Journal of clinical pharmacology最新文献

{"title":"Population Pharmacokinetics and Exposure-Response Modeling Analyses of Ustekinumab in Adults With Moderately to Severely Active Ulcerative Colitis.","authors":"Yan Xu,&nbsp;Chuanpu Hu,&nbsp;Yang Chen,&nbsp;Xin Miao,&nbsp;Omoniyi J Adedokun,&nbsp;Zhenhua Xu,&nbsp;Amarnath Sharma,&nbsp;Honghui Zhou","doi":"10.1002/jcph.1582","DOIUrl":"https://doi.org/10.1002/jcph.1582","url":null,"abstract":"<p><p>To characterize the pharmacokinetics (PK) and exposure-response (E-R) relationship of ustekinumab, an anti-interleukin-12/interleukin-23 (IL-12/IL-23) human monoclonal antibody, in the treatment of moderately to severely active ulcerative colitis (UC), population PK and E-R modeling analyses were conducted based on the data from the pivotal phase 3 induction and maintenance studies in UC patients. The observed serum concentration-time data of ustekinumab were adequately described by a 2-compartment linear PK model with first-order absorption and first-order elimination. Body weight, baseline serum albumin, sex, and antibodies to ustekinumab were the covariates to influence ustekinumab PK, but the magnitudes of the effects of these covariates were not considered clinically relevant, and dose adjustment was not warranted. Positive E-R relationships were demonstrated between ustekinumab exposure metrics and clinical endpoints (including clinical response, clinical remission, and endoscopic healing based on Mayo score) at induction week 8 and maintenance week 44, consistent with the effectiveness of ustekinumab in the induction and maintenance treatment of patients with UC. E-R modeling results suggest that ustekinumab ∼6 mg/kg intravenous induction and 90-mg subcutaneous every-8-week maintenance dose would produce greater efficacy than the 130 mg intravenous induction and the 90-mg subcutaneous every-12-week maintenance regimen, respectively. Our work provides a comprehensive evaluation of ustekinumab PK and E-R in a modeling framework to support ustekinumab dose recommendations in patients with UC.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"889-902"},"PeriodicalIF":2.9,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1582","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37615447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TMPRSS2: Potential Biomarker for COVID-19 Outcomes.","authors":"Jonathan D Strope,&nbsp;Cindy H Chau PharmD,&nbsp;William D Figg","doi":"10.1002/jcph.1641","DOIUrl":"https://doi.org/10.1002/jcph.1641","url":null,"abstract":"Coronavirus disease 2019 (COVID-19) clinical data has so far shown that the mortality rate for men is higher than for women. This disparity is observed worldwide and across different ethnic/racial groups (Table 1). Early reports from Italy and Germany show that while infection rates are similar between sexes, nearly 70% and 65%, respectively, of deaths aremales. InNewYork City, an epicenter of the US outbreak, 54% of those infected are men, yet men account for 63% of deaths. Epidemiologic data from the previous coronavirus infections, severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS), also indicated sex-based differences in disease susceptibility and outcomes. This discrepancy was attributed tomany factors, including smoking, immune differences, and other comorbidities. An initial report released by the Centers for Disease Control and Prevention (CDC) on population-based surveillance sampled across 14 states, representing 10% of the US population, has indicated that age and comorbidities are associated with increased hospitalization rates of patients with COVID19.1 The data on sex also suggest sexual dimorphism consistent with reports from other countries (Table 1). The preliminary data on race suggest that minority populations may be disproportionately impacted by the coronavirus, where blacks contributed to 33% of the hospitalizations despite representing only 18% of the sampled population. As more data become available, correlations between race and disease severity can be interrogated more thoroughly, including the role of socioeconomic factors on influencing this disparity. Investigations into the genetic and molecular differences between women and men are warranted to identify relevant biomarkers for disease susceptibility and outcomes. Based on data from literature, we propose a novel mechanism of the observed sex differences in clinical outcomes in patients and identify a role for the transmembrane protease serine 2 (TMPRSS2) as a contributing factor to the more severe outcomes noted for COVID-19.