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

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.

Download Full-text

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

CNS Spectrums ◽

10.1017/s109285292000262x ◽

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.

Download Full-text

Rectal Administration of Ibuprofen: Comparison of Enema and Suppository Form

Drug Research ◽

10.1055/a-1577-2955 ◽

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.

Download Full-text

An unresolved issue: The relationship between spot urine protein-to-creatinine ratio and 24-hour proteinuria

Journal of International Medical Research ◽

10.1177/0300060518819602 ◽

2019 ◽

Vol 47 (3) ◽

pp. 1179-1184 ◽

Cited By ~ 3

Author(s):

Davut Akin ◽

Sehmus Ozmen

Keyword(s):

Medical Records ◽

Urine Protein ◽

Entire Study ◽

Spot Urine ◽

Protein Excretion ◽

Ratio Data ◽

Study Population ◽

The Mean ◽

The Relationship ◽

H Protein

Objective To investigate the relationship between spot urine protein-to-creatinine (sP/Cr) ratio and 24-h protein excretion in patients with different diagnoses. Methods This retrospective study analysed data from the medical records of patients admitted for24-h proteinuria determination who also had sP/Cr ratio data for the same day. Results A total of 1222 urine samples obtained from 694 adult outpatients were analysed. The mean ± SD age of the patients was 53.6 ± 15.9 years. The mean ± SD 24-h proteinuria and sP/Cr were 1.7 ± 2.4 g/day and 1.8 ± 2.4, respectively. The correlation between the sP/Cr and 24-h protein excretion was high (R2 = 0.89). The sP/Cr ratio accounted for 72% of the variability in 24-h proteinuria in the entire study population. Areas under the curve for 24-h proteinuria at 0.3 g/day, 1.0 g/day and 3.0 g/day were 0.940, 0.966, and 0.949, respectively. The mean + 2SD limits of agreement were between +2.99 and –2.73 g/day according to the Bland Altman analysis. Conclusion This current study found a clinically unacceptable deviation between 24-h proteinuria and sP/Cr ratio. Therefore, the sP/Cr ratio cannot replace 24-h proteinuria. A new method using spot urine protein and creatinine values that is able to minimize under or over estimation is still warranted.

Download Full-text

Serum and Lung Pharmacokinetics of ASN100, a Monoclonal Antibody Combination for the Prevention and Treatment of Staphylococcus aureus Pneumonia

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.722 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S310-S310 ◽

Cited By ~ 4

Author(s):

Zoltan Magyarics ◽

Fraser Leslie ◽

Steven A Luperchio ◽

Johann Bartko ◽

Christian Schörgenhofer ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Bacterial Infections ◽

Phase 1 ◽

Fixed Dose ◽

Open Label ◽

Post Dose ◽

Double Blind ◽

Dose Time ◽

Prevention And Treatment ◽

Acute Bacterial Infections

Abstract Background Monoclonal antibodies (mAbs) are well-suited for the prevention and treatment of acute bacterial infections. ASN100 is a combination of two fully human IgG1 mAbs, ASN-1 and ASN-2 that together neutralize six Staphylococcus aureus cytotoxins, alpha-hemolysin (Hla) and five leukocidins (HlgAB, HlgCB, LukED, LukSF [PVL] and LukGH) that are important in the pathogenesis of S. Aureus pneumonia. We aimed to characterize the pharmacokinetics (PK) of ASN100 in both serum and lung epithelial lining fluid (ELF) in male and female healthy volunteers. Methods The safety, tolerability, and serum and lung PK of single intravenous infusion of ASN100 was evaluated in a Phase 1 study. Eight subjects (3:1 randomization) in two double-blind cohorts received ASN100 (doses of 3600 mg or 8000 mg) or placebo. ASN-1 and ASN-2 were administered in a fixed dose 1:1 ratio. Twelve subjects received ASN100 open-label at doses of 3600 mg or 8000 mg and each underwent two bronchoalveolar lavage (BAL) fluid collections either on days 1 and 30 or on days 2 and 8 post-dosing. ASN-1 and ASN-2 concentrations were determined by ELISA. The ELF concentrations were normalized based on urea concentrations in serum and BAL fluid. Results No dose limiting toxicity was observed. Adverse events (AEs) showed no association of increased incidence with higher dose. All AEs were mild or moderate in severity, with 83.3% of subjects receiving ASN100 reporting at least one AE vs. 100% of placebo subjects. A dose proportional increase in serum peak and exposure (AUC) of ASN-1 and ASN-2 was observed and the serum PK of ASN-1 and ASN-2 were comparable (approximate half-life of each antibody was 3 weeks). Penetration of ASN-1 and ASN-2 into the ELF of the lung was observed at the first post-dose time point of 24 hours, peak concentrations were observed after day 2 and the mAbs remained detectable at day 30. Conclusion ASN100 was safe and well tolerated at doses up to 8000 mg (4000 mg ASN-1 and 4000 mg ASN-2). The PK profiles of ASN-1 and ASN-2 were comparable following simultaneous administration. Significant lung concentrations of each mAb were demonstrated between day 1 and 30 post-dosing. These data support continued clinical development of ASN100 for the prevention and treatment of S. Aureus pneumonia. Disclosures Z. Magyarics, Arsanis Biosciences GmbH: Employee, Salary. Arsanis, Inc.: Shareholder, Share options. F. Leslie, Arsanis., Inc.: Employee and Shareholder, Salary. S. A. Luperchio, Arsanis Inc.: Employee and Shareholder, Salary. B. Jilma, Arsanis Biosciences GmbH: Investigator, Investigator fee. C. Stevens, Arsanis Inc.: Employee and Shareholder, Salary.E. Nagy, Arsanis: Employee and Shareholder, Salary.

