scholarly journals Comparative Bioavailability of Amphetamine Extended-Release Oral Suspension and Extended-Release Mixed Amphetamine Salts

CNS Spectrums ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 163-163
Author(s):  
Antonio Pardo ◽  
Mohammed Bouhajib ◽  
Eman Rafla ◽  
Thomas R. King ◽  
Judith C. Kando
Keyword(s):  
Single Dose ◽  
Safety Assessment ◽  
Extended Release ◽  
Healthy Adult ◽  
Geometric Mean ◽  
Oral Suspension ◽  
Open Label ◽  
Post Dose ◽  
Comparative Bioavailability ◽  
The Mean

AbstractPurposeThis open-label, single-dose, randomized, two-period, two-treatment, two-sequence, crossover study evaluated the comparative bioavailability between amphetamine extended-release oral suspension (treatment A: AMPH EROS, Dyanavel XR 2.5 mg/mL, 18.8 mg amphetamine base per 7.5 mL) and extended-release mixed amphetamine salts (treatment B: ER MAS, Adderall XR 30 mg capsules, equivalent to 18.8 mg amphetamine base per capsule) after a single dose in healthy adult subjects, under fasted conditions.MethodsThe crossover design allowed for intra-subject PK comparisons. Relative comparable bioavailability was determined by a statistical comparison of the AUC and Cmax parameters for both d- and l-amphetamine, where the geometric mean ratios for AUC and Cmax were within the 90% confidence limits (80.0%–125.0%) to determine comparable bioavailability between test products. Subjects in sequence 1 received treatment A followed by B; subjects in sequence 2 received treatment B followed by treatment A. PK samples were obtained at 0 (pre-dose) through 60 hours post-dose. The safety assessment was based on reported frequency and severity of adverse events.ResultsThirty (30) subjects were enrolled and 28 completed. The mean age of subjects was 35 years, with a mean BMI of 25.9 kg/m2. Most subjects were Male (63.3%) and Black (56.7%). The geometric mean ratios for Cmax and all AUC measurements were within the 80–125% bound indicating comparable bioavailability between both test products. Both test products were generally well-tolerated with no serious AEs reported.ConclusionsThe bioavailability of a single 7.5 mL dose of AMPH EROS 2.5 mg/mL was comparable to a single 30 mg capsule dose of ER MAS. AMPH EROS (both d- and l-amphetamine) showed equivalent peak and overall exposure to ER MAS under fasted conditions.FundingTris Pharma, Inc.

scholarly journals 178 Single-Dose Pharmacokinetics of Amphetamine Extended-Release Tablet Compared with Amphetamine Extended-Release Oral Suspension

CNS Spectrums ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 312-313
Author(s):  
Barry K. Herman ◽  
Judith C. Kando ◽  
Thomas King ◽  
Antonio Pardo
Keyword(s):  
Single Dose ◽  
Extended Release ◽  
Food Effect ◽  
Geometric Mean ◽  
Oral Suspension ◽  
Post Dose ◽  
Comparative Bioavailability ◽  
Extended Release Tablet ◽  
Funding Acknowledgements ◽  
Release Tablet