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"60 7","pages":"801-807"},"PeriodicalIF":2.9,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1641","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10702736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Severe Acute Lung Injury Related to COVID-19 Infection: A Review and the Possible Role for Escin.","authors":"Luca Gallelli,&nbsp;Leiming Zhang,&nbsp;Tian Wang,&nbsp;Fenghua Fu","doi":"10.1002/jcph.1644","DOIUrl":"https://doi.org/10.1002/jcph.1644","url":null,"abstract":"<p><p>Acute lung injury (ALI) represents the most severe form of the viral infection sustained by coronavirus disease 2019 (COVID-19). Today, it is a pandemic infection, and even if several compounds are used as curative or supportive treatment, there is not a definitive treatment. In particular, antiviral treatment used for the treatment of several viral infections (eg, hepatitis C, HIV, Ebola, severe acute respiratory syndrome-coronavirus) are today used with a mild or moderate effect on the lung injury. In fact, ALI seems to be related to the inflammatory burst and release of proinflammatory mediators that induce intra-alveolar fibrin accumulation that reduces the gas exchange. Therefore, an add-on therapy with drugs able to reduce inflammation, edema, and cell activation has been proposed as well as a treatment with interferon, corticosteroids or monoclonal antibodies (eg, tocilizumab). In this article reviewing literature data related to the use of escin, an agent having potent anti-inflammatory and anti-viral effects in lung injury, we suggest that it could represent a therapeutic opportunity as add-on therapy in ALI related to COVID-19 infection.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"815-825"},"PeriodicalIF":2.9,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1644","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37963532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Clinical Pharmacology in Chemotherapy of Multidrug-Resistant Plasmodium falciparum.","authors":"Juntra Karbwang,&nbsp;Kesara Na-Bangchang","doi":"10.1002/jcph.1589","DOIUrl":"https://doi.org/10.1002/jcph.1589","url":null,"abstract":"<p><p>Malaria remains one of the major global public health problems due to the emergence and spread of multidrug-resistant Plasmodium falciparum. In recent years, clinical pharmacology has significantly contributed to the optimal dosing regimens of antimalarial drugs. The application of pharmacometric modeling and simulation has assisted in the accurate characterization of pharmacokinetic-pharmacodynamic relationships and the optimization of the dosage regimens of existing antimalarial drugs, including new antimalarial candidates for multidrug-resistant P falciparum in different populations.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"830-847"},"PeriodicalIF":2.9,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1589","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37685311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of Similarity in Antipsychotic Exposure-Response Relationships in Clinical Trials Between Adults and Adolescents With Acute Exacerbation of Schizophrenia.","authors":"Shamir N Kalaria,&nbsp;Tiffany R Farchione,&nbsp;Mitchell V Mathis,&nbsp;Mathangi Gopalakrishnan,&nbsp;Islam Younis,&nbsp;Ramana Uppoor,&nbsp;Mehul Mehta,&nbsp;Yaning Wang,&nbsp;Hao Zhu","doi":"10.1002/jcph.1580","DOIUrl":"https://doi.org/10.1002/jcph.1580","url":null,"abstract":"<p><p>Despite agreement that early-onset schizophrenia is continuous with the adult-onset form, quantitative relationships between antipsychotic exposure and clinical response are relatively unexplored in adolescents, compared to adults. Clinical efficacy data from second-generation antipsychotic development programs (N = 5951 adults and N = 1035 adolescents ranging from 12 to 17 years old) were collected from available new drug applications submitted to the US Food and Drug Administration from 1993 to 2017. The developed disease-drug trial models adequately predicted the longitudinal trend in total positive and negative syndrome scale scores in both adults and adolescents using a Weibull placebo response, time-delayed drug effect, and a Weibull structural dropout model. Maximum drug effect was similar between the two populations and was estimated to be between a range of 5% to 11% in adults and 5% to 7% in adolescents. Half maximal effective concentration parameter estimates also indicated similar exposure-response relationships in adults and adolescents across all 4 antipsychotics. Simulated adolescent data using final model parameter estimates from the adult model were in agreement with adolescent observations. This analysis confirms similarity in exposure-response for efficacy and could expedite the development of second-generation antipsychotics for adolescents.