Clinical Pharmacology : Advances and Applications最新文献

{"title":"Species difference in paclitaxel disposition correlated with poor pharmacological efficacy translation from mice to humans.","authors":"Ying Fei Li,&nbsp;Chengyue Zhang,&nbsp;Simon Zhou,&nbsp;Miao He,&nbsp;Huixia Zhang,&nbsp;Nianhang Chen,&nbsp;Feng Li,&nbsp;Xin Luan,&nbsp;Manjunath Pai,&nbsp;Hebao Yuan,&nbsp;Duxin Sun,&nbsp;Yan Li","doi":"10.2147/CPAA.S185449","DOIUrl":"https://doi.org/10.2147/CPAA.S185449","url":null,"abstract":"<p><strong>Background: </strong>Paclitaxel (PTX) products currently approved by the Food and Drug Administration include Kolliphor EL-paclitaxel micelles (KoEL-paclitaxel, Taxol) and nanoparticle albumin-bound paclitaxel (<i>nab</i>-paclitaxel, Abraxane). Despite containing the same cytotoxic agent, different PTX formulations have distinct pharmacological responses and indications in patients with cancer. Several novel PTX delivery vehicles that have shown superior efficacy to Taxol in animal models failed to demonstrate efficacy in Phase II/III human clinical trials.</p><p><strong>Materials and methods: </strong>A 10 mg/kg IV dose of KoEL-paclitaxel or <i>nab</i>-paclitaxel was administered to mice, and the pharmacokinetics (PK) profile of PTX in mice was then compared with the human PK profile from clinical studies. Population PK model and simulation was used to delineate the distribution and elimination characteristics in each species. In addition, tumor shrinkage was measured after weekly administration of both formulations in mouse xenograft model.</p><p><strong>Results: </strong>Our pharmacokinetic modeling results suggested that elimination predominates over distribution in driving PTX disposition in mice, hence restricting the PTX tissue accumulation. Moreover, the rapid elimination of PTX in mice minimized the different formulation effects on PTX tissue distribution, which is believed to link to the superior efficacy of <i>nab</i>-paclitaxel over KoEL-paclitaxel seen in human. In contrast to mice, PTX distribution predominates over elimination in human, and the decline in plasma PTX concentration reflected the deeper tissue distribution by <i>nab</i>-paclitaxel.</p><p><strong>Conclusion: </strong>This species difference in PTX distribution and elimination hinders a simple direct extrapolation from animals to humans. Therefore, species difference in drug distribution and elimination should be carefully assessed during translational drug development.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"10 ","pages":"165-174"},"PeriodicalIF":2.0,"publicationDate":"2018-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CPAA.S185449","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36799523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of the single-dose pharmacokinetics and pharmacodynamics of apixaban in healthy Japanese and Caucasian subjects.","authors":"Charles Frost,&nbsp;Andrew Shenker,&nbsp;Stanford Jhee,&nbsp;Zhigang Yu,&nbsp;Jessie Wang,&nbsp;Alexander Bragat,&nbsp;Janice Pursley,&nbsp;Frank LaCreta","doi":"10.2147/CPAA.S169505","DOIUrl":"https://doi.org/10.2147/CPAA.S169505","url":null,"abstract":"<p><strong>Purpose: </strong>This double-blind, placebo-controlled, intra-subject, dose-escalation study assessed single-dose safety, pharmacokinetics, and pharmacodynamics of apixaban in healthy Japanese and Caucasian subjects.</p><p><strong>Subjects and methods: </strong>Sixteen healthy male Japanese and sixteen healthy male Caucasian subjects, matched for age, weight, and smoking status were randomized to receive four sequential single oral doses of either apixaban (2.5, 10, 25, and 50 mg) or matched placebo. Doses were separated by a ≥5-day washout. Blood samples were collected for the determination of apixaban plasma concentration, clotting times (international normalized ratio [INR], activated partial thromboplastin time, and modified prothrombin time [mPT]), and ex vivo thrombin generation (TG). Urine samples were collected for the analysis of apixaban concentration.