensively metabolized to d-amphetamine and its derivatives, and rapidly eliminated. Systemic exposure to d-amphetamine was approximately 20-fold higher than systemic exposure to intact lisdexamfetamine dimesylate in healthy adults. Lisdexamfetamine dimesylate, administered as a single 70 mg dose, was generally well tolerated in this study.

Long-term effectiveness and safety of lisdexamfetamine dimesylate in school-aged children with attention-deficit/hyperactivity disorder.

INTRODUCTION: Lisdexamfetamine dimesylate (LDX), a prodrug stimulant, is indicated for attention-deficit/hyperactivity disorder (ADHD) in children 6-12 years of age and in adults. In short-term studies, once-daily LDX provided efficacy throughout the day. This study presented here was conducted to assess the long-term safety, tolerability, and effectiveness of LDX in 6- to 12-year-olds with ADHD. METHODS: This open-label, multicenter, single-arm study enrolled children with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision criteria for ADHD. Following 1-week screening and washout periods, subjects were titrated to LDX 30, 50, or 70 mg/day over 4 weeks and placed on maintenance treatment for 11 months. The ADHD Rating Scale and Clinical Global Impression-Improvement scale measured effectiveness. RESULTS: Of 272 subjects receiving LDX, 147 completed the study. Most adverse events were mild to moderate and occurred during the first 4 weeks. There were no clinically meaningful changes in blood pressure or electrocardiographic parameters. From baseline to endpoint, mean ADHD Rating Scale scores improved by 27.2 points (P<.0001). Improvements occurred during each of the first 4 weeks, and were maintained throughout. Based on Clinical Global Impression-Improvement scale scores, >80% of subjects at endpoint and >95% of completers at 12 months were rated "improved." CONCLUSION: Long-term 30, 50, and 70 mg/day LDX was generally well tolerated and effective in children with ADHD.

Relative bioavailability of lisdexamfetamine 70-mg capsules in fasted and fed healthy adult volunteers and in solution: a single-dose, crossover pharmacokinetic study.

The relative bioavailability of oral lisdexamfetamine dimesylate, a prodrug of d-amphetamine, and active d-amphetamine was assessed in an open-label, single-dose, 3-treatment, 3-period, randomized, crossover study in 18 healthy adult volunteers. Following a fast of at least 10 hours, subjects were administered an intact capsule of 70 mg lisdexamfetamine, a solution containing the capsule contents, or an intact capsule with a high-fat meal. Standard meals started 4 hours following lisdexamfetamine administration. Blood samples were taken predose (0 hours) and 0.5 to 72 hours postdose, and the concentrations of d-amphetamine and lisdexamfetamine were measured. AUC and C(max) for d-amphetamine were similar when lisdexamfetamine 70 mg was administered to healthy adults in the fed or fasted state. The AUC of intact lisdexamfetamine was similar when the latter was taken without food or in solution, but C(max) was lower when lisdexamfetamine was administered with food. The t(max) of d-amphetamine and intact lisdexamfetamine was similar when taken in solution or in the fasted state but was about 1 hour longer when taken with food. Adverse events were typical for amphetamine products. These findings indicate that food does not have a significant effect on d-amphetamine or lisdexamfetamine bioavailability in healthy adults and that lisdexamfetamine was well tolerated.

Multiple daily-dose pharmacokinetics of lisdexamfetamine dimesylate in healthy adult volunteers.