Abstract:Objectives:Evaluate comparative bioavailability of single-dose amphetamine extended-release tablet (AMPH ER TAB, Tris Pharma, Inc., Monmouth Junction, NJ) 20 mg, swallowed whole or chewed and amphetamine extended-release oral suspension (AMPH EROS) 2.5 mg/mL; and evaluate whether a PK food effect exists on AMPH ER TAB (contains a 3.2:1 ratio of d- to l-amphetamine).METHODS:Healthy volunteers (18-55 yr) were randomized to 1 dose of AMPH ER TAB 20 mg swallowed (fasted), chewed (fed/fasted), or 20 mg AMPH EROS (fasted).A crossover design was used. Samples were collected each period pre-dose and at time points to 60 h post-dose. D-and l-amphetamine were measured, and PK was calculated (90% CIs of the ratios of the geometric mean plasma levels) for Cmax, AUCt, and AUC0∞. Comparative bioavailability was determined when ratios were within 80 and 125%. Safety was also assessed.RESULTS:32 subjects completed the study. Based on the calculated bioavailability ratios, for AMPH ER TAB swallowed vs. AMPH EROS fasted: d-amphetamine total and peak exposures were found to be similar: AUC0-t: 100.68-108.08%, AUC0-∞:101.47-109.52%, Cmax: 98.10-103.17%. For l-amphetamine, the total and peak exposures were similar: AUC0-t: 100.31-108.57%, AUC0-∞:101.27-111.09%, Cmax: 98.2-103.37%.AMPH ER TAB chewed vs. AMPH EROS fasted: For d-amphetamine, the total and peak exposures were similar: AUC0-t: 99.23-106.62%, AUC0-∞: 99.58-107.59%, Cmax: 99.91-105.14%. For l-amphetamine, the total and peak exposure was similar: AUC0-t: 98.16-106.35%, AUC0-∞: 98.44-108.11%, Cmax: 99.53-104.75%.Food effect: AMPH ER TAB, chewed, fasted vs. fed: For d-amphetamine, the total and peak exposure was similar: AUC0-t: 92.57-99.49%, AUC0-∞: 91.12-98.48%, Cmax: 94.22-99.17%.For l-amphetamine, the total and peak exposure was similar: AUC0-t: 91.27-98.91%, AUC0-∞: 88.44-97.17%, Cmax: 94.52-99.50%).No serious AEs were reported during the conduct of this study, and the AE profiles were observed to be similar in frequency of events and severity to other amphetamine formulations used in ADHD.CONCLUSIONS:Bioavailability of single dose of AMPH ER TAB for both d- and l-amphetamine was comparable, swallowed whole or chewed, to an equivalent 20 mg dose of the reference product AMPH EROS, 2.5 mg/mL fasted, and showed equivalent peak and overall exposure.No food effect was observed for AMPH ER TAB administered chewed. All AEs were mild in severity and AE profiles were similar to other amphetamine formulations used for treatment of ADHD.Funding Acknowledgements:Tris Pharma, Inc.

scholarly journals Single-Dose Pharmacokinetics of Amphetamine Extended-Release Oral Suspension (AMPH EROS) in 6–12-Year-Old Children with ADHD

CNS Spectrums ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 163-163
Author(s):  
Antonio Pardo ◽  
Ann C. Childress ◽  
Thomas R. King ◽  
Eman Rafla ◽  
Judith C. Kando
Keyword(s):  
Single Dose ◽  
Extended Release ◽  
Phase 1 ◽  
Study Cohort ◽  
Open Label ◽  
Post Dose ◽  
Entire Study ◽  
Elimination Half ◽  
Study Population ◽  
The Mean

AbstractMethodsThis Phase 1, open-label, single-dose, one-period, one-treatment PK study enrolled 12 children 6–12 y with ADHD. PK parameters for d- and l-amphetamine in plasma (Cmax, tmax, AUC0–8, and t1/2) were calculated and expressed as means, geometric means, and standard deviations. The primary endpoint was all objective PK measurements at 28 hours post-dose. PK was evaluated for 2 cohorts (6 pts ages 6–9 y and 6 pts aged 10–12 y). Safety was monitored continuously and assessed based on occurrence of adverse events.ResultsA single dose of 10 mg (4 ml) AMPH EROS (2.5 mg/ml) administered under fasted conditions resulted in a rapid rise in mean plasma concentration in d-amphetamine, reaching maximum concentrations within 5 hours. The overall study population mean (SD) plasma AUC0–8 (d-amphetamine) was 1061.2 (309) h*ng/mL, and for l-amphetamine was 380.5 (112) h*ng/mL. The mean maximum concentration (Cmax) for the overall study population was 54.91 ng/mL and 17.1 (5.2) ng/mL for d- and l-amphetamine, respectively. The overall study population median time to maximum concentrations (Tmax) for d-amphetamine were reached at 3.4 hours, and for l-amphetamine at 4.1 hours. The elimination half-life (t1/2) for the entire study cohort was 10.6 (2.0) hours for d-amphetamine, and 12.5 (3.2) hours for l-amphetamine. Directionally, a higher mean Cmax, AUC0–8, AUCt, and median Tmax were observed in the younger (6 to 9-year-old) age group, and this result was consistent with both the d- and l-amphetamine enantiomers. The mean elimination t1/2 for both d- and l-amphetamine was higher in the older cohort (10–12 years) than in the 6 to 12-year-olds. Study drug was well-tolerated by the subjects in this study. Two TEAEs were reported in one subject TEAEs (diarrhea and rash on legs) occurred approximately 12 hours postdose.ConclusionsThis study confirmed that the PK profile of AMPH EROS in 6 to 12-year-olds provided a consistent, predictable extended-release profile in a highly titratable liquid formulation, and this finding was relatively consistent and directionally predictable between the age groups assessed, with higher maximum concentrations and AUCs and shorter elimination half-lives noted in the younger population, with no anomalous parameters demonstrated, and no untoward or unexpected safety issues noted.FundingTris Pharma, Inc.

