Open-Label Dose Optimization of Methylphenidate Extended-Release Orally Disintegrating Tablet in a Laboratory Classroom Study of Children with Attention-Deficit/Hyperactivity Disorder.

Objective: To examine the efficacy, safety, and tolerability of methylphenidate extended-release orally disintegrating tablets (MPH XR-ODT) for the treatment of attention-deficit/hyperactivity disorder (ADHD) during the open-label dose-optimization/stabilization period of a phase 3 laboratory classroom study. Methods: Children (6-12 years) diagnosed with ADHD were enrolled. Treatment was initiated with MPH XR-ODT 20 mg daily. Doses were adjusted weekly by 10-20 mg during the 4-week dose-optimization period (visits 2-5) until an optimal dose was reached. The optimal dose was sustained during a 1-week stabilization period (visits 6-7). Efficacy was assessed using the ADHD Rating Scale-IV (ADHD-RS-IV) score and the Clinical Global Impression-Improvement (CGI-I) score. Adverse events (AEs) were recorded throughout the study. A secondary subgroup analysis by baseline ADHD-RS-IV score, sex, age, and weight was also performed. Results: The mean (standard deviation [SD]) final optimized MPH XR-ODT daily dose was 41.8 (14.6) mg and ranged from 20 to 60 mg. Final optimized dose was higher for children with more severe baseline ADHD-RS-IV total scores. ADHD-RS-IV total scores decreased progressively during dose optimization, with a mean (SD) change from baseline at visit 7 of -21.4 (8.9). CGI-I scores shifted from "minimally improved" (mean [SD]: 3.1 [1.1]) at visit 3 to "much improved" (1.6 [0.6]) at visit 7. Baseline ADHD-RS-IV total score was highest for participants optimized to 40 mg (mean [standard error]: 40.0 [1.4]) and lowest for those optimized to 20 mg (34.8 [2.1]). By visit 6, mean ADHD-RS-IV score was comparable for all optimized dose groups. Common treatment-emergent AEs (≥5% of participants) included decreased appetite, upper abdominal pain, headaches, and insomnia. Conclusions: Dose optimization of MPH XR-ODT led to a reduction in ADHD symptoms, indicated by a decrease in ADHD-RS-IV and CGI-I scores. AEs were consistent with those of other MPH products. Clinical Trial Registry: NCT01835548 (ClinicalTrials.gov).

An Open-Label, Multicenter, Single-Dose Pharmacokinetic Study of a Novel Amphetamine Extended-Release Orally Disintegrating Tablet in Preschool-Aged Children.

Objective: In the U.S. ∼33% of children with attention-deficit/hyperactivity disorder (ADHD) are diagnosed during their preschool years (<6 years of age). The majority of these children are treated with a psychopharmacological treatment, despite limited data on pharmacokinetics (PKs), efficacy, or safety of these medications in this population. A phase 4, single-dose open-label study was conducted to assess the PK profile of amphetamine extended-release orally disintegrating tablets (AMP XR-ODT) under fasted conditions in preschool-aged children with ADHD. Methods: Preschool-aged children (aged 4 to <6 years) with a confirmed ADHD diagnosis were enrolled and administered AMP XR-ODT 3.1 mg under fasted conditions. Plasma samples were analyzed for d- and l-amphetamine (AMP) via liquid chromatography-tandem mass spectrometry. Area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-inf), area under the concentration-time curve from time 0 to the last measurable plasma concentration (AUC0-T), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), terminal half-life (t1/2), apparent volume of distribution (Vz/F), and apparent clearance (CL/F) for d- and l-AMP and safety were assessed. Results: The PK and safety analyses included 15 preschool-aged children (4 years old, n = 6; 5 years old, n = 9); 14 completed the study. Quantifiable plasma concentrations for d- and l-AMP were observed 1.5 hours postdose and throughout the 24-hour sampling period. For d- and l-AMP, mean AUC0-inf was 315.2 and 104.4 h·ng/mL, AUC0-T was 296.0 and 96.8 h·ng/mL, t1/2 was 8.0 and 9.2 hours, Cmax was 23.0 and 7.0 ng/mL, Tmax was 3.9 and 4.0 hours, CL/F was 6996.3 and 6837.1 mL/h, and Vz/F was 75,874.5 and 84,140.0 mL, respectively. Adverse events included tachycardia (n = 2), neutropenia (n = 1), increased alanine aminotransferase (n = 1), and aspartate aminotransferase (n = 1). Conclusions: AMP XR-ODT 3.1 mg was well tolerated in preschool-aged children, with detectable plasma AMP concentrations over 24 hours, and a PK profile consistent with once-daily dosing.