Download Full-text

1027 AN OPEN-LABEL, SINGLE-DOSE, PHASE 1 STUDY OF THE PHARMACOKINETICS AND SAFETY OF JZP-110 IN SUBJECTS WITH NORMAL OR IMPAIRED RENAL FUNCTION AND WITH END-STAGE RENAL DISEASE REQUIRING HEMODIALYSIS

SLEEP ◽

10.1093/sleepj/zsx050.1026 ◽

2017 ◽

Vol 40 (suppl_1) ◽

pp. A382-A382 ◽

Cited By ~ 2

Author(s):

K Zomorodi ◽

D Chen ◽

L Lee ◽

K Lasseter ◽

T Marbury

Keyword(s):

Renal Function ◽

Single Dose ◽

Renal Disease ◽

End Stage Renal Disease ◽

Impaired Renal Function ◽

Phase 1 ◽

Open Label ◽

Phase 1 Study ◽

Stage Renal Disease ◽

End Stage

Download Full-text

Opposite Effects of Single-Dose and Multidose Administration of the Ethanol Extract of Danshen on CYP3A in Healthy Volunteers

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/730734 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

Furong Qiu ◽

Jian Jiang ◽

Yueming Ma ◽

Guangji Wang ◽

Chenglu Gao ◽

...

Keyword(s):

Single Dose ◽

Healthy Volunteers ◽

Plasma Concentrations ◽

In Vitro Study ◽

Ethanol Extract ◽

Tanshinone Iia ◽

Open Label ◽

The Mean

The aim of this study was to investigate the effect of single- and multidose administration of the ethanol extract of danshen on in vivo CYP3A activity in healthy volunteers. A sequential, open-label, and three-period pharmacokinetic interaction study design was used based on 12 healthy male individuals. The plasma concentrations of midazolam and its metabolite 1-hydroxymidazolam were measured. Treatment with single dose of the extract caused the meanCmaxof midazolam to increase by 87% compared with control. After 10 days of the danshen extract intake, the mean AUC0–12,Cmax, andt1/2of midazolam were decreased by 79.9%, 66.6%, and 43.8%, respectively. The mean clearance of midazolam was increased by 501.6% compared with control. The in vitro study showed that dihydrotanshinone I in the extract could inhibit CYP3A, while tanshinone IIA and cryptotanshinone could induce CYP3A. In conclusion, a single-dose administration of the danshen extract can inhibit intestinal CYP3A, but multidose administration can induce intestinal and hepatic CYP3A.

Download Full-text

NE-180, a Novel glycoPEGylated Erythropoietin Demonstrates Dose-Dependent Activity in a Phase 1 Single Dose, Dose Escalating Study in Normal Human Volunteers (NHV).

Blood ◽

10.1182/blood.v108.11.1149.1149 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1149-1149

Author(s):

Bruce A. Wallin ◽

Denise Ramjit ◽

Michael Seiberling ◽

David Zopf

Keyword(s):

