Pharmacokinetics, Safety, and Clinical Outcomes of Omadacycline in Women with Cystitis: Results from a Phase 1b Study

ABSTRACT Omadacycline, an aminomethylcycline antibiotic, is approved as once-daily intravenous (i.v.) and oral (p.o.) monotherapy for acute bacterial skin and skin structure infections and for community-acquired bacterial pneumonia, and it is under development for treatment of urinary tract infection (UTI). This is a phase 1b, randomized, open-label study of omadacycline in women with cystitis (defined as UTI symptoms and a positive urine leukocyte esterase test). Patients received omadacycline for 5 days (group 1: 200 mg intravenously on day 1, then 300 mg orally every 24 h [q24h]; group 2: 300 mg orally every 12 h [q12h] on day 1, then 300 mg orally q24h; group 3: 450 mg orally q12h on day 1, then 450 mg orally q24h). Blood and urine samples were collected over 5 days. Investigator-assessed clinical response was determined at end of treatment (EOT; day 6) and posttreatment evaluation (PTE; 5 to 9 days after last dosing). A total of 31 women were treated. At steady state (day 5), the range of mean omadacycline urine concentrations over 24 h across the groups was 17.94 to 48.12 μg/ml. The most common treatment-emergent adverse events were gastrointestinal (including nausea [60% to 73%] and vomiting [20% to 40%]) and were generally mild and transient. Investigator-determined clinical success was observed in 94% and 84% of patients at EOT and PTE, respectively, with similar results across groups. A favorable microbiological response at PTE was observed in 78% of patients who had a baseline pathogen. Omadacycline is partially excreted in urine and appears to be safe and well tolerated. These preliminary results indicate that omadacycline warrants further evaluation in larger controlled UTI studies.

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Ethanolic Extract of Herb Pugun Tanoh (Picria fel-terrae Lour.) Modulates TCD4+ and TCD8+ Cell Profile of Doxorubicin-Induced Immuno-Suppressed Rats

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2019.501 ◽

2019 ◽

Vol 7 (22) ◽

pp. 3774-3776

Author(s):

Mustafa Ridwan Lubis ◽

Reny Haryani ◽

Safriana Safriana ◽

Denny Satria

Keyword(s):

Ethanolic Extract ◽

Immune Functions ◽

Sprague Dawley ◽

Immunomodulatory Effects ◽

Once Daily ◽

Sprague Dawley Rats ◽

Group 3 ◽

Group 2 ◽

Cell Profile ◽

Group 1

AIM: To evaluate the immunomodulatory effects of ethanolic extract of herb pugun tanoh on TCD4 and TCD8 cells in Doxorubicin-induced rats. METHODS: Fifteen male Sprague Dawley rats were divided into five groups consisting of six rats each as follows: Group 1, DOX-treated rats (4.67 mg/kg BW body weight on day 1 and 4) and were administered normal saline 0.9% orally once daily for 7 consecutive days, Group 2, receiving Ethanolic Extract of Herb Pugun Tanoh (Picria fel-terrae Lour.) of dose 150 mg/kg BW orally, Group 3, receiving dose Ethanolic Extract of Herb Pugun Tanoh (Picria fel-terrae Lour.) 300 mg/kg BW orally. The rats of group 2-3 were intramuscularly administered with doxorubicin at a dose of 4.67 mg/kg BW at the days 1-4 to suppress immune functions. RESULTS: Treatment of 300 mg/kg BW of Ethanolic Extract of Herb Pugun Tanoh (Picria fel-terrae Lour.) succeeded in reducing side effect doxorubicin based on increasing the TCD4+ and TCD8+ blood level. CONCLUSION: Ethanolic Extract of Herb Pugun Tanoh (Picria fel-terrae Lour.) could increase the level of TCD4+ and TCD8+ in rats which induced by doxorubicin.

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A phase 1b multicenter, open-label study of investigational TAK-228 (MLN0128) plus TAK-117 (MLN1117) in adult patients with advanced nonhematologic malignancies

European Journal of Cancer ◽

10.1016/s0959-8049(16)32625-9 ◽

2016 ◽

Vol 69 ◽

pp. S11-S12 ◽

Cited By ~ 3

Author(s):

D. Juric ◽

J. Lopez ◽

D. Rasco ◽

T. Macarulla Mercadé ◽

Q. Xu ◽

...