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

2017 ◽  
Vol 24 (3) ◽  
pp. 414-419 ◽  
Author(s):  
Carolyn Sikes ◽  
Jeffrey G. Stark ◽  
Russ McMahen ◽  
Dorothy Engelking
Keyword(s):  
Single Dose ◽  
Extended Release ◽  
Healthy Adult ◽  
Bioequivalence Study ◽  
Oral Suspension ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Adult Participants ◽  
Study Results ◽  
Adult Volunteers

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.

scholarly journals 1159. Pharmacokinetics, Safety, and Tolerability of Imipenem/Cilastatin/Relebactam in Pediatric Participants With Confirmed or Suspected Gram-negative Bacterial Infections: A Phase 1b, Open-label, Single-Dose Clinical Trial

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S671-S671
Author(s):  
John S Bradley ◽  
Nataliia Makieieva ◽  
Camilla Tøndel ◽  
Emmanuel Roilides ◽  
Matthew S Kelly ◽  
...  
Keyword(s):  
Single Dose ◽  
Plasma Concentration ◽  
Bacterial Infections ◽  
Geometric Mean ◽  
Complicated Urinary Tract Infection ◽  
Research Support ◽  
Open Label ◽  
Gram Negative ◽  
Age Cohorts ◽  
The Mean

Abstract Background Imipenem/cilastatin/relebactam (IMI/REL) is approved for treating hospital-acquired/ventilator-associated bacterial pneumonia, complicated urinary tract infection, and complicated intra-abdominal infection in adults. This study assessed single-dose pharmacokinetics (PK), safety, and tolerability of IMI/REL in neonatal and pediatric participants with confirmed or suspected gram-negative bacterial infections. Methods This was a phase 1, open-label, non-comparative study (NCT03230916). Age- and weight-adjusted dosing is summarized in Table 1. The primary objective was to characterize the PK profiles for imipenem and relebactam after a single intravenous dose of IMI/REL. PK parameters were analyzed using population modeling. The PK target for imipenem was the percent time of the dosing interval that the unbound plasma concentration exceeded the minimum inhibitory concentration (%fT >MIC) of ≥30% (MIC used, 2 µg/mL). The PK target for relebactam was an area under the curve (AUC)/MIC ratio >8 (MIC used, 2 µg/mL), corresponding to AUC0-24h >58.88 μM∙h. Safety and tolerability were assessed for up to 14 days after drug infusion. Results Of the 46 participants who received IMI/REL, 42 were included in the PK analysis. The mean plasma concentration-time profiles for imipenem and relebactam were generally comparable across age cohorts (Figure). For imipenem, the geometric mean %ƒT >MIC ranged from 50% to 94% and the mean maximum concentration (Cmax) ranged from 65 μM to 126 μM (Table 2). For relebactam, the geometric Cmax ranged from 33 μM to 87 μM and mean AUC0-6h ranged from 51 μM·h to 159 μM·h across the age cohorts (Table 2). IMI/REL was well tolerated with 8 (17.4%) participants experiencing ≥1 adverse events (AE) and 2 (4.3%) participants experiencing AE that were deemed drug related by the investigator. Drug-related AE were increased alanine aminotransferase, increased aspartate aminotransferase, anemia, and diarrhea, which were non-serious, mild in severity, and resolved within the follow-up period of 14 days. Figure 1 Conclusion Imipenem and relebactam exceeded the pediatric plasma PK targets across pediatric age cohorts in the study; the single doses of IMI/REL were well tolerated. These results will inform IMI/REL dose selection for further pediatric clinical evaluation. Disclosures Camilla Tøndel, MD, PhD, Merck & Co., Inc., (Grant/Research Support) Emmanuel Roilides, MD, PhD, FIDSA, FAAM, FESCMID, FECMM, FISAC, Merck Sharp & Dohme Corp. (Consultant, Grant/Research Support) Matthew S. Kelly, MD, MPH, Merck Sharp & Dohme Corp. (Consultant, Grant/Research Support) Munjal Patel, PhD, Merck Sharp & Dohme Corp. (Employee, Shareholder) Pavan Vaddady, PhD, Merck Sharp & Dohme Corp. (Employee) Alok Maniar, MD, MPH, Merck Sharp & Dohme Corp. (Employee, Shareholder) Ying Zhang, PhD, Merck & Co., Inc. (Employee, Shareholder) Amanda Paschke, MD MSCE, Merck Sharp & Dohme Corp. (Employee, Shareholder) Joan R. Butterton, MD, Merck Sharp & Dohme Corp. (Employee, Shareholder) Luke F. Chen, MBBS MPH MBA FRACP FSHEA FIDSA, Merck (Employee)