Adverse Events ◽

Animal Studies ◽

Phase 1 ◽

Stopping Rules ◽

Open Label ◽

Serious Adverse Events ◽

Maximal Increase ◽

The Mean ◽

Dose Dependent

Abstract NE-180 is a glycoPEGylated recombinant human erythropoietin that binds to and activates the erythropoietin (EPO) receptor. It has demonstrated in vitro activities comparable to EPO and an extended serum half-life in animal studies. This may allow less frequent dosing in patients being treated with chronic anemia. METHODS: A single center, open-label study of NE-180, administered as single escalating doses given by the SC or IV route, was conducted to assess the safety, tolerability, PK and PD. Subjects (male or female NHV) were planned to be assigned to one of 4 dose groups, 10 subjects per dose with 5 SC and 5 IV subjects per group: 0.5, 1.5, 3, or 4.5 mg/kg. Each dose group was planned to be initiated in an ascending, sequential fashion unless or until stopping rules were met. RESULTS: 25 NHV (16 females) were enrolled in the first two dose cohorts and have completed 56 day follow-up. The 1.5 mg/kg IV cohort met the protocol-specified Hb rate of rise stopping rule (change in Hb greater than 1 g/dL during any 14 day period). Injections were generally well tolerated with no discontinuations for adverse events or serious adverse events. Reticulocyte increases were dose proportional. Average reticulocyte count at baseline was 1.0±0.3%. The maximal increase occurred at day 7. The mean change from baseline for the 0.5 and 1.5 mg/kg SC group was: 0.9±0.4% and 2.2±0.9%, respectively. The mean change from baseline for the 0.5 and 1.5 mg/kg IV group was: 1.7±0.8% and 2.3±0.8%, respectively. PK data will be presented. CONCLUSIONS: Single doses up to 1.5 mg/kg of NE-180 administered to NHV were generally well tolerated and demonstrated potent dose-dependent erythropoietic activity.

Download Full-text

Epacadostat plus nivolumab in patients with advanced solid tumors: Preliminary phase I/II results of ECHO-204.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.3003 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 3003-3003 ◽

Cited By ~ 48

Author(s):

Raymond P. Perez ◽

Matthew John Riese ◽

Karl D. Lewis ◽

Mansoor N. Saleh ◽

Adil Daud ◽

...

Keyword(s):

Phase 1 ◽

Open Label ◽

Common Grade ◽

Open Label Phase ◽

Study Population ◽

N Dose ◽

Grade 3 ◽

Tumor Types ◽

Preliminary Phase ◽

Clinical Trial Information

3003 Background: ECHO-204 is an ongoing, open-label, phase 1/2 (P1/2) study of epacadostat (E; potent and selective oral inhibitor of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1) plus PD-1 inhibitor nivolumab (N) in patients (pts) with advanced cancers (NSCLC, MEL, OVC, CRC, SCCHN, B-cell NHL [including DLBCL], GBM). Preliminary P1/2 safety and tolerability outcomes for the overall study population and P2 response for select tumor types (SCCHN, MEL, OVC, CRC) are reported. Methods: In P1 dose escalation, pts received E (25, 50, 100, 300 mg BID) + N (3 mg/kg Q2W); in P2 cohort expansion, pts received E (100 or 300 mg BID) + N (240 mg Q2W). Safety/tolerability was assessed in pts receiving ≥1 E + N dose. Response was assessed in RECIST v1.1 evaluable pts; for recently enrolled pt subgroups, only preliminary DCR (CR+PR+SD) is presented. Results: As of 29OCT2016,241 pts (P1, n = 36; P2, n = 205) were enrolled. No DLT was observed in P1. Most common TRAEs (≥15%) in pts treated with E 100 mg (n = 70) and E 300 mg (n = 135) were rash (33% and 22%, respectively), fatigue (26% and 31%), and nausea (24% and 19%). Rash was the most common grade ≥3 TRAE in E 100 mg and E 300 mg subgroups (10% and 12%). TRAEs led to discontinuation in 7% (E 100 mg) and 13% (E 300 mg) of pts. There were no TR-deaths. For the 23 recently enrolled, efficacy-evaluable SCCHN pts treated with E 300 mg, preliminary DCR was 70% (n = 16). Of 30 MEL pts, 8 were treated with E 100 mg and 22 were more recently enrolled and treated with E 300 mg. ORR (CR+PR) and DCR in MEL pts treated with E 100 mg were 75% (n = 6; all PR) and 100% (n = 8; 2 SD), respectively. Preliminary DCR in MEL pts treated with E 300 mg was 64% (n = 14). Of 29 OVC pts, 18 were treated with E 100 mg and 11 with E 300 mg.ORR and DCR for OVC pts treated with E 100 mg were 11% (n = 2; 2 PR) and 28% (n = 5; 3 SD); for 11 OVC pts treated with E 300 mg, ORR and DCR were 18% (n = 2; 2 PR) and 36% (n = 4; 2 SD).For 25 CRC pts (all E 100 mg), ORR and DCR were 4% (n = 1; PR) and 24% (n = 6; 5 SD).Safety/efficacy evaluations are ongoing for all cohorts. Conclusions: E + N was generally well tolerated up to the maximum E 300-mg dose. P2 ORR/DCR outcomes are promising, particularly in SCCHN and MEL pts. Updated data will be presented at the meeting. Clinical trial information: NCT02327078.

Download Full-text