A Single-Dose, Two-Way Crossover, Open-Label Bioequivalence Study of an Amphetamine Extended-Release Oral Suspension in Healthy Adults.

Objective: The purpose of this study was to compare the pharmacokinetics of a new extended-release amphetamine oral suspension (AMP XR-OS) with a standard extended-release mixed amphetamine salts product, Adderall XR®. Method: In this single-dose, open-label, randomized, two-period, two-treatment crossover study, 42 healthy adult volunteers received 15 mL of AMP XR-OS in one period and a 30 mg Adderall XR capsule in another period (both containing 18.8 mg of amphetamine base) under fasted conditions. Blood samples were analyzed for d- and l-amphetamine concentrations, and pharmacokinetic parameters Cmax, AUC0-5, AUC5-last, and AUCinf were calculated to determine bioequivalence. Safety was monitored throughout the study. Results: The 90% confidence intervals (CIs) for the log-transformed Cmax, AUC0-5, AUC5-last, and AUCinf fell within the accepted 80% to 125% range for establishing bioequivalence for d- and l-amphetamine. The most common adverse events were nausea and decreased appetite. Conclusion: AMP XR-OS is bioequivalent to Adderall XR in healthy adult participants.

Population Pharmacokinetic-Pharmacodynamic Modeling of a Novel Methylphenidate Extended-Release Orally Disintegrating Tablet in Pediatric Patients With Attention-Deficit/Hyperactivity Disorder.

PURPOSE/BACKGROUND: A methylphenidate (MPH) extended-release orally disintegrating tablet (MPH XR-ODT) formulation was recently approved for attention-deficit/hyperactivity disorder treatment in children 6 to 17 years of age. This analysis sought to develop a population pharmacokinetic (PK)/pharmacodynamic (PD) model to describe MPH XR-ODT PD-response data in a classroom study and use the model to simulate PD responses for a range of body weights and doses. METHODS/PROCEDURES: The MPH XR-ODT PK/PD model was developed with pediatric and adult PK data from prior studies and efficacy data from a laboratory classroom study in children with attention-deficit/hyperactivity disorder. In these studies, the safety profile of MPH XR-ODT was consistent with other extended-release MPH formulations. The PK/PD model efficacy end point was the Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale Combined score. Body weight effects on MPH clearance and volume of distribution were included in the resulting model. Simulations using the PK/PD model were performed for patients with body weights between 7 and 100 kg and MPH XR-ODT doses of 10 to 60 mg MPH hydrochloride equivalents. FINDINGS/RESULTS: In the PK/PD model, the maximal reduction in the Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale Combined score was approximately 38 units, and the MPH concentration required to achieve 50% of the maximal reduction was 14.24 ng/mL, suggesting favorable efficacy for MPH XR-ODT. Simulations showed a direct correlation between the effective MPH XR-ODT dose and body weight, with heavier participants requiring higher doses for symptom control. IMPLICATIONS/CONCLUSION: This model may help facilitate the dose-titration process by identifying an effective MPH XR-ODT target dose.

Pharmacokinetics of a New Amphetamine Extended-Release Oral Suspension in Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: An extended-release amphetamine (AMP) oral suspension has been developed to facilitate medication ingestion and dose titration. This study sought to determine the pharmacokinetic (PK) profile of this new formulation in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: This was an open-label, single-period, PK study in 29 pediatric participants with ADHD. Participants were stratified into age groups 1 (6-7 years), 2 (8-9 years), and 3 (10-12 years), and dosed with 15 mL extended-release AMP liquid suspension (equivalent to 30 mg mixed AMP salts) after an overnight fast. Blood samples were collected at prespecified time points and analyzed for d- and l-AMP concentrations. Key PK parameters included maximum plasma concentration (Cmax), time to maximum plasma concentration, half-life (T1/2), area under the curve from time 0 to last quantifiable concentration (AUClast) and to infinity (AUCinf), oral clearance (CL/F), and volume of distribution (Vz/F). The 95% confidence intervals (CIs) about the geometric means of the weight-normalized CL/F, Vz/F, and AUClast were determined. Safety was also assessed. RESULTS: All participants completed the study. As age increased, mean maximum and total exposure to AMP decreased; weight-normalized CL/F slightly increased, resulting in decreasing T1/2 values with age. For d- and l-AMP, the 95% CIs for the geometric means of weight-normalized CL/F/kg and Vz/F/kg were within the 60%-140% range for groups 2 and 3, while those of weight-normalized AUClast were within range for all age groups. Adverse events were mild and consistent with the safety profile of AMP. CONCLUSIONS: Exposure (Cmax, AUCinf, and AUClast) to AMP decreased with age, possibly as a result of the 30-mg/15-mL fixed dose across a range of weights (20-57 kg) and the consequent lower dose per kilogram in older participants, as well as the slight increase in clearance with age.

