scholarly journals 1393. A Phase 1, Randomized, Open-Label, Crossover Study in Healthy Subjects Under Fasting Conditions of Orally Administered Sulopenem Etzadroxil Alone or with Probenecid to Determine the Pharmacokinetics of Sulopenem

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S428-S429
Author(s):  
Michael Dunne ◽  
Steven Aronin ◽  
Elise Dunzo ◽  
Sailaja Puttagunta
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Phase 1 ◽  
Treatment Options ◽  
Parent Compound ◽  
Additional Treatment ◽  
Open Label ◽  
Males And Females ◽  
The Mean ◽  
Mean Time

Abstract Background Antimicrobial resistance to available oral antibiotics is becoming progressively more common, precipitating the need for additional treatment options as step-down from initial intravenous (IV) therapy as well as for treatment of infections in the community. Sulopenem (CP-70,429) is a thiopenem antibiotic active against quinolone non-susceptible and ESBL-producing Enterobacteriaceae. As the key pharmacokinetic-pharmacodynamic variable correlating with efficacy for penem antibiotics is time above minimum inhibitory concentration (T > MIC), we examined the utility of probenecid, an OAT-1 inhibitor of β-lactam excretion, on the pharmacokinetic (PK) parameters for the oral prodrug of sulopenem, sulopenem etzadroxil Methods Twelve healthy males and females received a single oral dose of 500 mg sulopenem etzadroxil as powder in bottle either alone or co-administered with a single oral dose of probenecid 500 mg in a crossover design with a washout period of 6 days. All doses were administered under fasting conditions. Blood samples for plasma PK analysis were collected and PK parameters for sulopenem, the parent compound of sulopenem etzadroxil, were determined. Results Treatment Conclusion Probenecid increases the AUC of sulopenem by 28% in the fasted state and extends the mean time over MIC. Disclosures M. Dunne, Iterum Therapeutics: Employee and Shareholder, Salary. S. Aronin, Iterum Therapeutics: Employee and Shareholder, Salary. E. Dunzo, Parexel: Consultant, Consulting fee. S. Puttagunta, Iterum Therapeutics: Employee and Shareholder, Salary.

scholarly journals No Dose Adjustment for Isavuconazole Based on Age or Sex

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Amit V. Desai ◽  
David Han ◽  
Donna L. Kowalski ◽  
Christopher Lademacher ◽  
Helene Pearlman ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Population Pharmacokinetic ◽  
Elderly Age ◽  
Open Label ◽  
Absorption Function ◽  
Significant Toxicity ◽  
Males And Females

ABSTRACT This phase 1, open-label, single-dose, parallel-group study evaluated the pharmacokinetics (PK) of isavuconazole after a single oral dose of the prodrug isavuconazonium sulfate in healthy nonelderly (age, 18 to 45 years) and elderly (age, ≥65 years) males and females. Overall, 48 subjects were enrolled in the study (n = 12 each in groups of nonelderly males and females and elderly males and females). All subjects received a single oral dose of 372 mg of isavuconazonium sulfate (equivalent to 200 mg isavuconazole). PK samples were collected for analysis of isavuconazole plasma concentrations from the predose time point up to 336 h postdose. Data were analyzed using population pharmacokinetic (PPK) analysis. The resulting PPK model included two compartments with Weibull absorption function as well as interindividual variability with respect to clearance, intercompartment clearance, volumes of central and peripheral compartments, and two Weibull absorption parameters, RA and KAMAX. The PPK analysis showed that elderly females had the highest exposure versus males (ratio of total area under the time-concentration curve [AUC], 138; 90% confidence interval [CI], 118 to 161) and versus nonelderly females (ratio of AUC, 147; 90% CI, 123 to 176). Higher exposures in elderly females were not associated with significant toxicity or treatment-emergent adverse events, as measured in this study. No dose adjustments appear to be necessary based on either age group or sex even with an increase in exposure for elderly females. (This study has been registered at ClinicalTrials.gov under registration no. NCT01657890.)

scholarly journals Urinary Excretion and Bactericidal Activities of a Single Oral Dose of 400 Milligrams of Fleroxacin versus a Single Oral Dose of 800 Milligrams of Pefloxacin in Healthy Volunteers

1998 ◽  
Vol 42 (7) ◽  
pp. 1659-1665 ◽  
Author(s):  
Kurt G. Naber ◽  
Ursula Theuretzbacher ◽  
Martina Kinzig ◽  
Orlin Savov ◽  
Fritz Sörgel
Keyword(s):  
Oral Dose ◽  
Healthy Volunteers ◽  
Single Oral Dose ◽  
E Coli ◽  
Wide Range ◽  
The Mean ◽  
Bactericidal Activities ◽  
Tract Infections ◽  
Time Kill ◽  
Randomized Crossover Study