</p><p><strong>Results: </strong>Ascending single doses of apixaban 2.5-50 mg were safe and well tolerated by all subjects. Apixaban exposure increased the dose proportionally up to 10 mg. Apixaban reached maximum concentrations (<i>C</i> _max) 3-4 h postdose, with mean <i>C</i> _max ranging from 52.5-485.0 to 44.8-494.3 ng/mL in Japanese and Caucasian subjects. The mean half-life was ~8 and ~13 h and the renal clearance was 1.1 and 0.8 L/h in Japanese and Caucasian subjects, respectively. Pharmacodynamic assessments were similar between ethnic groups, with comparable dose-related prolongation of INR and mPT and inhibition of TG.</p><p><strong>Conclusion: </strong>Ascending single doses of apixaban over a 20-fold dose range were safe and well tolerated in Japanese and Caucasian subjects in this study. The consistency between pharmacokinetic and pharmacodynamic measures in Japanese and Caucasian subjects indicates that apixaban may be administered as a fixed dose with no need for adjustment in Japanese patients.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"10 ","pages":"153-163"},"PeriodicalIF":2.0,"publicationDate":"2018-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CPAA.S169505","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36781757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of combined treatment with sodium phenylbutyrate and cisplatin, erlotinib, or gefitinib on resistant NSCLC cells.","authors":"Maha S Al-Keilani,&nbsp;Karem H Alzoubi,&nbsp;Saied A Jaradat","doi":"10.2147/CPAA.S174074","DOIUrl":"https://doi.org/10.2147/CPAA.S174074","url":null,"abstract":"<p><strong>Background: </strong>Chemotherapy resistance is the main cause of the marginal clinical benefit of platinum-based chemotherapy and tyrosine kinase inhibitors in advanced non-small-cell lung cancer (NSCLC). Thus, the identification of new therapeutic agents that can enhance the sensitivity of these drugs is of clinical importance. Histone deacetylase inhibitors (HDACIs) are emerging as new promising agents with strong antiproliferative effects against different types of cancers. This study investigates the synergistic potential of sodium phenylbutyrate (NaPB) added on top of standard chemotherapy used against NSCLC.</p><p><strong>Objective: </strong>The objective of this study was to evaluate the ability of NaPB to overcome the resistance of NSCLC cell lines to cisplatin, gefitinib, and erlotinib.</p><p><strong>Methods: </strong>MTT cell proliferation assay was used to measure the anticancer effects of cisplatin, erlotinib, or gefitinib alone or combined with various concentrations of NaPB against A549, Calu1, and H1650 NSCLC cell lines. Synergism was estimated by measuring synergy value (R), which is equal to the ratio of IC₅₀ of each primary drug alone divided by combination IC₅₀s. Student's <i>t</i>-test analysis was used to evaluate the potential differences between IC₅₀ values. ANOVA followed by Tukey's post hoc was used to evaluate the potential differences among monotherapy and combination treatment groups. Analyses were performed using R 3.3.2 software. <i>P</i>-value <0.05 was considered to be statistically significant.</p><p><strong>Results: </strong>NaPB was shown to inhibit the growth of A549, Calu1, and H1650 cell lines in a dose-dependent manner (IC₅₀ 10, 8.53, and 4.53 mM, respectively). Furthermore, the addition of NaPB along with cisplatin, erlotinib, or gefitinib to A549, Calu1, and H1650 cell lines resulted in a synergistic antiproliferative effect against the three NSCLC cell lines (<i>R</i>>1.6, <i>P</i>-value <0.05), thus suggesting that NaPB can potentiate the effect of cisplatin, erlotinib, and gefitinib on A549, Calu1, and H1650 cell lines.</p><p><strong>Conclusion: </strong>Current results suggest a potential role of NaPB as a sensitizing agent in NSCLC.