Fed and Fasted Administration of a Novel Extended-Release Methylphenidate Orally Disintegrating Tablet Formulation for the Treatment of ADHD.

Extended-release methylphenidate is a first-line treatment for attention-deficit/hyperactivity disorder. A methylphenidate extended-release orally disintegrating tablet (MPH XR-ODT) has recently been developed. Here we report an open-label, randomized, 2-period, 2-treatment crossover study to determine the effect of food on the bioavailability of a single 60-mg dose of MPH XR-ODT in healthy adults. Blood samples were collected predose through 36 hours postdose. Maximum plasma concentration (Cmax ), time to maximum plasma concentration (Tmax ), terminal elimination half-life (T1/2 ), overall systemic exposure (AUClast and AUCinf ), and partial areas under the concentration curve (AUC0-3 , AUC3-7 , and AUC7-12 ) were calculated. In total, 48 participants completed the study. For total methylphenidate from MPH XR-ODT, the lower limit of the 90% confidence interval (CI) around the geometric mean ratio (GMR, fed/fasted) for Cmax was below 80%, indicating a slightly decreased rate of absorption with food, whereas the 90%CIs around the GMRs of AUClast and AUCinf were within the 80%-125% limits, suggesting no food effect on exposure. The most common adverse events (AEs) were palpitations and decreased appetite. No serious, unusual, or unexpected AEs were reported. Thus, food had no substantial effect on overall bioavailability of MPH XR-ODT, which may be an important factor for some patients.

A Comparison of the Pharmacokinetics of Methylphenidate Extended-Release Orally Disintegrating Tablets With a Reference Extended-Release Formulation of Methylphenidate in Healthy Adults.

Extended-release (ER) methylphenidate (MPH) is a first-line treatment for attention-deficit/hyperactivity disorder. A methylphenidate extended-release orally disintegrating tablet (MPH XR-ODT) has recently been developed. This was a randomized, open-label, 3-period, 3-treatment study comparing the bioavailability and absorption of 2 MPH XR-ODT formulations with an MPH ER reference medication. Here we report the 2 treatments comparing the commercial MPH XR-ODT formulation and reference medication. Following a ≥10-hour fast, 42 healthy adults received 60 mg of reference medication or MPH XR-ODT (2 × 30 mg). The following pharmacokinetic (PK) parameters were calculated for total methylphenidate (d + l): maximum plasma concentration (Cmax ), time to maximum plasma concentration (Tmax ), terminal half-life (T1/2 ), and areas under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast ), and from time zero extrapolated to infinity (AUCinf ). Secondary PK end points included partial AUCs. Safety was also assessed. Overall systemic exposure to methylphenidate after MPH XR-ODT administration was similar to that of the reference product, and the concentration-time profiles for MPH XR-ODT and the reference drug were similar, although the Cmax was 25% higher for MPH XR-ODT. The most common treatment-emergent adverse events were nausea (6) and anxiety (4), which were similar across treatments.

Pharmacokinetics of a New Amphetamine Extended-release Oral Liquid Suspension Under Fasted and Fed Conditions in Healthy Adults: A Randomized, Open-label, Single-dose, 3-treatment Study.

