Maximum Serum Concentration Research Articles

In Vitro-In Vivo Correlation Using In Silico Modeling of Physiological Properties, Metabolites, and Intestinal Metabolism

Recently, pharmaceutical research has focused on in vitro-in vivo correlation as a novel challenge, and in silico modeling has been an important component. As in silico models are highly representative of practical use, regulatory agencies such as the US Food and Drug Administration and European Medicines Agency have recognized and utilized in silico modeling as a useful tool; this allows pharmaceutical organizations to use Physiologically Based Pharmacokinetic (PBPK) models for decision-making, which may aid the financial efficiency of a clinical trial. However, some studies have shown differences of up to approximately 40% in pharmacokinetic parameters such as area under the curve or maximum serum concentration between observed and simulated data. Gastroplus™ was used to demonstrate current PBPK simulation. 46 research papers were compared with each other's applications of PBPK simulation. To improve the accuracy of simulation, additional factors may need to be considered, such as precise volume of gastrointestinal sections, specific metabolism of the target drug, and physicochemical data of drug metabolites. Furthermore, the results of these simulations would be extremely valuable to the relevant applications. Simulation programs using Advanced Compartmental Absorption and Transit (ACAT)/PBPK modeling could be a powerful tool for companies performing pre-clinical experiments, and could provide a solution for the ethical issues and economic constraints of clinical trials. If in silico modeling produced more precise results that could closely match clinical data, it could be more readily used to screen drug pharmacodynamics in bodily systems, and the efficiency of clinical trials would be improved. However, simulation programs are currently limited in their accuracy of pharmacodynamic predictions. In developing new drugs, pharmaceutical companies should address this issue in order to improve in silico/PBPK modeling in the future.

A randomised trial comparing the pharmacokinetics and safety of the biosimilar CT-P6 with reference trastuzumab

PurposeAccess to trastuzumab, a valuable anti-cancer treatment, can be limited by cost. The primary aim of this study was to evaluate and compare the PK profiles of CT-P6, a biosimilar of trastuzumab, and US-licensed reference trastuzumab (Herceptin®) in healthy subjects. Secondary study aims included comparison of the safety and immunogenicity of CT-P6 and reference trastuzumab in these subjects.MethodsWe performed a single-dose, randomised, double-blind, parallel group study (NCT02665637) comparing CT-P6 with reference trastuzumab (6 mg/kg, 90 min intravenous infusion) in 70 healthy adult males. Pharmacokinetics, safety and immunogenicity were evaluated up to 10 weeks post-dose. Primary endpoints were area under the serum concentration–time curve (AUC) from time 0 to infinity (AUCinf); AUC from time 0 to last quantifiable concentration (AUClast); and observed maximum serum concentration (Cmax). The pre-determined equivalence criterion was a 90% confidence interval of 80–125% for ratios of geometric least squares (LS) means.ResultsEquivalence of CT-P6 and reference trastuzumab was demonstrated. Ratios (CT-P6/reference trastuzumab) of geometric LS means (90% confidence interval) were: AUCinf 99.05 (93.00, 105.51); AUClast 99.30 (92.85, 106.20); Cmax 96.58 (90.93, 102.59). Safety profiles were similar; treatment-emergent adverse events occurred in ten subjects (28.6%) in the CT-P6 group and 11 (31.4%) in the reference trastuzumab group. No serious adverse events or deaths occurred. No subjects tested positive for anti-drug antibodies.ConclusionsThese data add to the totality of evidence required to demonstrate biosimilarity. A phase III study of CT-P6—in which equivalent neoadjuvant efficacy to reference trastuzumab has been demonstrated—is ongoing.

Open-Label, Randomized, Two-Way, Crossover Study Assessing the Bioequivalence of the Liquid Formulation versus the Freeze-Dried Formulation of Recombinant Human FSH and Recombinant Human LH in a Fixed 2:1 Combination (Pergoveris®) in Pituitary-Suppressed Healthy Women.