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"10 ","pages":"135-140"},"PeriodicalIF":2.0,"publicationDate":"2018-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CPAA.S174074","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36608027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"12-month effects of incretins versus SGLT2-Inhibitors on cognitive performance and metabolic profile. A randomized clinical trial in the elderly with Type-2 diabetes mellitus.","authors":"Simone Perna, Manuela Mainardi, Paolo Astrone, Carlotta Gozzer, Anna Biava, Ruben Bacchio, Daniele Spadaccini, Sebastiano Bruno Solerte, Mariangela Rondanelli","doi":"10.2147/CPAA.S164785","DOIUrl":"10.2147/CPAA.S164785","url":null,"abstract":"<p><strong>Aim: </strong>The aim of the present study is to examine the effects on cognitive performance, anthropometric measures, and metabolic markers in 2 different treatments: Incretins vs sodium-glucose co-transporter-2 inhibitors (SGLT2-I).</p><p><strong>Materials and methods: </strong>A randomized controlled clinical trial was carried out on 39 elderly subjects (23 men and 16 women) with type 2 diabetes mellitus, with a mean age of 77.21±8.07 years. Body mass index (BMI) of 29.92±4.31 kg/m² and a cognitive status measured by a Mini Mental State Examination (scores >27 points). The subjects were on a 3-month treatment with a maximal dose of metformin as a stable regime, with the addition of incretins (liraglutide at doses of up to 1.8 mg/d; vildagliptin at 100 mg/d; sitagliptin 100 mg/d; and linagliptin 5 mg/d), or SGLT2-I (canagliflozin 300 mg/d; empagliflozin 25 mg/d; and dapagliflozin 10 mg/d). Glucose control was monitored by fasting glucose and glycosylated hemoglobin. Cognitive performance (by way of Verbal Fluency Test, Attentive Matrices Test, and Babcock Story Recall Test), anthropometric measures, and plasma lipids were also evaluated.</p><p><strong>Results: </strong>Cognitive status did not change significantly during the 12 months of treatment in either group: Verbal Fluency Test: (SGLT2-I: <i>P</i>=1.00, incretins: <i>P</i>=0.598); Babcock Story Recall Test (SGLT2-I: <i>P</i>=0.391; incretins: <i>P</i>=0.351); and Attentive Matrices Test (SGLT2-I: <i>P</i>=0.679, incretins: <i>P</i>=0.901). SGLT2-I also resulted in a reduction in weight (-1.95 kg; <i>P</i><0.05), in BMI (-0.69 kg/m²; <i>P</i><0.05) and an increase in high-density lipoprotein cholesterol (+5.73 mg/dl; <i>P</i><0.01).</p><p><strong>Conclusion: </strong>Preliminary data show that patients treated with incretins and SGLT2-I have not suffered a reduction in cognitive performance during the 1 year of treatment. Metabolic outcome seemed to benefit, in particular, in patients who were treated with SGLT2-I.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"10 ","pages":"141-151"},"PeriodicalIF":2.0,"publicationDate":"2018-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/52/16/cpaa-10-141.PMC6186903.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36608028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms and the clinical relevance of complex drug-drug interactions.","authors":"Arthur G Roberts,&nbsp;Morgan E Gibbs","doi":"10.2147/CPAA.S146115","DOIUrl":"https://doi.org/10.2147/CPAA.S146115","url":null,"abstract":"<p><p>As a result of an increasing aging population, the number of individuals taking multiple medications simultaneously has grown considerably. For these individuals, taking multiple medications has increased the risk of undesirable drug-drug interactions (DDIs), which can cause serious and debilitating adverse drug reactions (ADRs). A comprehensive understanding of DDIs is needed to combat these deleterious outcomes. This review provides a synopsis of the pharmacokinetic (PK) and pharmacodynamic (PD) mechanisms that underlie DDIs. PK-mediated DDIs affect all aspects of drug disposition: absorption, distribution, metabolism and excretion (ADME). In this review, the cells that play a major role in ADME and have been investigated for DDIs are discussed. Key examples of drug metabolizing enzymes and drug transporters that are involved in DDIs and found in these cells are described. The effect of inhibiting or inducing these proteins through DDIs on the PK parameters is also reviewed. Despite most DDI studies being focused on the PK effects, DDIs through PD can also lead to significant and harmful effects. Therefore, this review outlines specific examples and describes the additive, synergistic and antagonistic mechanisms of PD-mediated DDIs. The effects DDIs on the maximum PD response (<i>E</i> _max) and the drug dose or concentration (EDEC₅₀) that lead to 50% of <i>E</i> _max are also examined. Significant gaps in our understanding of DDIs remain, so innovative and emerging approaches are critical for overcoming them.