PURPOSE: A new amphetamine extended-release liquid formulation (AMP XR-OS), intended for the treatment of attention-deficit/hyperactivity disorder, has been developed. This study was performed to determine if administration with food affected the rate of absorption or bioavailability of AMP XR-OS. The formulation was also compared with an equivalent dose of an extended-release mixed amphetamine salts reference product (30 mg) under fed conditions. METHODS: Thirty adult volunteers participated in this single-dose, open-label, randomized, 3-period, 3-treatment crossover study. Each participant received a single 15-mL dose of AMP XR-OS (equivalent to 30 mg of the reference drug) under fasted conditions, a single 15-mL dose of AMP XR-OS under fed conditions, and a single dose of the reference drug under fed conditions. A 7-day washout separated the 3 treatment periods. Blood samples were collected at predetermined time points and analyzed for d- and l-amphetamine. Pharmacokinetic parameters reported are AUC0-5, AUC0-last, AUC5-last, and AUC0-∞; Cmax; elimination t1/2; and Tmax. The geometric mean ratios and 90% CIs of Cmax, AUC0-last, and AUC0-∞were determined for the comparison of AMP XR-OS fed and fasted, and Cmax, AUC0-5, AUC5-last, and AUC0-∞ were calculated for AMP XR-OS compared with the reference drug under fed conditions. Safety was also assessed. FINDINGS: Twenty-nine subjects completed the study. Subjects were mostly male, white, and of Hispanic/Latino ethnicity with a mean age of 35.83 years and a mean BMI of 25.36kg/m2. The 90% CIs of Cmax, AUC0-last, and AUC0-∞ for AMP XR-OS fasted versus fed were within the accepted 80% to 125% range, indicating lack of a food effect. In the comparison of AMP XR-OS fed versus the reference product, Cmax, AUC5-last, and AUC0-∞ were within the range to establish bioequivalence; however, AUC0-5 was significantly higher for AMP XR-OS compared with that of the reference drug. This difference between products was likely due to the known delay of Tmax and decreased exposure when the extended-release mixed amphetamine salts reference product is administered with food. A total of 36 mild or moderate adverse events were reported; 1 subject withdrew due to an adverse event, and no deaths occurred. These adverse events were consistent with the known pharmacodynamic effects of amphetamine. IMPLICATIONS: The absence of a food effect may allow for AMP XR-OS to be administered with or without a meal.

A Randomized Phase I Study to Assess the Effect of Alcohol on the Pharmacokinetics of an Extended-release Orally Disintegrating Tablet Formulation of Amphetamine in Healthy Adults.

PURPOSE: There is a strong association between attention-deficit/hyperactivity disorder (ADHD) and alcohol abuse, yet no studies have systematically assessed the effect of alcohol on the pharmacokinetics of psychostimulants such as amphetamine (AMP) in vivo. This study evaluated the effects of alcohol on the rate and extent of absorption of Adzenys™ XR-ODT*, a new extended-release orally disintegrating AMP tablet (AMP XR-ODT) for ADHD. METHODS: A Phase I single-dose, open-label study was conducted in 32 healthy adults. Participants were split into 2 cohorts, allowing for close monitoring of safety profile and tolerability, and were randomized 1:1:1:1 to receive treatment in 1 of 4 sequences. Each treatment included the administration of a single 18.8-mg dose of AMP XR-ODT, followed by 240 mL of deionized water or 4%, 20%, or 40% ethanol. Blood samples were collected at prespecified time points. The pharmacokinetic profiles of d- and l-AMP were comparable across treatment groups. FINDINGS: There was no change in the extent of absorption for d- or l-AMP with alcohol coingestion and no dose dumping of the extended-release portion of the formulation. The 90% CIs for the geometric mean ratios (4%, 20%, and 40% ethanol versus water) for Cmax and systemic exposure (AUC0-5, AUClast, and AUC0-∞) were within 80% to 125%. Adverse events were mild to moderate and were consistent with the known adverse event profile for AMP XR-ODT or alcohol. IMPLICATIONS: Varying concentrations of alcohol (4%-40%) did not significantly alter the pharmacokinetic profile of AMP XR-ODT. These findings are relevant to clinicians who have concerns about alcohol use and/or abuse when treating ADHD.

Pharmacokinetics of a Novel Amphetamine Extended-Release Orally Disintegrating Tablet in Children with Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: A novel formulation for treating attention-deficit/hyperactivity disorder (ADHD) has recently been developed-amphetamine extended-release orally disintegrating tablets (AMP XR-ODTs). In this study, we assessed the rate of absorption and exposure of AMP XR-ODT under fasted conditions in children with ADHD. METHODS: Children (6-12 years) with ADHD were enrolled in a single-dose, open-label, single-period pharmacokinetic (PK) study. Patients were stratified by age (6-7, 8-9, and 10-12 year olds) and were dosed with 18.8-mg AMP XR-ODT under fasted conditions. Plasma samples were analyzed for d-and l-amphetamine. Maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the concentration-time curve from time zero-infinity (AUCinf), weight-normalized clearance (CL/F), and weight-normalized volume of distribution (Vz/F) were assessed. The geometric mean and 95% confidence intervals (CIs) were calculated for weight-normalized CL/F and Vz/F in each age group to determine if the 95% CIs were within the target range of 60%-140%. RESULTS: A total of 28 children completed the study. The 95% CIs for the geometric mean CL/F/kg and Vz/F/kg for both d- and l-amphetamine fell within the target range of 60%-140% for each age group, thus meeting the primary end point. Four participants experienced treatment-related adverse events, including vomiting (n = 3), abdominal pain (n = 2), dry mouth (n = 1), and insomnia (n = 1). CONCLUSIONS: AMP XR-ODT, a novel formulation that does not require swallowing an intact tablet or capsule, was well tolerated and demonstrated a PK profile consistent with once-daily dosing in children with ADHD.