Keyword(s):

Adult Patients ◽

Open Label ◽

Open Label Study ◽

Label Study ◽

Phase 1B

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Fosamprenavir plus Ritonavir Increases Plasma Ketoconazole and Ritonavir Exposure, while Amprenavir Exposure Remains Unchanged

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00008-07 ◽

2007 ◽

Vol 51 (8) ◽

pp. 2982-2984 ◽

Cited By ~ 4

Author(s):

Mary B. Wire ◽

Charles H. Ballow ◽

Julie Borland ◽

Mark J. Shelton ◽

Yu Lou ◽

...

Keyword(s):

Steady State ◽

Healthy Subjects ◽

Open Label ◽

Time Curve ◽

Once Daily ◽

Open Label Study ◽

Label Study ◽

Concentration Time

ABSTRACT Plasma ketoconazole (KETO), amprenavir (APV), and ritonavir (RTV) pharmacokinetics were evaluated in 15 healthy subjects after being treated with KETO at 200 mg once daily (QD), fosamprenavir (FPV)/RTV at 700/100 mg twice daily (BID), and then KETO at 200 mg QD plus FPV/RTV at 700/100 mg BID in this open-label study. The KETO area under the concentration-time curve at steady state was increased 2.69-fold with FPV/RTV. APV exposure was unchanged, and RTV exposure was slightly increased.

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Steady-State Pharmacokinetics of Tenofovir-Based Regimens in HIV-Infected Pediatric Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01334-10 ◽

2011 ◽

Vol 55 (9) ◽

pp. 4290-4294 ◽

Cited By ~ 12

Author(s):

Jennifer R. King ◽

Ram Yogev ◽

Patrick Jean-Philippe ◽

Bobbie Graham ◽

Andrew Wiznia ◽

...

Keyword(s):

Fixed Dose ◽

Target Range ◽

Pharmacokinetic Parameters ◽

Time Interval ◽

Minimum Concentration ◽

Once Daily ◽

Daily Group ◽

Group 3 ◽

Group 2 ◽

Group 1

ABSTRACTHIV-infected children are treated with tenofovir in combination with other, potentially interacting, antiretroviral agents. We report the pharmacokinetic parameters of tenofovir in combination with efavirenz, darunavir-ritonavir, or atazanavir-ritonavir in HIV-infected children. HIV-infected patients 8 to 18 years of age receiving a tenofovir (300 mg)-based regimen containing efavirenz (300 or 600 mg) once daily (group 1), darunavir (300 or 600 mg)-ritonavir (100 mg) twice daily (group 2), or atazanavir (150 to 400 mg)-ritonavir (100 mg) once daily (group 3) were enrolled. Plasma samples were collected over a 24-h time interval. The 90% confidence intervals (90% CI) of the geometric means for the area under the plasma concentration-time curve (AUC) and the minimum concentration of drug in serum (Cmin) of each antiretroviral were computed and checked for overlap with intervals bracketing published values obtained in adult or pediatric studies demonstrating safety and/or efficacy. Group 1 efavirenz plasma concentrations were observed to be higher in patients receiving fixed-dose combination tablets compared with subjects receiving the individual formulation. In group 2, tenofovir and darunavir exposure was observed to be lower than expected. In group 3, tenofovir and atazanavir administered concomitantly produced exposures similar to those published for adult patients. The 90% CI of AUC andCminfor tenofovir overlapped the target range for all combinations. Informal comparisons of treatment groups did not indicate any advantage to any combination with respect to tenofovir exposure. Further study of exposures achieved with antiretrovirals administered in combination is warranted.

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6587 POSTER A Phase 1b, Open-Label Study to Evaluate the Safety of Ganitumab (AMG 479) in Combination With Gemcitabine as First-line Therapy in Patients With Metastatic Pancreatic Cancer

European Journal of Cancer ◽

10.1016/s0959-8049(11)71898-6 ◽

2011 ◽

Vol 47 ◽

pp. S467 ◽

Cited By ~ 1

Author(s):

M. Ikeda ◽

T. Okusaka ◽

A. Fukutomi ◽

S. Otani ◽

K. Shibayama ◽

...