This was a Phase I, open-label, randomized, two-period, two-sequence crossover study [ClinicalTrials.gov NCT02317809 (https://www.clinicaltrials.gov/ct2/show/NCT02317809); EudraCT 2014-003506-32] assessing the bioequivalence of the liquid and freeze-dried formulations of fixed-dose, fixed-ratio (2:1) combination recombinant human follicle-stimulating hormone plus recombinant human luteinizing hormone (r-hFSH/r-hLH). The safety and tolerability of the two formulations were also assessed. Healthy premenopausal women were randomized to one of two crossover dosing schedules. Subjects in Treatment Sequence 1 received a single subcutaneous dose (900/450 IU r-hFSH/r-hLH) of the liquid formulation of r-hFSH/r-hLH on Day 1 of Dose Period 1 and, after a washout period of at least 14 days, a single subcutaneous dose (900/450 IU r-hFSH/r-hLH) of the freeze-dried formulation of r-hFSH/r-hLH (reconstituted in water for injection prior to administration) on Day 1 of Dose Period 2. Subjects in Treatment Sequence 2 received the treatments in reverse order. The primary endpoints were AUC0–t (area under the serum concentration–time curve from time 0 to the time of the last quantifiable concentration) and Cmax (maximum serum concentration) for FSH and LH, both baseline corrected. A total of 34 subjects were randomized, and 22 subjects were included in the bioequivalence evaluation. Overall, the mean observed PK profiles and individual PK parameters were comparable for the liquid and freeze-dried formulations, although a median difference in the tmax (time to reach maximum observed concentration) of FSH of ~4.5 h was observed between the formulations. The calculated 90% confidence intervals of the mean liquid formulation/freeze-dried formulation ratios for Cmax and AUC0–t were within the bioequivalence range (80–125%) for both LH and FSH, confirming bioequivalence between the two formulations. The safety and tolerability profiles of the two formulations were similar. The liquid formulation can, therefore, be expected to provide the same efficacy as the freeze-dried formulation, with no differences in tolerability.

Effect of Diabetes on the Pharmacokinetic Profile of Fluoroquinolones

Effect of Diabetes on the Pharmacokinetic Profile of Fluoroquinolones Faith Onyinye Okpana, Peter Achunike Akah Abstract Fluoroquinolones are broad spectrum antibiotics used clinically to treat bacterial infectious diseases. They are among the commonly and widely prescribed antibiotics. Reports have linked the use of fluoroquinolones to significant dysglycemia. This work was designed to investigate the pharmacokinetic profile of ciprofloxacin, levofloxacin and moxifloxacin in diabetic rats. Methods. Streptozotocin-induced diabetic rats were treated orally with the fluoroquinolones for 7 days, Blood samples were collected from the retro orbital plexus for the estimation of serum concentration, area under the curve, mean retention time, half lives, volume of distribution and other pharmacokinetic indices. Results: The result revealed increase in the values of maximum serum concentration (Cmax), area under the curve (AUC), area under the moment curve (AUMC), mean resident time (MRT), half life (t1/2), volume of distribution (Vd) and decreased clearance rate (Cl) compared with the values in non diabetic rats. The effects were more on moxifloxacin and least on ciprofloxacin. Conclusion: Diabetes state significantly (p < 0.05) elevated the pharmacokinetic indices of fluoroquinolones. Full Text: PDF DOI: 10.15640/ijmp.v6n2a4

Steady-State Pharmacokinetics of Oral Ciprofloxacin in Continuous Cycling Peritoneal Dialysis Patients: Brief Report.

Steady-state pharmacokinetics of oral ciprofloxacin in 3 continuous cycling peritoneal dialysis (CCPD) outpatients given ciprofloxacin 750 mg b.i.d. for 5 doses was determined. Mean steady-state maximum serum concentration and half-life were 4.4 ± 1.5 mg/L and 10.3 ± 2.6 hours, respectively. Mean maximum dialysate concentration in the daytime long dwell and overnight continuous cycling dwell were 7.4 ± 1.2 mg/L and 3.3 ± 1.2 mg/L, respectively. Oral ciprofloxacin 750 mg b.i.d. may be reasonable for bloodstream and peritoneal infections caused by susceptible bacteria in CCPD patients.

Influence of sevoflurane anesthesia with mechanical ventilation and fluid-therapy on distribution of subcutaneously administered robenacoxib in dogs.