Efficacy, Safety, and Tolerability of an Extended-Release Orally Disintegrating Methylphenidate Tablet in Children 6-12 Years of Age with Attention-Deficit/Hyperactivity Disorder in the Laboratory Classroom Setting.

OBJECTIVE: Methylphenidate extended-release orally disintegrating tablets (MPH XR-ODTs) represent a new technology for MPH delivery. ODTs disintegrate in the mouth without water and provide a pharmacokinetic profile that is consistent with once-daily dosing. This study sought to determine the efficacy, safety, and tolerability of this novel MPH XR-ODT formulation in school-age children with attention-deficit/hyperactivity disorder (ADHD) in a laboratory classroom setting. METHODS: Children aged 6-12 years with ADHD (n = 87) were enrolled in this randomized, multicenter, double-blind, placebo-controlled, parallel, laboratory classroom study. The MPH XR-ODT dose was titrated to an optimized dose during a 4-week open-label period and maintained on that dose for 1 week. Participants (n = 85) were then randomized to receive their optimized dose of MPH XR-ODT or placebo once daily for 1 week (double blind), culminating in a laboratory classroom testing day. Efficacy was evaluated using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Attention, Deportment, and Combined scores along with Permanent Product Measure of Performance (PERMP; Attempted and Correct) assessments. Onset and duration of drug action were also evaluated as key secondary endpoints. Safety assessments included adverse events (AEs), physical examinations, electrocardiograms (ECGs), and the Columbia Suicide Severity Rating Scale (C-SSRS). RESULTS: The average SKAMP-Combined score on the classroom study day was significantly better for the MPH XR-ODT group (n = 43) than for the placebo group (n = 39; p < 0.0001). The effect was evident at 1 hour and lasted through 12 hours postdose. The average SKAMP-Attention, SKAMP-Deportment, PERMP-A, and PERMP-C scores were indicative of significantly greater ADHD symptom control for the MPH XR-ODT group. The most common AEs reported were decreased appetite, upper abdominal pain, headache, insomnia, upper respiratory tract infection, affect lability, irritability, cough, and vomiting. CONCLUSIONS: MPH XR-ODT was effective and well tolerated for the treatment of children with ADHD in a laboratory classroom setting. Clinical Trial Registry: NCT01835548 ( ClinicalTrials.gov ).

A randomized crossover study to assess the pharmacokinetics of a novel amphetamine extended-release orally disintegrating tablet in healthy adults.

OBJECTIVES: In this pharmacokinetic (PK) study in healthy adults, we sought to: (1) compare the PK properties of a novel amphetamine extended-release orally disintegrating tablet formulation (Adzenys XR-ODT™ [AMP XR-ODT]) to a reference extended-release mixed amphetamine salts (MAS ER) formulation and (2) assess the effect of food on AMP XR-ODT. METHODS: Forty-two adults were enrolled in a single-dose, open-label, 3-period, 3-treatment, randomized crossover study and received an 18.8-mg dose of AMP XR-ODT (fasted or fed) or equivalent dose (30 mg) of MAS ER (fasted). Plasma samples were analyzed for d-and l-amphetamine. Maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), elimination half-life (T1/2), area under the concentration-time curve from time zero to last quantifiable concentration (AUClast), from time zero to infinity (AUCinf), relevant partial AUCs, and weight-normalized clearance (CL/F/kg) were assessed. The PK parameters were compared across treatments using an ANOVA. Safety was also assessed. RESULTS: A total of 39 adults completed this study. The geometric mean ratios (90% confidence interval [CI]) for AMP XR-ODT/MAS ER Cmax, AUC5-last, AUClast, and AUCinf were within 80%-125% for both d-and l-amphetamine. The 90% CIs for AUC0-5 were slightly below the 80%-125% range. When AMP XR-ODT was administered with food, there was a slight decrease in the d-and l-amphetamine Cmax and approximately a 2-hour delay in Tmax. The most common adverse events reported (>5% of participants) were dry mouth, palpitations, nausea, dizziness, headache, anxiety, and nasal congestion. CONCLUSIONS: AMP XR-ODT displayed a PK profile similar to MAS ER, and no clinically relevant food effect was observed.