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"848-859"},"PeriodicalIF":2.9,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1580","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37589255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proton Pump Inhibitor Use Before ICU Admission Is Not Associated With Mortality of Critically Ill Patients.","authors":"Lin Shi,&nbsp;Dan Zhang","doi":"10.1002/jcph.1585","DOIUrl":"https://doi.org/10.1002/jcph.1585","url":null,"abstract":"<p><p>Some studies have shown that the long-term use of proton pump inhibitors (PPIs) is associated with many adverse events that may increase mortality; however, the relationship between premorbid PPI use and in-hospital mortality has yet to be validated in critically ill patients. Therefore, we performed this study to determine whether the preadmission use of PPIs is associated with mortality in patients admitted to the intensive care unit. This was a retrospective study with a large and freely accessible database in critical-care medicine (the Multiparameter Intelligent Monitoring in Intensive Care III project). The clinical data and outcomes of 17 473 patients, consisting of 1895 in the PPI group, 514 in the H₂ -receptor antagonist group, and 15 064 control subjects, were collected during their hospital stay. The study outcome was in-hospital mortality. A total of 17 473 patients were included in our study. PPI use was associated with significantly increased in-hospital mortality in the original model without adjustment for any parameters (odds ratio 1.19; 95%CI 1.03-1.38; P = .02). However, after adjustments had been made for age, sex, Elixhauser score, Simplified Acute Physiology Score, laboratory results, vasopressor use, ventilator use, and other parameters, PPIs were not associated with significantly increased in-hospital mortality (odds ratio 1.04; 95%CI 0.87-1.26; P = .614). In the subgroup analysis among patients with renal or liver disease, we still found that PPIs were not associated with a significant increase in in-hospital mortality. We found no association between PPI use before ICU admission and increased in-hospital mortality in critically ill patients compared with control subjects.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"860-866"},"PeriodicalIF":2.9,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1585","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37632099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetics and Pharmacodynamics of Ontamalimab (SHP647), a Fully Human Monoclonal Antibody Against Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1), in Patients With Ulcerative Colitis or Crohn's Disease.","authors":"Yi Wang,&nbsp;Jean-Francois Marier,&nbsp;Jean Lavigne,&nbsp;Nastya Kassir,&nbsp;Patrick Martin","doi":"10.1002/jcph.1590","DOIUrl":"https://doi.org/10.1002/jcph.1590","url":null,"abstract":"<p><p>Ontamalimab (SHP647) is a fully human, immunoglobulin G₂ , antihuman mucosal addressin cell adhesion molecule-1 (MAdCAM-1) monoclonal antibody being developed for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). A population pharmacokinetic/pharmacodynamic (PK/PD) analysis was conducted using clinical phase 2 study data to evaluate the PK and PD of ontamalimab following subcutaneous administrations of 7.5, 22.5, 75, and 225 mg every 4 weeks in patients with moderate to severe UC or CD. A total of 440 patients with UC (n = 249; 56.6%) or CD (n = 191; 43.4%) were included in the analysis. A 2-compartment model with parallel linear and nonlinear elimination adequately characterized concentration-time profiles of ontamalimab. The apparent clearance and volume of distribution were 0.0127 L/h (0.305 L/day) and 6.53 L, respectively. Apparent clearance and volume of distribution were mainly dependent on baseline albumin and body weight, respectively. No differences in the PK properties of ontamalimab were observed between patients with UC or CD. The presence of antidrug antibodies did not impact the PK of ontamalimab. Nonlinear elimination occurred at very low concentrations and was unlikely to contribute to the elimination half-life under steady-state conditions. A linear PK/PD model described the relationship between ontamalimab and free MAdCAM-1. Minimum concentrations of ontamalimab at steady state following 75 mg every 4 weeks were associated with >95% suppression of circulating free MAdCAM-1. The PK/PD properties characterized support phase 3 testing in UC and CD.