OBJECTIVE: To evaluate the pharmacokinetics of lisdexamfetamine dimesylate (LDX; Vyvanse) in fasting healthy adult volunteers. BACKGROUND: LDX is the first pro-drug stimulant and is indicated for the treatment of attention-deficit/hyperactivity disorder. LDX was developed with the goal of providing an extended effect that is consistent throughout the day, with a reduced potential for abuse, overdose toxicity, and drug tampering. METHODS: This was an open-label, multipledose phase 1 study. LDX 70 mg/d was administered in the morning to 12 subjects for 7 days. Twenty blood samples were drawn during the study. Descriptive statistics were used for pharmacokinetic parameters. RESULTS: Based on C(min), steady-state d-amphetamine concentration (20.6 ng/mL) was reached by day 5, whereas LDX was undetectable, and 95% of the d-amphetamine was eliminated within 48 hours following the final dose on day 7. At steady state, d-amphetamine achieved a mean +/- standard deviation C(max) of 90.1 +/- 29.6 ng/mL, with a median T(max) of 3.0 hours. The AUC(0-inf) for d-amphetamine was 1453 +/- 645.7 ng.h/mL. Complete elimination of the pro-drug occurred approximately 6 hours following the final dose on day 7. Adverse events were mild to moderate and similar to other oral amphetamines. CONCLUSIONS: This study describes the steady-state pharmacokinetics of LDX, a new pro-drug stimulant. Possible study limitations include an open-label design and a small sample size.

Toxicity profile of lisdexamfetamine dimesylate in three independent rat toxicology studies.

Lisdexamfetamine dimesylate (LDX) is a d-amphetamine prodrug developed for the treatment of attention-deficit/hyperactivity disorder. The toxicity profile of orally administered LDX has been evaluated in rats. In an acute study, LDX doses of 60 mg/kg and higher caused increased motor activity. At 1000 mg/kg, one rat died and another was euthanized. In a 7-day repeat-dose study, all rats dosed with LDX (14 per dose group for each sex) showed increased activity; 10 male rats and 11 female rats at 300 mg/kg/day and 3 female rats at 100 mg/kg/day were euthanized because of self-mutilation and 1 male rat at 300 mg/kg/day was found dead. In a 28-day study, only rats at 80 mg/kg showed signs of self-mutilation and thin body condition. In both the 7- and 28-day studies, LDX caused significant changes in some blood chemistry parameters (e.g. blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase) and organ weights (e.g. particularly heart, liver, brain, and spleen). Overall, no apparent treatment-related histopathologic changes were observed. Toxicokinetic assessments indicated that as the dose of LDX was increased, rats were exposed to increasing levels of LDX and d-amphetamine. The extent of exposure to LDX and d-amphetamine increased after repeated-dose in the 28-day study. The findings of the repeat-dose studies indicate that the toxicity profile in rats administered LDX orally is comparable to that for d-amphetamine; however, the apparent lethal dose of LDX in rats is more than five times higher than the LD(50) of orally administered d-amphetamine, supporting a putative protective effect of conjugating amphetamine with lysine.

Lisdexamfetamine dimesylate and mixed amphetamine salts extended-release in children with ADHD: a double-blind, placebo-controlled, crossover analog classroom study.

BACKGROUND: Lisdexamfetamine dimesylate is a therapeutically inactive prodrug in which d-amphetamine is covalently bound to l-lysine, a naturally occurring amino acid. Pharmacologically active d-amphetamine is released from lisdexamfetamine following oral ingestion. METHODS: This phase 2, randomized, double-blind, placebo- and active-controlled crossover study compared the efficacy and safety of lisdexamfetamine (LDX: 30, 50, or 70 mg) with placebo, with mixed amphetamine salts extended-release (MAS XR: 10, 20, or 30 mg) included as a reference arm of the study, in 52 children aged 6 to 12 years with attention-deficit/hyperactivity disorder (ADHD) in an analog classroom setting. The primary efficacy measure was the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale; secondary efficacy measures included the Permanent Product Measure of Performance (PERMP) Derived Measures, and the Clinical Global Impression (CGI) Scale. RESULTS: LDX treatment significantly improved scores on SKAMP-deportment, SKAMP-attention, PERMP-attempted, PERMP-correct, and CGI-improvement from baseline. Adverse events were similar for both active treatments. CONCLUSIONS: In a laboratory classroom environment, LDX significantly improved ADHD symptoms versus placebo in school-age children with ADHD.

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.

