Pharmacokinetics of AR19, an Immediate-Release Amphetamine Sulfate Formulation Designed to Deter Manipulation for Administration Via Nonoral Routes: Bioequivalence to Reference Racemic Amphetamine Sulfate, Dose Proportionality, and Food Effect

2020 ◽  
Vol 30 (2) ◽  
pp. 69-80
Author(s):  
Steven Caras ◽  
Terrilyn Sharpe
Keyword(s):  
Food Effect ◽  
Immediate Release ◽  
Dose Proportionality ◽  
Amphetamine Sulfate

scholarly journals 81 Bioequivalence of a Manipulation-Resistant Immediate-Release Amphetamine Sulfate Formulation Compared with Reference Standard

CNS Spectrums ◽  
2019 ◽  
Vol 24 (1) ◽  
pp. 216-216
Author(s):  
Steve Caras ◽  
Terrilyn Sharpe
Keyword(s):  
Single Dose ◽  
Healthy Volunteers ◽  
Peak Concentration ◽  
Immediate Release ◽  
Open Label ◽  
Time Curve ◽  
Time To Peak ◽  
Amphetamine Sulfate ◽  
Quantifiable Concentration ◽  
Funding Acknowledgements

AbstractStudy ObjectivesWe compared the bioavailability of racemic amphetamine (d-amphetamine and l-amphetamine) from a manipulation-resistant immediate-release (IR) amphetamine sulfate capsule (AR19) versus amphetamine sulfate IR tablets (reference).MethodIn this open-label, randomized, two-period, two-treatment, two-sequence, crossover study, 36 healthy volunteers aged 18–45 received a single dose (20-mg capsule) of AR19 in one period and a single dose (2 x 10-mg tablets) of reference in another period, after a 10-hour overnight fast. Each drug administration was separated by a washout period of at least 6days. Bioequivalence for d- and l-amphetamine was assessed using time to peak concentration (Tmax), peak concentration in plasma (Cmax), and area under the plasma concentration–time curve from time-zero to the time of the last quantifiable concentration (AUClast) and extrapolated to infinity (AUCinf).ResultsAll 36 volunteers completed both treatment sequences. Mean (standard deviation; SD) Tmax for d- and l-amphetamine was similar for AR19 (2.84[1.05]; 3.05[1.22], respectively) and reference (2.52[0.75]; 2.75[1.00], respectively). The geometric least-squares mean ratios and 90% confidence intervals were within the boundary of 80%–125% for bioequivalence for Cmax (d-amphetamine, 98.35% [96.12–100.64]; l-amphetamine, 98.82% [96.42–101.28]), AUClast (d-amphetamine, 99.45% [96.92–102.05]; l-amphetamine, 99.29% [96.55–102.10]), and AUCinf (d-amphetamine, 99.50%[96.77–102.30]; l-amphetamine, 99.23% [96.06–102.50]). A total of 13 mild adverse events were reported by 7 volunteers (AEs; AR19, n=5; reference, n=8). No serious AEs were reported.ConclusionAR19 was well tolerated and was bioequivalent to reference when administered as a 20-mg dose in healthy volunteers.Funding Acknowledgements: This study was funded by Arbor Pharmaceuticals, LLC.

scholarly journals 10 Pharmacodynamics and Tolerability of Intranasally Administered Immediate-Release Amphetamine Sulfate Among Recreational Intranasal StimulantUsers

CNS Spectrums ◽  
2019 ◽  
Vol 24 (1) ◽  
pp. 178-178
Author(s):  
Beatrice Setnik ◽  
Steve Caras ◽  
Terrilyn Sharpe ◽  
Stephen V. Faraone
Keyword(s):  
Active Drug ◽  
Immediate Release ◽  
Abuse Potential ◽  
Post Dose ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Study Objective ◽  
Amphetamine Sulfate ◽  
Drug Liking ◽  
Intranasal Dose

AbstractStudy ObjectiveDespite increased nonmedical use of ADHD prescription stimulants, there are limited data to inform selection of intranasal doses for abuse-potential evaluations. This study determined a dose of amphetamine sulfate that is tolerable and distinguishable from placebo on pharmacodynamic (PD) measures.MethodsIn this randomized, double-blind, placebo-controlled, dose-escalation study, healthy, nondependent, recreational stimulant users received a single intranasal dose of amphetamine sulfate (20, 30, or 40mg ; n=6 per group) or placebo (n=2 per group). PD and safety were assessed pre-dose and ≤24hours post-dose. Drug Liking was measured using a bipolar Visual Analogue Scale (VAS; 0–100). Dose selection criteria were complete dose insufflation (≥95%); demonstration of peak Drug Liking ≥75 points, and ≥15 points greater than placebo in ≥3 participants receiving active drug; and tolerability.ResultsPeak Drug Liking criteria were met in the 20-, 30-, and 40-mg groups by 2, 0, and 6 participants, respectively. Mean (SD) peak Drug Liking was 62 (13.0), 71 (17.8), and 93 (8.7) for amphetamine sulfate versus 54 (3.5), 76 (34.6), and 51 (0) for placebo in the 20-, 30-, and 40-mg groups, respectively. Thirteen participants experienced mild AEs (n=1, 4, 6, and 1 in 20-, 30-, 40-mg, and placebo groups, respectively), there were no serious or clinically significant AEs. The most common AE was nostril burning sensation (active drug, n=7). There were no instances of an incompletely insufflateddose.ConclusionA 40-mg intranasal dose produced distinguishable PD effects and was well tolerated. This dose has been selected for further abuse-potential evaluations.Funding Acknowledgements: This study was funded by Arbor Pharmaceuticals, LLC.