ABSTRACT Twelve healthy volunteers participated in this randomized crossover study to compare the concentrations and recovery levels of fleroxacin and pefloxacin in urine and to assess their bactericidal activities against 12 strains of urinary pathogens with different susceptibilities over a wide range of MICs. The volunteers received a single oral dose of 400 mg of fleroxacin or 800 mg of pefloxacin. The mean cumulative renal excretion of unchanged fleroxacin,N-demethyl-fleroxacin, and N-oxide-fleroxacin accounted for 67, 7, and 6% of the total dose, respectively. The total urinary recovery of pefloxacin and the active metabolite norfloxacin was 34%. In the time-kill and the urinary bactericidal titer (UBT) studies, only the subjects’ urine not supplemented with broth was used. With most tested organisms and both quinolones it took more than 8 h to achieve a reduction in CFU of 99.9% (3 log units). Overall, there was a good correlation between UBTs and MICs for the strains. Against Escherichia coli ATCC 25922 the median UBTs were similar for both antibiotics and at least 1:8 for 96 h; against the E. coli strain for which the MIC was 0.5 μg/ml the UBT was at least 1:4 for 48 h. The UBTs of both drugs against Klebsiella pneumoniae were at least 1:16 for 72 h. The UBTs for Staphylococcus aureus (the MIC for which was 16 μg/ml) of both antibiotics were low, and in some of the samples, no bactericidal titers were observed. UBTs for Proteus mirabilis of pefloxacin are significantly higher than those of fleroxacin. For Pseudomonas aeruginosa the median UBTs were present for the 24-to-48-h interval. The same is true forEnterococcus faecalis. Against Staphylococcus saprophyticus, UBTs were present for at least 48 h with both quinolones. Overall, a single oral dose of 400 mg of fleroxacin exhibits UBTs comparable to those of 800 mg of pefloxacin. Therefore, it may be expected that half of the dose of fleroxacin gives comparable results in the treatment of urinary tract infections; this should be substantiated in comparative clinical trials.

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.

Automated Needle Targeting (ANT) Device-Assisted Renal Access during Percutaneous Nephrolithotripsy (PCNL) Puncture: A Pilot Study to Assess the Safety and Efficacy of a Novel Technique

2020 ◽  
Author(s):  
Chu Ann Chai ◽  
W.S Yeoh ◽  
A.N Fadzli ◽  
T.A Ong ◽  
S Kuppusamy ◽  
...  
Keyword(s):  
Adverse Events ◽  
Radiation Exposure ◽  
Renal Stones ◽  
Open Label ◽  
Primary Endpoints ◽  
Ethical Approval ◽  
The Mean ◽  
Set Up ◽  
Surgical Duration ◽  
Mean Time

Abstract Background: To explore the use of an automated needle targeting (ANT) device as an assistive intraoperative navigation modality during PCNL for the treatment of large renal stones, with the aim of reducing surgical durations and radiation exposure.Methods: This open-label, single-surgeon clinical trial included patients with a diagnosis of renal stones for whom PCNL using the ANT device via the percutaneous access technique was indicated. Ethical approval was obtained from the UMMC ethics review board (Ref. 20118105-6740). The ANT was assembled after an initial motor calibration, and the image calibration was performed using the patient’s fluoroscopic images. Subsequently, the ANT software calculated a bullseye alignment before percutaneous puncture. Accurate renal access was confirmed by the efflux of urine in the Chiba biopsy needle, as well as by imaging with the C-arm intensifier at different angles. The primary endpoints were the time to successful renal access (from ANT set-up to urine efflux) and adverse events.Results: In all cases, successful renal access was achieved with a single attempt. The mean time to renal access was 6 minutes, 8 seconds. The mean fluoroscopy duration was 101 seconds, with a mean radiation dose of 23.46 mGy. No adverse events were documented.Conclusion: The ANT device enabled successful, safe and efficient renal access for PCNL in this study. Further research is needed to justify the effectiveness of this device in terms of enabling accurate renal access while reducing the surgical duration and radiation exposure to both surgeons and patients.

scholarly journals Absolute Bioavailability of Esaxerenone and Food Effects on its Pharmacokinetics After a Single Oral Dose in Healthy Japanese Subjects: An Open-Label Crossover Study

2019 ◽  
Vol 36 (7) ◽  
pp. 1618-1627 ◽  
Author(s):  
Akifumi Kurata ◽  
Hidetoshi Furuie ◽  
Tomoko Ishizuka ◽  
Takafumi Nakatsu ◽  
Takako Shimizu ◽  
...  
Keyword(s):  
Oral Dose ◽  
Crossover Study ◽  
Single Oral Dose ◽  
Absolute Bioavailability ◽  
Food Effects ◽  
Open Label ◽  
Japanese Subjects

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 ◽  
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.