A Single-Dose, Single-Period Pharmacokinetic Assessment of an Extended-Release Orally Disintegrating Tablet of Methylphenidate in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: To determine the pharmacokinetic (PK) profile of a proprietary formulation of methylphenidate (MPH) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) in a phase 1 study. Methylphenidate extended-release orally disintegrating tablets (MPH XR-ODTs) combine two technologies in a single-tablet formulation-an extended-release profile that was designed for once-daily dosing in an ODT that does not require water or chewing for ingestion. METHODS: This was a single-dose, open-label, single-period, single-treatment study, in which 32 children with ADHD who were receiving MPH in doses of 40 or 60 mg before beginning the study each received a 60-mg dose (2 × 30 mg) of MPH XR-ODT. The following plasma PK parameters of MPH were determined for participants grouped by age (6-7, 8-9, 10-12, and 13-17 years old): maximum concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (T½), area under the curve from 0 hours to infinity (AUCinf), oral clearance (CL/F), and volume of distribution in the terminal phase (Vz/F). Safety and tolerability were also assessed. RESULTS: A total of 32 participants received the study drug. For all participants, plasma concentration-time profiles of MPH exhibited a broad peak after administration of MPH XR-ODT through ∼8 hours, indicating extended release from the formulation, followed by an apparent first-order elimination phase. As age increased, MPH exposure decreased and mean estimates of CL/F increased; however, weight-normalized CL/F values were comparable across age groups. Similarly, mean estimates of Vz/F increased with age, but weight-normalization decreased differences across age groups, with the exception of the youngest age group, which had higher values. All adverse events (AEs) were mild. CONCLUSION: This XR-ODT formulation of MPH demonstrated weight-normalized clearance rates that were consistent across all age groups, a PK profile consistent with once-daily dosing, and an AE profile consistent with this class of medication in children and adolescents with ADHD.

Randomized, double-blind comparison of sertraline and placebo for posttraumatic stress disorder in a Department of Veterans Affairs setting.

OBJECTIVE: To evaluate the efficacy of sertraline in the treatment of posttraumatic stress disorder (PTSD) in a Veterans Affairs (VA) clinic setting involving patients with predominantly combat-related PTSD. METHOD: 169 outpatient subjects with a DSM-III-R diagnosis of PTSD and who scored 50 or higher on Part 2 of the Clinician-Administered PTSD Scale (CAPS-2) at the end of a 1-week placebo run-in period participated. Patients recruited from 10 VA medical centers were randomly assigned to 12 weeks of flexibly dosed sertraline (25-200 mg/day) (N = 86; 70% with combat-related PTSD; 79% male) or placebo (N = 83; 72% combat-related PTSD; 81% male) between May 1994 and September 1996. The primary efficacy measures were the mean change in CAPS-2 total severity score from baseline to endpoint, in the total score from the Impact of Event Scale, and in the Clinical Global Impressions-Severity of Illness and Improvement scales. RESULTS: There were no significant differences between sertraline and placebo on any of the primary or secondary efficacy measures at endpoint. In order to understand the results, gender, duration of illness, severity of illness, type of trauma, and history of alcohol/substance abuse were explored as potential moderators of outcome, but no consistent effects were uncovered. Sertraline was well tolerated, with 13% of patients discontinuing due to adverse events. CONCLUSION: Sertraline was not demonstrated to be efficacious in the treatment of PTSD in the VA clinic settings studied.

Efficacy of eletriptan in triptan-naïve patients: results of a combined analysis.