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"903-914"},"PeriodicalIF":2.9,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1590","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37695170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydroxychloroquine and Azithromycin to Treat Patients With COVID-19: Both Friends and Foes?","authors":"Bruno Mégarbane,&nbsp;Jean-Michel Scherrmann","doi":"10.1002/jcph.1646","DOIUrl":"https://doi.org/10.1002/jcph.1646","url":null,"abstract":"The world is facing a frightening pandemic due to coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) with thousands of severe infections and fatalities. Since no therapy has proven effective, an extraordinary race is taking place to identify an effective and safe treatment able to limit the disease progression and severity. Two nonrandomized open-label trials conducted in France and China1,2 established the effectiveness of hydroxychloroquine alone or combined with azithromycin in decreasing nasopharyngeal viral load and carriage duration in patients with COVID-19, although evidence to support clinical benefits remained low. Thereafter, many studies, still unpublished in peer-reviewed journals for the majority, showed contrasting results and revealed potential safety hazards (Table 1).3-11 To date, multiple trials aiming at investigating chloroquine or hydroxychloroquine at various dose regimens to treat COVID-19 (N = 81) or prevent the disease in high-risk populations (N = 19) are cited on clinicaltrials.gov (accessed April 21, 2020). Interestingly, only 14 trials (17%) will investigate the azithromycin-hydroxychloroquine combination.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"808-814"},"PeriodicalIF":2.9,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1646","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37959403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intuitive Global Insight Into COVID-19 Clinical Research Activities-The \"COVID-19 Map of Hope\".","authors":"Markus Ries,&nbsp;Konstantin Mechler,&nbsp;Donna L Smith,&nbsp;Benjamin Herfort,&nbsp;Johannes Visintini,&nbsp;Amon Veiga Santana,&nbsp;Alexander Zipf,&nbsp;Sven Lautenbach","doi":"10.1002/jcph.1643","DOIUrl":"https://doi.org/10.1002/jcph.1643","url":null,"abstract":"","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"826-827"},"PeriodicalIF":2.9,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1643","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37959679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Randomized, Doubled-Blind Clinical Trial on the Effect of Zataria multiflora on Clinical Symptoms, Oxidative Stress, and C-Reactive Protein in COPD Patients.","authors":"Vahideh Ghorani,&nbsp;Omid Rajabi,&nbsp;Majid Mirsadraee,&nbsp;Fariba Rezaeitalab,&nbsp;Saeideh Saadat,&nbsp;Mohammad Hossein Boskabady","doi":"10.1002/jcph.1586","DOIUrl":"https://doi.org/10.1002/jcph.1586","url":null,"abstract":"<p><p>The effects of Zataria multiflora on clinical symptoms, pulmonary function tests, oxidative stress, and C-reactive protein levels in chronic obstructive pulmonary disease (COPD) patients were evaluated. Forty-five patients were allocated to 3 groups: placebo group and 2 groups that received 3 and 6 mg/kg/day Z. multiflora extract (Z3 and Z6) for 2 months. Clinical symptoms, pulmonary function tests, oxidative stress, and serum C-reactive protein levels were evaluated pretreatment (step 0) and 1 (step I) and 2 (step II) months after treatment. Clinical symptoms including breathlessness and chest wheeze in Z3- and Z6-treated groups and sputum production only in the Z6-treated group were significantly improved 1 and 2 months after treatment compared with baseline values (P < .01 to P < .001). The FEV₁ was significantly increased after 2 months of treatment with Z3 and Z6 (P < .05 to P < .01). Malondialdehyde and nitrite levels were significantly decreased after a 2-month treatment with Z6 compared with step 0 (P < .05 to P < .01). The thiol contents in the Z6 group as well as superoxide dismutase and catalase activities in both groups treated with the extract were significantly increased in step II compared with step 0 (P < .05 to P < .01). The C-reactive protein level at the end of the study was significantly reduced compared with the step 0 in both treated groups (P < .05 for both cases). Two-month treatment with Z. multiflora improved clinical symptoms, pulmonary function tests, oxidative stress, and C-reactive protein in COPD patients. The results suggest that this herbal medicine could be of therapeutic value as a preventive drug for the treatment of COPD.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"867-878"},"PeriodicalIF":2.9,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1586","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37762548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}