Robenacoxib is a novel nonsteroidal anti-inflammatory drug approved for dogs. The present study aimed to evaluate influences of sevoflurane anesthesia on the distribution of robenacoxib in dogs. Ten healthy beagle dogs (1 to 11 years old, 9.3 to 14.3 kg body weight, 6 males and 4 females) were subcutaneously administered robenacoxib (2 mg/kg) under conscious condition or sevoflurane anesthesia inhaled a 1.3-fold predetermined individual minimum alveolar concentration of sevoflurane at a 28-day interval. The dogs under sevoflurane anesthesia were also mechanically ventilated and received fluid-therapy. On each occasion, serum samples were collected from the dogs before and at 5, 15, 30, 60, 120, 180, and 240 min after the robenacoxib administration. Serum robenacoxib concentration was measured by a liquid chromatography-tandem mass spectrometry. Maximum serum concentration of robenacoxib (Cmax) was 2.2 µg/ml [range: 1.2–4.6] (median [range: minimum-maximum]) and time of Cmax (Tmax) was 90 min [range: 60–120] in the conscious dogs. In the sevoflurane-anesthetized dogs, the Cmax significantly declined (1.3 µg/ml [range: 0.8–1.4], P=0.008) and Tmax was delayed (120 min [range: 120–240], P=0.018) compared with those in the conscious dogs. The serum robenacoxib concentration at 240 min (C240) decreased to 0.5 µg/ml [range: 0.2–0.9] in the conscious dogs, while it remained higher in the sevoflurane-anesthetized dogs (1.0 µg/ml [range: 0.3–1.4], P=0.011). In conclusion, the anesthetic procedure with sevoflurane, mechanically ventilated, and received fluid-therapy might affect the pharmacokinetics of subcutaneously administered robenacoxib in dogs.

Association between serum concentration of parathyroid hormone and left ventricle ejection fraction, and markers of heart failure and inflammation in ST elevation myocardial infarction patients treated with primary percutaneous coronary intervention

Background/Aim. Previous studies have shown increased serum concentration of parathyroid hormone (PTH) in acute myocardial infarction and heart failure. In this study we examined the relation-ships between parathyroid hormone status and biochemical markers of myocardial injury and heart failure, as well as electrocardio-graphic (ECG) and echocardiographic indicators of infarction size and heart failure. Methods. In 390 consecutive patients with ST segment elevation myocardial infarction (STEMI), average age 62 ? 12 years, laboratory analysis of serum concentrations of creatine kinase MB isoenzyme (CK-MB), C-reactive protein (CRP) and in-tact PTH and plasma concentration of brain natriuretic peptide (BNP) were done during the first three days after admission. All patients were treated with primary percutaneous coronary intervention (PCI). Exclusion criterion was severe renal insufficiency (glomerular filtration rate ? 30 mL/min). Serum concentration of PTH was measured on the 1st, 2nd and, in some cases, on the 3rd morning after admission and maximum level of PTH was taken for analysis. Patient cohort was divided into four groups according to quartiles of PTH maximum serum concentration (I ? 4.4 pmol/L; II &gt; 4.4 pmol/L and &lt; 6.3 pmol/L; III ? 6.3 pmol/L and &lt; 9.2 pmol/L; IV ? 9.2 pmol/L). Selvester?s ECG score, left ventricle ejection fraction and wall motion index (WMSI) were determined at discharge between 5?14 days after admission. Results. We found that LVEF at discharge significantly decreased (p &lt; 0.001) and WMSI at discharge and ECG Selvester?s score significantly increased across the quartiles of PTH max. level (p &lt; 0.001 for both parameters). BNP, CRP and CK-MB isoenzyme level significantly increased across the quartiles of PTH max. level (p &lt; 0.001; p &lt; 0.001 and p = 0.004, retrospectively). Conclusion. The patients in the 4th quartile of PTH had significantly lower LVEF and higher WMSI and Selvester?s ECG score at discharge. This group of patients also had higher levels of BNP, CRP and CK-MB in blood in the early course of STEMI.

Subcutaneous cefazolin to reduce surgical site infections in a porcine model

BackgroundSurgical site infections (SSIs) pose a significant health and financial burden. A key aspect of appropriate prophylaxis is the administration of antibiotics intravenously (IV). However, subcutaneous administration of antibiotics is not well described in the literature. During surgery, we hypothesize that subcutaneous injection may provide better protection against SSIs. To better understand the kinetics after subcutaneous injection, we describe the serum concentrations of cefazolin in a porcine model. Materials and methodsJuvenile mini-Yucatan pigs were administered 20 mL of 25 mg/kg cefazolin subcutaneously, and serial blood samples were taken for 3 h. Blood samples were analyzed for cefazolin concentration using chromatography. Pharmacokinetic data were calculated based on the blood serum concentrations. ResultsMaximum serum concentrations of cefazolin were achieved 42.6 ± 2.0 min after the time of injection and were found to be 18.8 ± 7.4 μg/mL. The elimination rate constant was 0.0033 ± 0.0016 min−1 and the half-life was 266 ± 149 min. The area under the curve was 4940 ± 1030 μg × min/mL. The relative bioavailability of subcutaneous injection was 95% +5%/−20%. ConclusionsSubcutaneous administration of cefazolin achieves a significantly lower maximum serum concentration than IV injection. As a result, higher doses of antibiotic can be injected locally without incurring systemic toxicity. Subcutaneous administration will therefore result in higher concentrations of antibiotic for a longer time at the incision site compared with standard IV administration. This strategy of antibiotic delivery may be more effective in preventing SSIs. Further studies are needed to detail the exact effect of subcutaneous antibiotic injection on SSI rates.