OBJECTIVE: To compare the efficacy and tolerability of eletriptan 20 mg, 40 mg, and 80 mg in triptan-naïve patients (who have not previously used triptans) versus triptan-experienced patients (who have previously used triptans). METHODS: Efficacy and tolerability data for eletriptan 20 mg, 40 mg, and 80 mg were pooled from 10 similarly designed, randomized, parallel-group studies, and triptan-naïve and triptan-experienced patients were compared with placebo across the 3 triptan doses. The primary efficacy endpoint was headache response at 2 hours postdose. Secondary efficacy endpoints were 2-hour pain-free response, 2-hour absence of associated symptoms, 2-hour functional response, 24-hour sustained headache response, and 24-hour sustained pain-free response. RESULTS: For eletriptan 20 mg, 40 mg, and 80 mg versus placebo, respectively, triptan-naïve patients showed significantly higher 2-hour headache response (54%, 61%, 66% vs. 31%; P < .0001), 2-hour pain-free response (20%, 28%, and 31% vs. 8%; P < .0001), and 24-hour sustained headache response (34%, 45%, and 51% vs. 20%; P < .0001). A similarly significant efficacy advantage was also observed in the triptan-experienced subgroup for 2-hour headache response (46%, 63%, 69% vs. 21%; P < .0001), 2-hour pain-free response (13%, 32%, and 38% vs. 4%; P < .0001), and 24-hour sustained headache response (29%, 41%, and 45% vs. 9%; P < .0001). Previous treatment status did not influence tolerability, and all 3 doses of eletriptan were well tolerated. CONCLUSIONS: These data suggest that eletriptan has comparable efficacy versus placebo among both triptan-naïve and triptan-experienced patients.

Comparative sensitivity of stopwatch methodology and conventional pain assessment measures for detecting early response to triptans in migraine: results of a randomized, open-label pilot study.

BACKGROUND: The standard measure of efficacy used in migraine trials is a 4-point patient-rated headache pain intensity (HPI) scale. However, it has been suggested that using a stopwatch to measure the time to meaningful pain relief can provide a more precise measurement of treatment response. OBJECTIVE: This study evaluated the sensitivity of a stopwatch method for detecting meaningful relief of headache pain and the correlation of this method with the HPI scale and a 5-point pain relief scale. METHODS: In this open-label, parallel-group pilot study, patients were randomized to receive oral eletriptan 40 mg, eletriptan 80 mg, or rizatriptan 10 mg for the treatment of a single acute migraine attack. The effect of study treatment on migraine pain was assessed immediately before dosing and at 0.5, 1, 1.5, 2, 3, and 4 hours after dosing. At each time point, patients recorded the 3 types of pain assessment in a patient diary. HPI was rated using the standard 4-point International Headache Society pain intensity scale (from 0 = no pain to 3 = severe pain). Pain relief was rated on a 5-point pain relief scale (from 4 = no relief to 0 = complete relief). The time to the onset of meaningful pain relief was measured using a stopwatch. At 4 hours after dosing, patients provided a global rating of the overall efficacy of study medication on a 5-point scale (from 0 = poor to 4 = excellent). RESULTS: Seventy-nine patients participated in the trial (78.5% female; mean [SD] age, 37.7 [9.8] years; 58.2% white). The median times to meaningful pain relief measured by stopwatch were 84, 72, and 93 minutes for eletriptan 40 mg, eletriptan 80 mg, and rizatriptan 10 mg, respectively (log-rank P = 0.029, eletriptan 80 mg vs rizatriptan 10 mg). At 90 minutes (approximating the median time to meaningful pain relief on the stopwatch), headache response rates using HPI scoring (mild to no pain) were 65%, 68%, and 52% in the respective treatment groups, with no significant difference between groups. On the pain relief scale, the corresponding mean (SD) scores at 90 minutes were 1.6 (1.2), 1.4 (1.3), and 2.0 (1.4) (P = NS). The pain relief-defined response (> or = 75% pain relief) at 90 minutes did not differ significantly between the 3 treatment groups (62%, 56%, and 48%). Detection of early improvement (0.5 and 1 hour) was similar with the HPI and pain relief scales. CONCLUSION: The results of this open-label pilot study suggest the convergent validity of 3 pain-assessment methods in migraine, but indicate that the use of a stopwatch may be a more sensitive method for detecting between-group differences.

Eletriptan in migraine patients reporting unsatisfactory response to rizatriptan.