A phase I study to evaluate the pharmacokinetics of a new oncology nce, apatinib mesylate tablets, with and without food following single and multiple doses in healthy subjects.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14049-e14049 ◽  
Author(s):  
Luana Pesco Koplowitz ◽  
Barry Koplowitz ◽  
Cheol Hee Park ◽  
Arlo N. McGinn
Keyword(s):  
Food Effect ◽  
Dose Proportionality ◽  
Metabolic Effects ◽  
Open Label ◽  
Male And Female ◽  
Study Section ◽  
Delayed Initiation ◽  
Dosing Regimens ◽  
Intermediate Metabolizers ◽  
Female Subjects

e14049 Background: Apatinib Mesylate (YN968D1) is a selective inhibitor of VEGFR-2 being developed for the treatment of advanced gastric cancer. Objectives: 1. Evaluate single- and multiple-dose PKs 2. Evaluate food effect on bioavailability 3. Evaluate dose-proportionality 4. Determine CYP3A4 and 2C19 metabolic effects on the PKs Methods: Single ascending-dose (SAD), open-label, crossover of 2 oral doses of apatinib mesylate tablets (100 mg and 250 mg, [81 mg and 201 mg apatinib]) in healthy male and female volunteers with a minimum 3-day washout between dosing, plus a multiple ascending-dose (MAD), open-label, crossover study of the same doses. Both doses were administered with and without food in a crossover for the SAD and MAD parts. PK blood samples were collected for each dosing period. Subjects were genotyped for CYP3A4 and CYP2C19. WinNonlin 6.4 used for analysis. Results: 24 male and female subjects completed the SAD study section. They were extensive or intermediate metabolizers of CYP2C19, and 23/24 were normal metabolizers of CYP3A4. 22 male and female subjects completed the MAD study section. Most were extensive, intermediate or ultra-rapid metabolizers of CYP2C19; 21/22 subjects were normal metabolizers of CYP3A4. Conclusions: For the 100 mg dose in the SAD and MAD parts of the study, there was no significant food effect. For the 250 mg dose in SAD and MAD parts, food appeared to increase bioavailability by 20–30% in the SAD part, and 30–40% in the MAD part. Noncompartmental PK analysis of the SAD and MAD showed medium tmaxvalue delayed at 2 doses when apatinib was administered with food. Compartmental PK analysis showed food delayed initiation in absorption and reduced first order absorption rate constant. Dose proportionality was confirmed only for the AUC0-∞ value from the SAD-fasted cohort but inconclusive for Cmax and AUC parameters under other dosing regimens. Visual inspection of the effect of CYP2C19 genotype on the clearance of apatinib did not show correlation. Inspection of CYP3A4 genotype on the calculated clearance values was tenuous given the intermediate metabolizers (N = 1), compared to extensive metabolizers.

scholarly journals On Absorption Modeling and Food Effect Prediction of Rivaroxaban, a BCS II Drug Orally Administered as an Immediate-Release Tablet

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 283
Author(s):  
Varun Kushwah ◽  
Sumit Arora ◽  
Miklós Tamás Katona ◽  
Dattatray Modhave ◽  
Eleonore Fröhlich ◽  
...  
Keyword(s):  
Pbpk Model ◽  
Food Effect ◽  
Solid Dispersions ◽  
Immediate Release ◽  
Oral Solution ◽  
In Vitro Dissolution ◽  
Fed State ◽  
Release Tablet

The present work evaluates the food effect on the absorption of rivaroxaban (Riva), a BCS II drug, from the orally administered commercial immediate-release tablet (Xarelto IR) using physiologically based pharmacokinetic (PBPK) and conventional in vitro–in vivo correlation (IVIVC) models. The bioavailability of Riva upon oral administration of Xarelto IR tablet is reported to exhibit a positive food effect. The PBPK model for Riva was developed and verified using the previously reported in vivo data for oral solution (5 and 10 mg) and Xarelto IR tablet (5 and 10 mg dose strength). Once the PBPK model was established, the in vivo performance of the tablet formulation with the higher dose strength (Xarelto IR tablet 20 mg in fasted and fed state) was predicted using the experimentally obtained data of in vitro permeability, biorelevant solubility and in vitro dynamic dissolution data using United States Pharmacopeia (USP) IV flow-through cell apparatus. In addition, the mathematical IVIVC model was developed using the in vitro dissolution and in vivo profile of 20 mg strength Xarelto IR tablet in fasted condition. Using the developed IVIVC model, the pharmacokinetic (PK) profile of the Xarelto IR tablet in fed condition was predicted and compared with the PK parameters obtained via the PBPK model. A virtual in vivo PK study was designed using a single-dose, 3-treatment cross-over trial in 50 subjects to predict the PK profile of the Xarelto® IR tablet in the fed state. Overall, the results obtained from the IVIVC model were found to be comparable with those from the PBPK model. The outcome from both models pointed to the positive food effect on the in vivo profile of the Riva. The developed models thus can be effectively extended to establish bioequivalence for the marketed and novel complex formulations of Riva such as amorphous solid dispersions.

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