Safety, Pharmacokinetics, and Immunogenicity of Obiltoxaximab After Intramuscular Administration to Healthy Humans.

Inhalational anthrax is a highly lethal infection caused by Bacillus anthracis and a serious bioterrorism threat. Protective antigen (PA) is a critical component required for the virulence of Bacillus anthracis. Obiltoxaximab, a high‐affinity monoclonal antibody that neutralizes PA, is approved in the United States for intravenous use for the treatment of inhalational anthrax in combination with appropriate antibacterial drugs and for prophylaxis of inhalational anthrax when alternative therapies are not available or appropriate. Here, we explored the safety, pharmacokinetics (PK), and immunogenicity of obiltoxaximab administered by intramuscular injection at doses of 4, 8, 16, 20, and 24 mg/kg in healthy humans. Systemic exposures were approximately dose proportional, maximum serum concentrations were observed after 6–9 days, and terminal half‐life ranged from 16 to 23 days. Average absolute intramuscular bioavailability was 64%. Obiltoxaximab was well tolerated, and local tolerability was acceptable up to 24 mg/kg intramuscularly, up to 6 injections per dose, and up to 5 mL per injection. No injection‐site abscesses or hypersensitivity reactions occurred; no subjects developed treatment‐emergent antitherapeutic antibodies over the study period of 71 days.

Correction: Iron Pharmacokinetics in Women with Iron Deficiency Anaemia Following A Single Oral Dose of a Novel Formulation of Tardyferon (Prolonged Release Ferrous Sulphate).

Numerous iron-containing preparations are available on the market; these vary in dosage, salt, chemical state of iron (ferric or ferrous) and in the iron delivery process (immediate or prolonged-release). Tardyferon® is a prolonged-release tablet containing 80 mg ferrous sulphate. The formulation has recently been modified; changes to the excipients which constitute the inert formulation matrix have allowed a decrease in tablet size for easier swallowing. The aim of this multicenter open-label study was to characterize the serum pharmacokinetics of iron in non-pregnant women aged 23-45 years with iron deficiency anaemia (IDA) following single oral administration of 160 mg Tardyferon® under fasting conditions. Blood samples were collected from the 29 participants before dosing and until 24 h post-dosing. Serum iron concentrations were determined using a routine colorimetric analytical method; pharmacokinetic parameters were derived using a non-compartmental approach. In these patients, median time to maximum serum concentrations (Tmax) was 4 h. Serum profiles were consistent with prolonged release; iron levels were elevated up to 12 h after dosing, with mean C12h still more than 7 times higher than baseline (CT0), and mean C2h and C8h representing 69.7% and 81.9% of the Cmax, respectively. In vitro dissolution testing performed on the clinical batch also demonstrated prolonged release of iron from this formulation. A single oral dose of 160 mg Tardyferon® administered under fasting conditions to this target population resulted in a long-lasting release of iron in the gastrointestinal tract, leading to optimal iron absorption. Moreover, Tardyferon® was well tolerated.

Single-dose pharmacokinetic study comparing the pharmacokinetics of recombinant human chorionic gonadotropin in healthy Japanese and Caucasian women and recombinant human chorionic gonadotropin and urinary human chorionic gonadotropin in healthy Japanese women.

PurposeRecombinant hCG (r‐hCG) was approved in Japan in 2016. As a prerequisite for a Phase III study in Japan related to this approval, the pharmacokinetic (PK) profile of r‐hCG was investigated.MethodsAn open‐label, partly randomized, single‐center, single‐dose, group‐comparison, Phase I PK‐bridging study was done that compared a single 250 μg dose of r‐hCG with a single 5000 IU dose of urinary hCG (u‐hCG) in healthy Japanese women, as well as comparing a single 250 μg dose of r‐hCG in Japanese and Caucasian women. The Japanese participants were randomized 1:1 to receive either r‐hCG or u‐hCG, while the Caucasian participants were weight‐matched to the Japanese participants who were receiving r‐hCG in a 1:1 fashion. The primary PK parameters were the area under the serum concentration–time curve from time 0 extrapolated to infinity (AUC 0–∞) and the maximum serum concentration (Cmax).ResultsThe mean serum hCG concentration–time profiles of r‐hCG in the Japanese and Caucasian participants were a similar shape, but the level of overall exposure was ~20% lower in the Japanese participants. For the Japanese participants, r‐hCG resulted in an 11% lower Cmax but a 19% higher AUC 0–∞ compared with u‐hCG. No new safety signal was identified.ConclusionThis study cannot exclude a potential difference in the PK profile of r‐hCG between Japanese and Caucasian participants. However, this study does not indicate that there are clinically relevant differences in the serum PK of r‐hCG and u‐hCG in the Japanese participants.