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"10 ","pages":"123-134"},"PeriodicalIF":2.0,"publicationDate":"2018-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CPAA.S146115","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36618033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting EGFR and uPAR on human rhabdomyosarcoma, osteosarcoma, and ovarian adenocarcinoma with a bispecific ligand-directed toxin.","authors":"Felix Oh,&nbsp;Deborah Todhunter,&nbsp;Elizabeth Taras,&nbsp;Daniel A Vallera,&nbsp;Antonella Borgatti","doi":"10.2147/CPAA.S160262","DOIUrl":"https://doi.org/10.2147/CPAA.S160262","url":null,"abstract":"<p><strong>Purpose: </strong>Human sarcomas are rare and difficult to treat cancerous tumors typically arising from soft tissue or bone. Conversely, carcinomas are the most common cancer subtype in humans and the primary cause of mortality across all cancer patients. While conventional therapeutic modalities can prolong disease-free intervals and survival in some cases, treatment of refractory or recurrent solid tumors is challenging, and tumor-related mortality remains unacceptably high. The identification of overexpressed cell surface receptors on sarcoma and carcinoma cells has provided a valuable tool to develop targeted toxins as an alternative anticancer strategy. Recent investigation of recombinant protein-linked toxins that specifically target these cancer receptors has led to the development of highly specific, cytotoxic, and deimmunized drugs that can kill cancer cells.</p><p><strong>Methods: </strong>This study investigated a recombinant protein called epidermal growth factor bispecific angiotoxin (eBAT), which is designed to target the epidermal growth factor receptor (EGFR) on cancer cells and the urokinase plasminogen activator receptor (uPAR) on cancer cells and associated tumor vasculature. Both receptors are expressed by a variety of human sarcomas and carcinomas. Flow cytometry techniques were used to determine binding affinity of eBAT to cancer cells, and proliferation assays were performed to calculate tumor killing ability based on half-maximal inhibitory concentrations.</p><p><strong>Results: </strong>eBAT demonstrated cytotoxicity against a variety of sarcoma and carcinoma cells that overexpress EGFR and uPAR in vitro and showed greater cell killing ability and binding affinity to cancer cells compared with its monospecific counterparts.</p><p><strong>Conclusion: </strong>The results of our study are promising, and further studies will be necessary to confirm the applicability of eBAT as a supplementary therapy for a variety of sarcomas, carcinomas, and possibly other refractory malignancies that express EGFR and uPAR.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"10 ","pages":"113-121"},"PeriodicalIF":2.0,"publicationDate":"2018-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CPAA.S160262","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36558829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics of evocalcet in secondary hyperparathyroidism patients receiving hemodialysis: first-in-patient clinical trial in Japan.","authors":"Takashi Shigematsu,&nbsp;Ryutaro Shimazaki,&nbsp;Masafumi Fukagawa,&nbsp;Tadao Akizawa","doi":"10.2147/CPAA.S171044","DOIUrl":"https://doi.org/10.2147/CPAA.S171044","url":null,"abstract":"<p><strong>Purpose: </strong>Cinacalcet is a positive allosteric modulator of calcium-sensing receptors in the parathyroid gland and an effective treatment for secondary hyperparathyroidism. However, this agent has considerable side effects and dosage limitations, which impair effective treatment. Therefore, we investigated the pharmacokinetics, pharmacodynamics, and safety of the novel calcimimetic, evocalcet.</p><p><strong>Patients and methods: </strong>This was a multicenter, open-label study of single oral doses of 1, 4, and 12 mg evocalcet using an intrapatient dose escalation protocol in 29 Japanese secondary hyperparathyroidism patients receiving hemodialysis. Pharmacokinetics was assessed by plasma evocalcet concentrations. Pharmacodynamic evaluations consisted of measuring intact parathyroid hormone, serum corrected calcium, and fibroblast growth factor 23 concentrations. Safety and tolerability were evaluated by the analysis of adverse events (AEs).