scholarly journals 87 Efficacy Measures in an Open-label Dose-Optimization of an Amphetamine Extended-Release Oral Suspension in Children with Attention-Deficit/Hyperactivity Disorder

CNS Spectrums ◽  
2019 ◽  
Vol 24 (1) ◽  
pp. 218-219
Author(s):  
Andrew Cutler ◽  
Antonio Pardo ◽  
Thomas R. King ◽  
Judith C. Kando ◽  
Barry K. Herman
Keyword(s):  
Primary Endpoint ◽  
Extended Release ◽  
Rating Scale ◽  
Oral Suspension ◽  
Dose Optimization ◽  
Open Label ◽  
Parent Rating ◽  
Post Dose ◽  
Duration Of Action ◽  
Label Dose

AbstractObjectivesReport the efficacy of open-label amphetamine extended-release oral suspension (AMPH EROS) for the treatment of children with ADHD.AMPH EROS has a 1-hr onset of effect and a duration of action of 13hours and was approved by FDA for treatment of ADHD in children aged 6–17 years based on a double-blind, placebo-controlled efficacy and safety study in children aged 6–12 years with ADHD. A significant treatment difference in change from pre-dose SKAMP-combined score was observed at the primary endpoint of 4hours post-dose (p<0.0001) and each post-dose time point assessed (1, 2, 4, 6, 8, 10, 12, 13hours).Data reported here are from the 5-week, open-label dose optimization period. These efficacy data support the primary endpoint result.MethodsMales and females aged 6 to 12 years with ADHD enrolled and began open-label treatment with 2.5 mg or 5mg/day of AMPH EROS titrated in 2.5–10mg/day increments until optimal dose (maximum 20mg/day). Doses could be decreased for tolerability. Subjects took morning AMPH EROS for 5weeks. Other efficacy outcomes during the open-label dose optimization phase: ADHD-RS (ADHD-Rating Scale), CGI-S (Clinical Global Impression of Severity), CGI-I (CGI-of Improvement) and CPRS (Conners’ Parent Rating Scale). All subjects were assessed for safety.ResultsFor the ITT population (n=99): treatment with AMPH EROS was associated with a mean change in ADHD-RS-IV (baseline to end of the open-label dose optimization; week 6) of 28.2 (±9.03) (Baseline score = 41.3±7.95). 90.9% of subjects had a change from baseline to open-label week 6 of ≥50% in the ADHD-RS-IV total score and were defined as responders. The CGI-S scores decreased continuously from baseline, with a high 4.8 at baseline to a low of 2.0 at open-label week 6. The percentage of subjects classified as moderately ill or greater correspondingly decreased from 97% at Baseline to 1% at open-label week 6. The decrease in the CGI-I over the study was similar to the change in CGI-S scores. CPRS for most categories decreased continuously from Baseline to open-label week 6. Mean change from baseline to open-label week 6 on the CPRS inattention T-score subscale was –25.3 (±14.38) and –24.4 (±13.87).Adverse events (>5%) reported during dose optimization were decreased appetite, insomnia, affect lability, upper abdominal pain, mood swings and headache.ConclusionAMPH EROS was effective in reducing symptoms of ADHD in this open-label dose optimization. The AE profile of AMPH EROS was consistent with those of other amphetamine products.Funding Acknowledgements: This work was funded by Tris Pharma, Inc.

scholarly journals Comparison of Azithromycin Pharmacokinetics following Single Oral Doses of Extended-Release and Immediate-Release Formulations in Children with Acute Otitis Media