OBJECTIVE: The objective of this open-label study was to evaluate the efficacy of switching patients who had a previous unsatisfactory response to rizatriptan to eletriptan 40 mg. Background.-The characteristics of individual migraine patients can vary tremendously and can have a significant impact on treatment outcomes. In addition, clinical experience has demonstrated that the triptans are not identical or interchangeable and that patients who respond poorly or who are dissatisfied with one agent can derive benefit by being switched to another agent within the triptan class. METHODS: Patients were eligible if they met International Headache Society criteria for migraine, with a frequency of 1 to 6 migraine attacks per month, and had documented "unsatisfactory treatment response" to rizatriptan within the past year (54% on the melt formulation; 46% on tablets). Reasons for dissatisfaction with rizatriptan (>1 could be cited) included inadequate (84%) or slow onset (50%) of pain relief, high recurrence rate (69%), and lack of improvement in associated symptoms (60%). One hundred twenty-three patients were eligible for treatment. Patients were instructed to take eletriptan 40 mg as soon as they were certain that their headache was a migraine, regardless of level of pain severity (8% treated headaches that were mild). RESULTS: Headache response at 2 hours (first-attack data) was 64%. Absence of nausea (from baseline to 2 hours) increased from 50% to 78%, absence of photophobia from 30% to 72%, and absence of phonophobia from 39% to 77%. Functional response at 2 hours was 63%, with 41% of patients reporting normal functioning. Treatment with eletriptan 40 mg was associated with a 27% to 40% reduction in migraine attack-related functional impairment, as measured by the PQ-7. Recurrence rates were 36.6%. Overall, 72% of patients rated eletriptan as a "good-to-excellent" treatment, and 78% reported overall satisfaction with the degree of headache relief. CONCLUSION: The results of this study suggest that eletriptan is an efficacious treatment option for patients who are dissatisfied with their response to rizatriptan.

In vivo disintegration profiles of encapsulated and nonencapsulated sumatriptan: gamma scintigraphy in healthy volunteers.

The goal of this exploratory pilot study was to use gamma scintigraphy to evaluate, under physiological conditions, disintegration profiles of encapsulated and nonencapsulated formulations of 100 mg sumatriptan. Using a crossover design, healthy volunteers (n = 10) ingested 100-mg doses of sumatriptan tablets radiolabeled with 111Indium, as well as encapsulated sumatriptan tablets that were prepared similarly, then placed within a gelatin capsule and backfilled with an excipient blend radiolabeled with 99mTechnetium. A gamma camera recorded scintigraphic images until 5 hours postdose. Initial disintegration of the gelatin capsule was observed at a mean (range) of 5 minutes (1-11 minutes); disintegration was complete within 14 minutes (5-24 minutes). For nonencapsulated versus encapsulated tablets, the mean (+/- standard deviation) time to initial disintegration (6 +/- 5 minutes vs 8 +/- 5 minutes) and time to complete disintegration (18 +/- 14 minutes vs 16 +/- 7 minutes) were comparable. Results of this study demonstrate that encapsulated and nonencapsulated sumatriptan have equivalent in vivo dissolution rates.

Severe vascular events in migraine patients.

OBJECTIVE: To estimate rates of vascular events in relation to dispensing of triptans and ergot alkaloids among migraineurs, and to compare these rates with those of nonmigraineurs. CONTEXT: It has been speculated that the use of triptans or ergot alkaloid drugs might increase risk of ischemic events through vasoconstriction. DESIGN: A retrospective cohort study of 130,411 migraineurs and 130,411 age-, sex-, and health plan-matched nonmigraineurs who were members of UnitedHealthcare during 1995 through 1999. The data source for this study was Ingenix's research database containing pharmacy and medical claims for UnitedHealthcare members, and the National Death Index. MAIN OUTCOME MEASURES: Incidence of cardiovascular and cerebrovascular events and mortality. RESULTS: Migraineurs and nonmigraineurs had identical rates of myocardial infarction: 1.4 per 1000 person-years. Migraineurs were 67% more likely to suffer a stroke than nonmigraineurs (adjusted relative risk [RR] 1.67, 95% confidence interval [CI] 1.31-2.13), and had higher rates of unstable angina and transient ischemic attacks. There was no increase in risk of myocardial infarction with current (adjusted RR 0.80, 95% CI 0.58-1.11) or recent (adjusted RR 1.15, 95% CI 0.71-1.87) triptan use. Neither current (adjusted RR 0.90, 95% CI 0.64-1.26) nor recent (adjusted RR 0.84, 95% CI 0.46-1.55) triptan use was associated with risk of stroke. Current users of ergot alkaloids were somewhat more likely to have a stroke than other migraineurs (adjusted RR 1.49, 95% CI 0.93-2.41), but there was no dose-response relationship. CONCLUSIONS: Use of triptans is not associated with increased risk of any ischemic events, including myocardial infarction and stroke, or mortality. Consistent with previous studies, migraineurs in general have an elevated risk of stroke, but not myocardial infarction, compared with nonmigraineurs.