</p><p><strong>Results: </strong>After a single 1-, 4-, or 12-mg dose, plasma evocalcet levels increased dose proportionally in a linear manner. Pharmacodynamic analyses showed that evocalcet effectively reduced intact parathyroid hormone and serum corrected calcium levels in a dose-dependent manner. AEs occurred in 31.0%, 28.6%, and 38.5% of patients receiving a single dose of 1, 4, or 12 mg, respectively. Most AEs were mild in severity.</p><p><strong>Conclusion: </strong>Evocalcet is effective in the short term, has linear pharmacokinetics, and is well tolerated as observed by the low incidence of AEs.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"10 ","pages":"101-111"},"PeriodicalIF":2.0,"publicationDate":"2018-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CPAA.S171044","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36522481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase I, open-label, randomized, crossover study in healthy subjects to evaluate the bioavailability of, and the food effect on, a pomalidomide oral liquid suspension.","authors":"Yan Li,&nbsp;Liangang Liu,&nbsp;Lian Huang,&nbsp;Xiaomin Wang,&nbsp;Matthew Hoffmann,&nbsp;Josephine Reyes,&nbsp;Maria Palmisano,&nbsp;Simon Zhou","doi":"10.2147/CPAA.S171735","DOIUrl":"https://doi.org/10.2147/CPAA.S171735","url":null,"abstract":"<p><strong>Objective: </strong>The aim of this study was to evaluate the bioavailability of a pomalidomide oral liquid suspension relative to the commercial capsule formulation and to assess the food effect on the pomalidomide oral liquid suspension when administered as a single 4 mg dose.</p><p><strong>Methods: </strong>This was an open-label, randomized, three-period, two-sequence crossover study in healthy subjects consisting of a screening phase, a baseline assessment phase, a treatment phase with three periods, and a follow-up phone call phase. Blood samples for pharmacokinetics (PK) assessment were collected up to 48 h postdose during each treatment period. Safety was evaluated throughout the study.</p><p><strong>Results: </strong>Pomalidomide exposures were comparable in healthy subjects administered with a single oral 4 mg dose as the reference capsule or as the test liquid suspension formulations, demonstrated as the 90% confidence intervals of the geometric mean ratios for area under the plasma concentration-time curve calculated from time 0 to the last measurable concentration at time <i>t</i> (AUC_0-t), area under the plasma concentration-time curve from time 0 to infinity (AUC_0-∞), and peak (maximum) plasma drug concentration (<i>C</i>_max) were completely contained within the bioequivalence range of 80-125%. Administration of the pomalidomide liquid suspension with a high fat meal resulted in a 3.0 h delay in pomalidomide time to <i>C</i>_max (<i>t</i>_max) and an ~ 34.5% reduction in <i>C</i>_max. However, the AUCs were comparable after dose administration with and without food.</p><p><strong>Conclusion: </strong>A single oral dose of 4 mg of liquid suspension was bioequivalent to a single oral dose of 4 mg of capsule formulation. There was no clinically relevant impact of food on pomalidomide liquid suspension. Single oral doses of 4 mg pomalidomide were safe and well tolerated when administered as a liquid suspension under fed and fasted conditions or as a capsule under fasted conditions.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"10 ","pages":"89-99"},"PeriodicalIF":2.0,"publicationDate":"2018-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CPAA.S171735","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36346088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and neutralizing rabies antibody in healthy subjects given a single dose of rabies immune globulin caprylate/chromatography purified.","authors":"Kim Hanna,&nbsp;Maria Cristina Cruz,&nbsp;Elsa Mondou,&nbsp;Edward Corsi,&nbsp;Peter Vandeberg","doi":"10.2147/CPAA.S166454","DOIUrl":"https://doi.org/10.2147/CPAA.S166454","url":null,"abstract":"<p><strong>Background: </strong>Rabies immune globulin (RIG) and vaccination series are necessary for postexposure prophylaxis. A new formulation of RIG (human) purified by caprylate/chromatography (RIG-C) was evaluated.