2011 ◽  
Vol 55 (11) ◽  
pp. 5022-5026 ◽  
Author(s):  
Ping Liu ◽  
Annie F. Fang ◽  
Robert R. LaBadie ◽  
Penelope H. Crownover ◽  
Adriano G. Arguedas
Keyword(s):  
Single Dose ◽  
Otitis Media ◽  
Extended Release ◽  
Geometric Mean ◽  
Acute Otitis Media ◽  
Lower Boundary ◽  
Systemic Exposure ◽  
Immediate Release ◽  
Oral Suspension ◽  
Tolerability Profile

ABSTRACTAn azithromycin extended-release (ER) oral suspension was developed to improve the gastrointestinal tolerability profile without substantially compromising systemic exposure. A single dose of 30 mg/kg azithromycin immediate-release (IR) oral suspension has been used in children to treat acute otitis media (AOM). This study was conducted to compare the pharmacokinetics of a 60-mg/kg azithromycin ER single dose with a 30-mg/kg azithromycin IR single dose in children with AOM aged 6 months to 6 years (n= 19 per treatment). Serum samples were collected at 1, 2, 3, 4, 8, 24, 48, and 72 h after dosing. The area under the curve from time zero to 72 h postdosing (AUC0-72) was calculated based on a noncompartmental method. One-way analysis of variance (ANOVA) was used to compare exposure parameters (e.g., AUC0-72and peak concentration) as well as concentrations at each time point. The adjusted geometric mean ratio of the ER/IR AUC0-72was 157.98% (90% confidence interval [CI], 98.87%, 252.44%), which met the predefined criterion of the lower boundary of the 90% CI of ≥80%. As expected, due to the slower-release profile of the ER formulation, the concentrations of the ER formulation during the first 3 h were lower than those of the IR formulation. After 3 h postdosing, the lower boundaries of the 90% CI for the ER/IR concentration ratios were greater than 100%. These results indicated that a 60-mg/kg single dose of ER azithromycin provides similar or greater systemic exposure in children than the 30-mg/kg single dose of IR azithromycin.

Rectal Administration of Ibuprofen: Comparison of Enema and Suppository Form

Drug Research ◽  
2021 ◽  
Author(s):  
Budi Prasaja ◽  
Yahdiana Harahap ◽  
Monika Sandra ◽  
Irene Iskandar ◽  
Windy Lusthom ◽  
...  
Keyword(s):  
Phase 1 ◽  
Rectal Administration ◽  
Pharmacokinetic Parameters ◽  
P Value ◽  
Open Label ◽  
Post Dose ◽  
Anova Model ◽  
Equal Dose ◽  
Rate Of Absorption ◽  
The Mean

AbstractIbuprofen is a widely used and well-tolerated analgesic and antipyretic. It is desirable to have a formulation with a rapid rate of absorption because it is required for rapid pain relief and temperature reduction. Previous studies have described the pharmacokinetic profiles of ibuprofen suppository and the mean peak times of ibuprofen suppository were around 1.8 hours, indicating a slower rate of absorption. The aim of this study is to compare the pharmacokinetic parameters of rectal administration of ibuprofen between enema and suppository form in order to provide evidence for the faster absorption rates of ibuprofen enema. This study was a phase-1 clinical study, open-label, randomized and two-way crossover with one-week washout period comparing the absorption profile of equal dose of ibuprofen administered rectally in two treatment phases: ibuprofen suppository and enema. Blood samples were collected post dose for pharmacokinetic analyses. Tmax was analyzed using a Wilcoxon matched paired test. A standard ANOVA model, appropriate for bioequivalence studies was used and ratios of 90% confidence intervals were calculated. This study showed that Tmax for ibuprofen enema was less than half that of ibuprofen suppository (median 40 min vs. 90 min, respectively; p-value=0.0003). Cmax and AUC0–12 for ibuprofen enema were bioequivalent to ibuprofen suppository, as the ratio of test/reference=104.52%, 90% CI 93.41–116.95% and the ratio of test/reference=98.12%, 90%CI 93.34–103.16%, respectively, which fell within 80–125% bioequivalence limit. The overall extent of absorption was similar to the both, which were all well tolerated. In terms of Tmax, Ibuprofen enema was absorbed twice as quickly as from ibuprofen suppository. Therefore it is expected that an ibuprofen enema may provide faster onset of analgesic and antipyretic benefit.

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