Keyword(s):

Pancreatic Cancer ◽

Metastatic Pancreatic Cancer ◽

First Line ◽

Open Label ◽

Open Label Study ◽

Label Study ◽

First Line Therapy ◽

Line Therapy ◽

Phase 1B

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Effects of Pleuran (Β–Glucan from Pleurotus Ostreatus) Supplementation on Incidence and Duration of COPD Exacerbations

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2017.198 ◽

2017 ◽

Vol 5 (7) ◽

pp. 893-898 ◽

Cited By ~ 1

Author(s):

Jordan Minov ◽

Jovanka Bislimovska-Karadzhinska ◽

Tatjana Petrova ◽

Kristin Vasilevska ◽

Sasho Stoleski ◽

...

Keyword(s):

Vitamin C ◽

Stable Disease ◽

Pleurotus Ostreatus ◽

Control Group ◽

Open Label ◽

Once Daily ◽

Copd Patients ◽

Group 2 ◽

Group D ◽

Group 1

BACKGROUND: 1,3/1,6-β–glucans are recognised as immunomodulators in human and veterinary medicine for over 50 years.AIM: To assess the effects of pleuran (1,3/1,6-β–glucan from Pleurotus ostreatus) on incidence and duration of bacterial exacerbations in patients with COPD.METHODS: We performed an observational, non-randomized, open-label study including 32 COPD patients (Group D) in whom besides the recommended chronic treatment for the stable disease were administered supplement combination containing pleuran 100 mg, vitamin C 60 mg and zinc 5 mg once daily over a three month-period (Group 1). Also, an equal number of Group D COPD patients who besides the recommended treatment for stable disease received the supplement combination containing vitamin C 60 mg and zinc 5 mg once daily, matched to the study subjects of the Group 1 by sex and age served as control (Group 2).RESULTS: Over the study period 57 exacerbations (24 in the Group 1 and 33 in the Group 2) were documented. A mean number of exacerbations over the study period was significantly lower in the Group1 (0.7 ± 0.4) as compared to their mean number in the Group 2 (1.0 ± 0.6) (P = 0.0218). Furthermore, a mean duration of exacerbations expressed in days needed for cure or clinical improvement (i.e. complete resolution of symptoms or return of the symptoms to their baseline severity) in the Group 1 (6.7 ± 0.8 days) was significantly shorter than the mean duration of exacerbations in the Group 2 (7.4 ± 1.3 days) (P = 0.0118). There was not reported any adverse effect during the study period by study subjects from both examined groups.CONCLUSION: Our findings indicated that pleuran might impact the incidence and duration of bacterial exacerbations in patients with COPD. There is a need for further studies for more precise determination of the influence of pleuran on the course of COPD.

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Tolerogenic nanoparticles mitigate the formation of anti-drug antibodies against pegylated uricase in patients with hyperuricemia

Nature Communications ◽

10.1038/s41467-021-27945-7 ◽

2022 ◽

Vol 13 (1) ◽

Author(s):

Earl Sands ◽

Alan Kivitz ◽

Wesley DeHaan ◽

Sheldon S. Leung ◽

Lloyd Johnston ◽

...

Keyword(s):

Primary Endpoint ◽

Standard Of Care ◽

Secondary Endpoint ◽

Dependent Manner ◽

Open Label ◽

Biologic Drugs ◽

Double Blind ◽

Open Label Study ◽

Phase 1B ◽

Dose Dependent

AbstractBiologic drugs have transformed the standard of care for many diseases. However, many biologics induce the formation of anti-drug antibodies (ADAs), which can compromise their safety and efficacy. Preclinical studies demonstrate that biodegradable nanoparticles-encapsulating rapamycin (ImmTOR), but not free rapamycin, mitigate the immunogenicity of co-administered biologic drugs. Here we report the outcomes from two clinical trials for ImmTOR. In the first ascending dose, open-label study (NCT02464605), pegadricase, an immunogenic, pegylated uricase enzyme derived from Candida utilis, is assessed for safety and tolerability (primary endpoint) as well as activity and immunogenicity (secondary endpoint); in the second single ascending dose Phase 1b trial (NCT02648269) composed of both a double-blind and open-label parts, we evaluate the safety of ImmTOR (primary endpoint) and its ability to prevent the formation of anti-drug antibodies against pegadricase and enhance its pharmacodynamic activity (secondary endpoint) in patients with hyperuricemia. The combination of ImmTOR and pegadricase is well tolerated. ImmTOR inhibits the development of uricase-specific ADAs in a dose-dependent manner, thus enabling sustained enzyme activity and reduction in serum uric acid levels. ImmTOR may thus represent a feasible approach for preventing the formation of ADAs to a broad range of immunogenic biologic therapies.

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