BACKGROUND: Lisdexamfetamme dimesylate (LDX) is a therapeutically inactive amphetamine prodrug. It was developed with the goal of providing an extended duration of effect that is consistent throughout the day, with a reduced potential for abuse, overdose toxicity, and drug tampering. Following ingestion, the pharmacologically active d-amphetamine molecule is gradually released by rate-limited hydrolysis. OBJECTIVES: The aims of this study were to assess the efficacy and tolerability of LDX in school-aged children with attention-deficit/hyperactivity disorder (ADHD) treated in the community, and to characterize the duration of action of LDX compared with placebo. METHODS: This Phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study was conducted at 40 centers across the United States. Male and female children aged 6 to 12 years with ADHD were randomly assigned to receive LDX 30, 50, or 70 mg with forced-dose titration, or placebo, PO QD for 4 weeks. Efficacy was assessed using the ADHD Rating Scale Version IV (ADHD-RS-IV), the Conners' Parent Rating Scale (CPR'), and the Clinical Global Impression of Improvement scale. Tolerability was assessed throughout the study. RESULTS: Of the 290 randomized patients (201 boys, 89 girls; mean [SD] age, 9 [1.8] years), 230 completed the trial (LDX 30 mg, n=56; LDX 50 mg, n=60; LDX 70 mg, n=60; and placebo, n=54). The most common reasons for study discontinuation (n=60) were lack of efficacy (LDX 30 mg, 1%; LDX 50 mg, 0%; LDX 70 mg, 1 %; and placebo, 17%) and adverse events (AEs) (LDX 30 mg, 9%; LDX 50 mg, 5%; LDX 70 mg, 14%; and placebo, 1%). Significant improvements in ADHD-RS-IV scores were seen with all doses of LDX compared with placebo (all, P<0.001), and in CPRS scores with all LDX doses versus placebo throughout the day (all, P<0.001 for all comparisons). Efficacy was observed by the first week of treatment, and improvements were observed throughout the day up to approximately 6 PM. The most frequently reported AEs among patients receiving LDX were typical of amphetamine products: decreased appetite (39% with active treatment vs 4% with placebo), insomnia (19% vs 3%), upper abdominal pain (12% vs 6%), headache (12% vs 10%), irritability (10% vs 0%), vomiting (9% vs 4%), weight decrease (9% vs 1%), and nausea (6% vs 3%); most were mild to moderate and occurred in the first week. CONCLUSION: In this population of children with ADHD, treatment once daily with the prodrug LDX at doses of 30 to 70 mg appeared to be effective and had a tolerability profile similar to those of currently marketed extended-release stimulants.

An evaluation of the cytochrome p450 inhibition potential of lisdexamfetamine in human liver microsomes.

The human cytochrome P450 (P450) system is implicated in many drug interactions. Lisdexamfetamine dimesylate (NRP104), the proposed generic name for a new agent under investigation for treatment of attention deficit hyperactivity disorder, was recently analyzed for inhibitory drug-drug interactions with seven major P450 isoforms using pooled human liver microsomes. Probe substrates were used near the K(m) concentration values reported in the literature for CYP1A2 (phenacetin), CYP2A6 (coumarin), CYP2B6 (bupropion), CYP2C9 (tolbutamide), CYP2C19 ([S]-mephenytoin), CYP2D6 (dextromethorphan), and CYP3A4 (midazolam and testosterone), and lisdexamfetamine was evaluated at concentrations ranging from 0.01 to 100 muM for its ability to inhibit the activity of these seven P450 isoforms. NADPH was added to one set of samples to initiate metabolic reactions, which were then terminated by adding organic solvent, vortexing the samples, and placing them on ice. The relevant substrates were then introduced to both sets of samples so that the percentage of remaining activity could be measured and compared. In addition, these samples were compared with other samples with the same concentrations of lisdexamfetamine but without preincubation. None of the seven P450 isoforms showed any concentration-dependent inhibition. Comparison of results from microsomes preincubated with and without NADPH showed no mechanism-based inhibition. Neither concentration-dependent nor mechanism-based inhibition caused by time-dependent inactivation of human P450 isoforms was shown for lisdexamfetamine during in vitro testing. The evidence suggests that lisdexamfetamine has a low potential for drug-drug interactions or initiation of drug-drug interactions.