Influence of Disease and Patient Characteristics on Daratumumab Exposure and Clinical Outcomes in Relapsed or Refractory Multiple Myeloma.

ObjectiveThe aim of this study was to understand the influence of disease and patient characteristics on exposure to daratumumab, an immunoglobulin Gκ (IgGκ) monoclonal antibody, and clinical outcomes in relapsed or refractory multiple myeloma (MM).Patients and MethodsBaseline myeloma type, albumin levels, renal/hepatic function, age, sex, race, weight, Eastern Cooperative Oncology Group (ECOG) status, refractory status, and number of prior therapies were evaluated using data from two clinical studies—GEN501 (N = 104) and SIRIUS (N = 124).ResultsDaratumumab clearance was approximately 110% higher in IgG myeloma patients than non-IgG myeloma patients, leading to significantly lower exposure in IgG myeloma patients based on maximum trough serum concentrations (p < 0.0001). However, the overall response rate was similar for IgG and non-IgG myeloma patients (odds ratio 1.08, 95% confidence interval 0.54–2.17, p = 0.82). For a given exposure, the drug effect was significantly higher (approximately two times) in IgG versus non-IgG patients (p = 0.03). The influence of other patient and disease characteristics on daratumumab exposure was minimal and no significant effect on efficacy was observed (p ≥ 0.1). The incidences of infections and overall grade 3 or higher adverse events in subpopulations were generally consistent with that of the overall population.ConclusionDue to competition with the MM-produced IgG M-protein for neonatal Fc receptor protection from clearance, IgG-based monoclonal antibodies in general may have significantly higher clearance and lower concentrations in IgG MM patients compared with non-IgG MM patients. Careful evaluation of the impact of exposure and patient and disease characteristics on safety and efficacy is warranted for all IgG-based monoclonal antibodies used in MM.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0598-1) contains supplementary material, which is available to authorized users.

Pharmacokinetics and pharmacodynamics of meldonium in exercised thoroughbred horses.

Although developed as a therapeutic medication, meldonium has found widespread use in human sports and was recently added to the World Anti-Doping Agency's list of prohibited substances. Its reported abuse potential in human sports has led to concern by regulatory authorities about the possible misuse of meldonium in equine athletics. The potential abuse in equine athletes along with the limited data available regarding the pharmacokinetics and pharmacodynamics of meldonium in horses necessitates further study. Eight exercised adult thoroughbred horses received a single oral dose of 3.5, 7.1, 14.3 or 21.4 mg/kg of meldonium. Blood and urine samples were collected and analyzed using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were determined using non-compartmental analysis. Maximum serum concentrations ranged from 440.2 to 1147 ng/mL and the elimination half-life from 422 to 647.8 h. Serum concentrations were below the limit of quantitation by days 4, 7, 12 and 12 for doses of 3.5, 7.1, 14.3 and 21.4 mg/kg, respectively. Urine concentrations were below the limit of detection by day 44 following administration of 3.5 mg/kg and day 51 for all other dose groups. No adverse effects were observed following meldonium administration. While the group numbers were small, changes in heart rate were observed in the 3.5 mg/kg dose group (n = 1). Glucose concentrations changed significantly in all dose groups studied (n = 2 per dose group). Similar to that reported for humans, the detection time of meldonium in biological samples collected from horses is prolonged, which should allow for satisfactory regulation in performance horses. Copyright © 2017 John Wiley & Sons, Ltd.

Efficacy, pharmacokinetics, and safety of the biosimilar CT-P10 compared with rituximab in patients with previously untreated advanced-stage follicular lymphoma: a randomised, double-blind, parallel-group, non-inferiority phase 3 trial