Subcutaneous or intravenous administration of romiplostim in thrombocytopenic patients with myelodysplastic syndrome (MDS)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7009-7009
Author(s):  
M. Sekeres ◽  
H. Kantarjian ◽  
P. Fenaux ◽  
P. Becker ◽  
A. Boruchov ◽  
...  
Keyword(s):  
Treatment Options ◽  
Open Label ◽  
Eligibility Criteria ◽  
Subcutaneous Injections ◽  
Open Label Study ◽  
Future Studies ◽  
Intravenous Injections ◽  
The Past ◽  
The Mean ◽  
Administration Schedules

7009 Background: Thrombocytopenia is common in patients (pts) with MDS, and treatment options are currently limited to platelet (plt) transfusions. Romiplostim is an Fc-peptide fusion protein (peptibody) that stimulates plt production by the same mechanism as thrombopoietin. Methods: This was a phase II, multicenter, single arm, open-label study. Eligibility criteria included IPSS low or intermediate-1 risk MDS and a mean baseline plt count ≤50x109/L. Safety and efficacy of romiplostim were evaluated in pts receiving 750μg romiplostim according to one of 3 schedules: weekly or biweekly subcutaneous injections (QWSC or Q2WSC), or biweekly intravenous injections (Q2WIV). Plt responses were measured per IWG 2006 criteria. Results: Of the 28 pts enrolled, 17 (61%) completed the study; 22 (79%) were male and the mean (±SD) baseline plt count was 29 (±10) x 109/L. The mean age was 71 years and 19 pts (68%) had received plt transfusions in the past year. Mean duration of exposure to romiplostim was 12 (±8) weeks. The most common adverse events (AEs) were fatigue and headache (both 18%). Five pts experienced serious AEs, and there were 2 cases of disease progression to AML: one pt in the QWSC cohort who received romiplostim for 4 weeks and one in the Q2WSC cohort who received romiplostim for 20 weeks. For pts who completed 8 weeks treatment, 15/23 (65%) achieved a plt response, defined by IWG 2006 criteria, and 14/23 (61%) did not require a plt transfusion during this period. The small number of pts limited the ability to compare administration schedules; minor differences were observed in plt responses and plt transfusions, and the incidence of AEs appeared similar among cohorts. Conclusions: IV and SC romiplostim appeared well-tolerated and effective in raising plt counts and avoiding plt transfusions in low and intermediate-1 risk MDS pts. The dose recommendation for future studies is 750μg, given QW or Q2W SC. [Table: see text] [Table: see text]

A phase 2 study of BGJ398 in patients (pts) with advanced or metastatic FGFR-altered cholangiocarcinoma (CCA) who failed or are intolerant to platinum-based chemotherapy.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 335-335 ◽  
Author(s):  
Milind M. Javle ◽  
Rachna T. Shroff ◽  
Andrew Zhu ◽  
Saeed Sadeghi ◽  
SuPin Choo ◽  
...  
Keyword(s):  
Phase 1 ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Genetic Alterations ◽  
Phase 2 ◽  
Open Label ◽  
Overall Response ◽  
Platinum Based Chemotherapy ◽  
Metastatic Setting

335 Background: CCA is a hepatobiliary malignancy with poor prognosis and few treatment options following cytotoxic therapy in the first-line metastatic setting. The fibroblast growth factor receptor (FGFR) axis may promote CCA tumorigenesis. FGFR2 fusions (in up to 17% of intrahepatic CCAs) may predict FGFR inhibitor sensitivity. A prior phase 1 trial of the selective pan-FGFR inhibitor BGJ398 showed antitumor activity in a pt with CCA harboring an FGFR2 fusion. Methods: This ongoing phase 2, open-label study is evaluating oral BGJ398 125 mg once daily on a 3-week-on/1-week-off schedule (28-day cycle) in pts with advanced or metastatic CCA with FGFR2 fusions (n ≈ 40) or other FGFR genetic alterations (n ≤ 15) who progressed after cisplatin/gemcitabine or are cisplatin intolerant (NCT02150967). The primary endpoint is investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints include progression-free survival, best overall response (BOR), disease control rate (DCR), overall survival, safety, and pharmacokinetics. Results: As of 10 July 2015, 26 pts with CCA harboring FGFR2 fusions (n = 22) or other FGFR alterations (n = 4), pretreated with 1 to ≥ 4 prior regimens, were enrolled. Common adverse events (AEs; ≥ 20% of pts), were hyperphosphatemia (50%), fatigue (42%), constipation (38%), cough (23%), and nausea (23%). Grade 3/4 AEs occurring in ≥ 2 pts were hyper/hypophosphatemia, lipase increase, and hyponatremia. AEs were manageable, reversible, and rarely led to treatment discontinuation. Among 22 pts evaluable for BOR, 3 achieved partial response and 15 had stable disease, including 10 with tumor reductions (-41%, n = 1; -2% to -29%, n = 9). Overall DCR was 82%. As of the cutoff date, 18 pts remained on therapy, of which 13 were on for > 120 days. Kaplan-Meier estimated lower limit (95% CI) of median time on study was 143 days. Conclusions: BGJ398 shows impressive anti-tumor activity and a manageable safety profile in pts with advanced FGFR-altered CCA, an indication of high unmet medical need. Updated data including additional responses post data cutoff will be presented. Clinical trial information: NCT02150967.

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