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov identifier: NCT02139657.</p><p><strong>Materials and methods: </strong>This open-label, single-arm study in healthy subjects evaluated neutralizing rabies antibody concentrations produced from a single 20 IU/kg intramuscular (IM) dose of RIG-C as measured by rapid fluorescent focus inhibition test (50% neutralization endpoint) 1-hour postdose and on days 1, 2, 4, 6, 8, 10, 14, 18, and 21.</p><p><strong>Results: </strong>Twelve subjects were enrolled into the study. No discontinuations, serious adverse events (AEs), or treatment-emergent clinically significant changes in laboratory parameters were observed. All AEs resolved and were mild except 1 moderate AE of oropharyngeal pain. Injection site pain (4 subjects) was most commonly reported. RIG-C produced a rapid increase in neutralizing rabies antibody: mean value 0.113 IU/mL at 24 hours after IM injection, peak on day 4 (0.132 IU/mL), persisting through day 21 (0.116 IU/mL). The mean reciprocal titer was 11.5 by day 2; the peak value of 12.1 was achieved on day 4; and a mean value ≥10.6 was maintained through day 21.</p><p><strong>Conclusion: </strong>RIG-C was well tolerated and provided neutralizing rabies antibodies, which combined with vaccine series after rabies exposure, should result in effective prophylaxis per World Health Organization/Centers for Disease Control and Prevention guidelines.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"10 ","pages":"79-88"},"PeriodicalIF":2.0,"publicationDate":"2018-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CPAA.S166454","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36292899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic evaluation of D-ribose after oral and intravenous administration to healthy rabbits.","authors":"Karem H Alzoubi, Zuhair Bani Ismail, Mohamed K Al-Essa, Osama Y Alshogran, Reem F Abutayeh, Nareman Abu-Baker","doi":"10.2147/CPAA.S167150","DOIUrl":"10.2147/CPAA.S167150","url":null,"abstract":"<p><strong>Introduction: </strong>This study explored D-ribose pharmacokinetics after intravenous (IV) and oral administration to healthy rabbits.</p><p><strong>Materials and methods: </strong>D-ribose was administered once as 420 mg/kg (N=4) or 840 mg/kg (N=6) dose intravenously, or as an oral dose of 420 mg/kg (N=3) or 840 mg/kg (N=3). Serum was obtained at various time points, up to 210 minutes after administration. Urine was also collected after IV administration. Pharmacokinetic parameters were determined from drug concentration-time data using Kinetica software.</p><p><strong>Results: </strong>The findings showed that D-ribose follows a dose-dependent kinetic profile. With doubling the IV dose, AUC_total was significantly increased by threefold, while the clearance was decreased by 44%. The half-life was 1.7-fold longer at the higher dose. Similar nonsignificant trends were also observed at oral administration. D-ribose was rapidly absorbed (T_max=36-44 minutes) and rapidly disappeared from plasma (within <140 minutes). Additionally, D-ribose was partially (18-37.5%) recovered from urine.</p><p><strong>Conclusion: </strong>Collectively, D-ribose showed a dose-dependent kinetic profile, where parameters change according to dosing levels. D-ribose clearance seems to follow first-order kinetics at low dose. Thereafter, elimination systems are saturated, and elimination continues in a fast manner. Urine recovery was partial, which could be attributed to the several metabolic pathways that pentose can undergo.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"10 ","pages":"73-78"},"PeriodicalIF":2.0,"publicationDate":"2018-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/59/61/cpaa-10-073.PMC6003283.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36244784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}