Studies in patients with rheumatoid arthritis have shown that the rituximab biosimilar CT-P10 (Celltrion, Incheon, South Korea) has equivalent efficacy and pharmacokinetics to rituximab. In this phase 3 study, we aimed to assess the non-inferior efficacy and pharmacokinetic equivalence of CT-P10 compared with rituximab, when used in combination with cyclophosphamide, vincristine, and prednisone (CVP) in patients with newly diagnosed advanced-stage follicular lymphoma. In this ongoing, randomised, double-blind, parallel-group, active-controlled study, patients aged 18 years or older with Ann Arbor stage III-IV follicular lymphoma were assigned 1:1 to CVP plus intravenous infusions of 375 mg/m2 CT-P10 or rituximab on day 1 of eight 21-day cycles. Randomisation was done by the investigators using an interactive web or voice response system and a computer-generated randomisation schedule, prepared by a clinical research organisation. Randomisation was balanced using permuted blocks and was stratified by country, gender, and Follicular Lymphoma International Prognostic Index score (0-2 vs 3-5). Study teams from the sponsor and clinical research organisation, investigators, and patients were masked to treatment assignment. The study was divided into two parts: part 1 assessing equivalence of pharmacokinetics (in the pharmacokinetics subset), and part 2 assessing efficacy in all randomised patients (patients from the pharmacokinetics subset plus additional patients enrolled in part 2). Equivalence of pharmacokinetics was shown if the 90% CIs for the geometric mean ratio of CT-P10 to rituximab in AUCτ and CmaxSS were within the bounds of the equivalence margin of 80% and 125%. Non-inferiority of response was shown if the one-sided 97·5% CI lay on the positive side of the -7% margin, using a one-sided test done at the 2·5% significance level. The primary efficacy endpoint was the proportion of patients who had an overall response over eight cycles and was assessed in the efficacy population (all randomised patients). The primary pharmacokinetic endpoints were area under the serum concentration-time curve at steady state (AUCτ) and maximum serum concentration at steady state (CmaxSS) at cycle 4, assessed in the pharmokinetic population. This trial is registered with ClinicalTrials.gov, number NCT02162771. Between July 28, 2014, and Dec 29, 2015, 140 patients were enrolled. Here we report data for the eight-cycle induction period, up to week 24. The proportion of patients with an overall response in the efficacy population was 64 (97·0%) of 66 patients in the CT-P10 treatment group and 63 (92·6%) of 68 patients in the rituximab treatment group (4·3%; one-sided 97·5% CI -4·25), which lay on the positive side of the predefined non-inferiority margin. The ratio of geometric least squares means (CT-P10/rituximab) was 102·25% (90% CI 94·05-111·17) for AUCτ and 100·67% (93·84-108·00) for CmaxSS, with all CIs within the bioequivalence margin of 80-125%. Treatment-emergent adverse events were reported for 58 (83%) of 70 patients in the CT-P10 treatment group and 56 (80%) of 70 in the rituximab treatment group. The most common grade 3 or 4 treatment-emergent adverse event in each treatment group was neutropenia (grade 3, 15 [21%] of 70 patients in the CT-P10 group and seven [10%] of 70 patients in the rituximab group). The proportion of patients who experienced at least one treatment-emergent serious adverse event was 16 (23%) of 70 patients in the CT-P10 group and nine (13%) of 70 patients in the rituximab group. In this study, we show that CT-P10 exhibits non-inferior efficacy and pharmacokinetic equivalence to rituximab. The safety profile of CT-P10 was comparable to that of rituximab. CT-P10 might represent a new therapeutic option for advanced-stage follicular lymphoma. Celltrion, Inc.

Antitumour Effects of Intravenous Administration of BK-UM, a Novel Inhibitor of HB-EGF, in Ovarian Cancer Therapy.

Patients with ovarian cancer with high levels of heparin-binding epidermal growth factor-like growth factor have a poor prognosis. Here we assessed the pharmacokinetics and tumour-inhibiting effects of cross-reacting material 197, produced commercially as BK-UM, and examined the efficacy and safety of its intravenous (i.v.) administration. BK-UM was administered to rats, and its serum levels were measured. Ovarian cancer cell lines were either intraperitoneally (i.p.) or subcutaneously administered into mice, to establish a mouse model of ovarian cancer. BK-UM was then administered i.p. or i.v., and its tumour-inhibiting effects were examined. Higher maximum serum concentration (Cmax) values resulted from i.v. administration, whereas longer time to maximum serum (Tmax) values resulted from i.p. administration. In the peritoneal dissemination model, i.p. administration inhibited tumour growth and increased survival rate, whereas in the subcutaneous model, i.v. administration significantly inhibited tumour growth compared to i.p. administration. Administration of BK-UM by i.v. is both efficacious and safe.

Vascular Graft Impregnation with Antibiotics: The Influence of High Concentrations of Rifampin, Vancomycin, Daptomycin, and Bacteriophage Endolysin HY-133 on Viability of Vascular Cells.

BackgroundRifampin-soaked synthetic prosthetic grafts have been widely used for prevention or treatment of vascular graft infections (VGIs).This in vitro study investigated the effect of the antibiotics daptomycin and vancomycin and the new recombinant bacteriophage endolysin HY-133 on vascular cells, as potential alternatives compared to rifampin.Material/MethodsPrimary human ECs, vascular smooth muscle cells (vSMC), and fibroblasts were cultivated in 96-well plates and incubated with rifampin, daptomycin, vancomycin, and endolysin HY-133 for 24 h. Subsequently, after washing, cell viability was determined by measuring mitochondrial ATP concentration. Antibiotics were used in their corresponding minimum and maximum serum concentrations, in decimal multiples and in maximum soaking concentration. The experiments were performed in triplicate.ResultsThe 10-fold max serum concentrations of rifampin, daptomycin, and vancomycin did not influence viability of EC and vSMC (100 μg/ml, p>0.170). Higher concentrations of rifampin (>1 mg/ml) significantly (p<0.001) reduced cell viability of all cell types. For the other antibiotics, high concentrations (close to maximum soaking concentration) were most cytotoxic for EC and vSMC and fibroblasts (p<0.001). Endolysin did not display any cytotoxicity towards vascular cells.ConclusionsResults of this in vitro study show the high cytotoxicity of rifampin against vascular cells, and may re-initiate the discussion about the benefit of prophylactic pre-soaking in high concentrations of rifampin. Further studies are necessary to determine the influence of rifampin on the restoration of vessel functionality versus its prophylactic effect against VGIs. Future use of recombinant phage endolysins for alternative prophylactic strategies needs further investigations.

A Randomized Single Dose Parallel Study on Enhancement of Nitric Oxide in Serum and Saliva with the Use of Natural Sports Supplement in Healthy Adults

ABSTRACT Sports supplements that stimulate the production of nitric oxide (NO) are widely promoted agents in the sports nutrition domain, and nitric oxide plays an important role to enhance the cardiovascular and physical fitness of the sports participants. The purpose of the study is to investigate whether oral intake of a sports nutritional supplement (Fitnox) is able to increase nitrate (NO3 −) and nitrite (NO2 −) levels in blood serum and saliva of healthy adults. Fitnox is a unique blend of Kaempferia parviflora methoxy flavones, pomegranate peel polyphenols, and Moringa oleifera leaf saponins. Twenty-four healthy male adults were equally divided and underwent the double-blind, placebo-controlled clinical trial with a single oral dose of sports nutrition formulation (250 mg capsules); blood and saliva samples were analyzed at different time intervals by high-performance liquid chromatography (HPLC). After administration of Fitnox (250 mg capsule as single dose), NO3 − and NO2 − levels in serum and saliva were found to be significantly higher (p <.05) than in the placebo group in 24 hours. Pharmacokinetic parameters such as the area under the plasma concentration-time curve extrapolated to infinity (AUC0-inf), AUC calculated to the last measured concentration (AUC0-t), maximum drug serum concentrations (Cmax), time of maximum concentration in serum observed (Tmax), and time required for the concentration of the drug to reach half of its original value (Thalf) were also statistically significant (p <.05) compared with the placebo. The results indicate that a single oral dose of Fitnox is able to increase the NO3 − and NO2 − levels considerably in the body relative to placebo for at least 12 hours. Therefore, Fitnox can improve the overall performance of sport participants and enhance physical endurance.

Pharmacokinetics and Tolerance of the Phage Endolysin-Based Candidate Drug SAL200 after a Single Intravenous Administration among Healthy Volunteers

ABSTRACTThis study was a phase 1, single-center, randomized, double-blind, placebo-controlled, single-dosing, and dose-escalating study of intravenous SAL200. It is a new candidate drug for the treatment of antibiotic-resistant staphylococcal infections based on a recombinant form of the phage endolysin SAL-1. The study evaluated the pharmacokinetics, pharmacodynamics, and tolerance among healthy male volunteers after the intravenous infusion of single ascending doses of SAL200 (0.1, 0.3, 1, 3, and 10 mg/kg of body weight). SAL200 was well tolerated, and no serious adverse events (AEs) were observed in this clinical study. Most AEs were mild, self-limiting, and transient. The AEs reported in more than three participants were fatigue, rigors, headache, and myalgia. No clinically significant values with respect to the findings of clinical chemistry, hematology, and coagulation analyses, urinalysis, vital signs, and physical examinations were observed, and no notable trends in our electrocardiogram (ECG) results for any tested dose were noticed. A greater-than-dose-proportional increase with regard to systemic exposure and the maximum serum concentration was observed when the SAL200 dose was increased from 0.1 mg/kg to 10 mg/kg. This investigation constitutes the first-in-human phase 1 study of an intravenously administered, phage endolysin-based drug. (This study has been registered at ClinicalTrials.gov under identifier NCT01855048 and at the Clinical Research Information Service [https://cris.nih.go.kr/cris/] under identifier KCT0000968.).

Markers of gut dysfunction do not explain low rifampicin bioavailability in HIV-associated TB.

Rifampicin is the key drug responsible for sterilizing activities in the first-line TB treatment regimen. Damage to the gut during acute and chronic HIV infection may inhibit drug absorptive capacity. We sought to test the hypothesis that markers of intestinal damage, bacterial translocation and systemic immune activation would relate to rifampicin bioavailability among HIV/TB patients. We conducted a prospective cohort study of rifampicin pharmacokinetics in HIV/TB patients in Gaborone, Botswana. We performed two intensively sampled pharmacokinetic visits, before and after ART initiation. Non-linear mixed-effects modelling was performed to determine whether variability in markers of gut damage, microbial translocation or systemic immune activation contributed to variability in rifampicin bioavailability before and after the initiation of ART. We enrolled 40 HIV/TB patients in the first pharmacokinetic visit and 24 patients returned for the second pharmacokinetic visit after initiating ART. Low rifampicin exposure, as defined by the maximum serum concentration, was observed in 40% of patients prior to initiating ART and 46% of patients after initiating ART. In the non-linear mixed-effects model, we did not observe significant covariate effects of markers of gut damage, microbial translocation or immune activation on rifampicin bioavailability before and after ART initiation. Markers of intestinal damage, microbial translocation and systemic immune activation did not explain variability in rifampicin bioavailability. The a priori identification of HIV/TB patients at risk for low rifampicin concentrations remains a challenge, supporting a role for therapeutic drug monitoring during HIV/TB therapy.

КІНЕТИКА АБСОРБЦІЇ МІГУ-6 – ПОТЕНЦІЙНОГО ЗАСОБУ ФАРМАКОТЕРАПІЇ ЕНДОТОКСЕМІЇ

Актуальною проблемою сучасної медицини є лікування синдрому ендогенної інтоксикації (СЕІ), що є поліетіологічним невідкладним станом, та потребує патогенетично обґрунтованої раціональної фармакотерапії. Раніше доведено, що оригінальна координаційна сполука германію із магнієм та оксиетилідендифосфоновою кислотою (МІГУ-6) є безпечною та проявляє високу детоксикаційну активність при СЕІ на моделі синдрому тривалого розчавлювання (СТР).Мета дослідження – порівняльне фармакокінетичне вивчення процесів абсорбції МІГУ-6 в щурів у нормі та за умов ендотоксикозу посттравматичного генезу.Матеріали і методи. Експериментальною моделлю слугував патологічний процес, що розвивався в щурів у результаті розчавлювання м’яких тканин задніх кінцівок. Оригінальну сполуку вводили у вигляді 1% водного розчину в дозі 140,6 мг/кг безпосередньо перед декомпресією. Фармакокінетику МІГУ-6 вивчали шляхом визначення концентрації германію у тканинах тварин на тлі СТР та в інтактних тварин. Забір біоматеріалу здійснювали через 30 хв, 1, 4, 8, 12 та 24 год з моменту введення МІГУ-6 та проводили порівняльний аналіз таких показників: константа швидкості абсорбції (К01), період напівабсорбції (t1/2,а), максимальна концентрація препарату у крові (Cmax), час досягнення максимальної концентрації в крові (tmax).Результати досліджень та їх обговорення. Порівняльний аналіз дозволяє констатувати, що процес всмоктування МІГУ-6 у нормі й на тлі ендотоксемії відбувається досить швидко. При цьому в тварин, які перенесли СТР, реєструються більші концентрації МІГУ-6, ніж у тварин без патології. Швидкість надходження даної сполуки в системний кровообіг у здорових тварин становить 0,71 год-1, у тварин з СТР перевершує аналогічний параметр здорових тварин у 5,4 раза. Період напівабсорбції корелює з константою швидкості абсорбції. Максимальна концентрація МІГУ-6 у сироватці крові в умовах ендотоксикозу достовірно збільшується порівняно з групою здорових щурів (119,36 мкг/л) та становить 152,85 мкг/л. tmax у 2,3 раза швидший у групі тварин із СТР.Висновки. На тлі ендотоксикозу посттравматичного генезу фармакокінетичні параметри, що характеризують абсорбцію МІГУ-6, зазнають істотних змін у бік підвищення інтенсивності всмоктування даної сполуки у системний кровообіг.