Journal of clinical pharmacology最新文献

{"title":"Commentary on Pharmacologically Meaningful Half-Life.","authors":"Nick Holford","doi":"10.1002/jcph.2051","DOIUrl":"https://doi.org/10.1002/jcph.2051","url":null,"abstract":"Chaiken and Pai have proposed that there is a need for a pharmacologically meaningful half-life in order to provide a single descriptor to account for the duration of pharmacologic effect and dosing interval.1 Although they show in their introductory remarks that they are aware of pharmacometrics and systems biology, they have also clearly illustrated the limitations of a single parameter to describe the relationship between concentration and effect. A description of the time course of drug effect, and hence the duration, requires, at a minimum, a description of the time course of concentration and the relationship between concentration and effect. The simplest pharmacokinetic model for the time course of concentration involves a bolus input, a single distribution volume (V), and a first-order elimination process, defined by clearance (CL). The simplest realistic pharmacodynamic model has a maximum effect (Emax) and the concentration at 50% of Emax (C50). Ignoring more realistic input processes and delays between plasma concentration and effect, this means that a minimum of four parameters are required (V, CL, Emax, and C50). Thus, even the simplest description that can account for the duration of pharmacologic effect requires four parameters it is logically impossible and scientifically incorrect to imagine that a single half-life parameter can be found to describe the complexity. This is illustrated in Figures 1–3, which show the dramatic change in the duration of drug effect with increasing initial concentration (equivalent to increasing dose). The pharmacokinetic and pharmacodynamic parameters rest unchanged only the dose has changed. There is no single half-life that can predict or explain these changes based on the simplest possible realistic description of drug effect. Instead of searching for the impossible by looking for a single half-life to describe complex drug effects, clinicians are advised to learn the basic principles Figure 1. Time course of concentration (blue) and effect (red) with a peak concentration equal to C50. The concentration half-life is about 7 time units. Concentrations are mainly lower than the C50, and thus the effect is approximately proportional to the concentration. The time course of the effect is similar to the time course of concentration, but does not follow the exponential decrease and therefore cannot be described with a half-life of effect.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"62 7","pages":"833-834"},"PeriodicalIF":2.9,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1c/bb/JCPH-62-833.PMC10138753.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9416409","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":"Role of Physiologically Based Pharmacokinetic Modeling and Simulation in Enabling Model-Informed Development of Drugs and Biotherapeutics.","authors":"Vikram Arya, Karthik Venkatakrishnan","doi":"10.1002/jcph.1770","DOIUrl":"https://doi.org/10.1002/jcph.1770","url":null,"abstract":"Model-informed drug development (MIDD) strategies and associated quantitative approaches have enhanced the design, development, and benefit-risk assessment of therapeutics. With advances in our understanding of disease biology and pathophysiology, the complexities of mechanisms of action of emerging therapeutics are steadily on the rise. Taken together with the growing diversity of therapeutic modalities ranging from traditional small molecules to complex genetically engineered cell therapies, clinical use of contemporary therapies demands commitment to integrative “systems” approaches that iteratively exploit the totality of drug-, disease-, and population-level knowledge to guide objective decisions. The inclusion of MIDD-related performance goals in the Prescription Drug Use Fee Act VI is a strong testament to the interest and commitment around the use of novel methodologies to facilitate the conduct of efficient clinical trials. The need for a holistic approach to advance the vision of MIDD and the impact of MIDD-based approaches on dose optimization, informing clinical trial design and providing supportive evidence of efficacy, has also been discussed. 1,2","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"60 Suppl 1 ","pages":"S7-S11"},"PeriodicalIF":2.9,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1770","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38721332","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":"Clinical Pharmacology Considerations for Developing Small-Molecule Treatments for COVID-19.","authors":"Priya Brunsdon,&nbsp;Bhawana Saluja,&nbsp;Chandrahas Sahajwalla","doi":"10.1002/jcph.1697","DOIUrl":"https://doi.org/10.1002/jcph.1697","url":null,"abstract":"<p><p>Numerous drugs are being investigated for the treatment of COVID-19, including antivirals and therapies targeting complications related to COVID-19. The clinical presentation of COVID-19 varies from mild fever, cough, and dyspnea in the early stages of disease to severe complications such as acute respiratory distress syndrome, systemic hyperinflammation, and sepsis. A thorough understanding of the disease pathogenesis and the disease complications is essential to developing effective therapies to treat this potentially life-threatening disease. This review offers key clinical pharmacology considerations involved in the development of small molecules for the treatment of COVID-19. They are based on the major observed disease complications that impact drug absorption, distribution, metabolism, and elimination. We also address considerations regarding potential drug interactions, alternative routes and methods of administration, and dosing in patients on hemodialysis.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"60 9","pages":"1147-1154"},"PeriodicalIF":2.9,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1697","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38079702","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":"Overmedication in COVID-19 Context: A Report From Peru.","authors":"Raisa N Martinez-Rivera,&nbsp;Alvaro Taype-Rondan","doi":"10.1002/jcph.1704","DOIUrl":"https://doi.org/10.1002/jcph.1704","url":null,"abstract":"","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"60 9","pages":"1155-1156"},"PeriodicalIF":2.9,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1704","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38111415","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 Association Between Concurrence of Infection and the Onset of Severe Eruption or Liver Injury in Patients Using Antipyretic Analgesics: A Matched, Nested Case-Control Study.","authors":"Takuya Imatoh, Kimie Sai, Yoshiro Saito","doi":"10.1002/jcph.1613","DOIUrl":"10.1002/jcph.1613","url":null,"abstract":"<p><p>Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) or drug-induced liver injury (DILI) are severe drug-induced reactions, known as idiosyncratic drug reactions. It is believed that immune response can lead to these severe adverse drug reactions. Our previous analysis of the Japanese Spontaneous Drug Reaction database suggested that the onset of SJS/TEN and DILI was strongly associated with infection. Hence, we conducted a matched, nested case-control study to elucidate the association between concurrent infection and the onset of SJS/TEN or liver injury in patients prescribed antipyretic analgesics. We extracted 4 112 055 patients who were prescribed antipyretic analgesics between January 2014 and December 2015. Amongst them, 553 (0.01%) were diagnosed with SJS/TEN and 12 606 (0.3%) with liver injury. In a matched, nested case-control study, 131 and 2847 cases matched for SJS/TEN or liver injury, respectively. For each case, 3 controls were randomly matched with the case for age at index date and sex. In the conditional logistic regression analysis, there was a significant association between the combination of infection and antipyretic analgesics and the onset of SJS/TEN or liver injury (SJS/TEN: adjusted OR, 5.59; 95%CI, 2.01-15.51; liver injury: adjusted OR, 2.79; 95%CI, 2.24-3.46). Although it was not possible to distinguish whether the associations were caused by the infection or were a direct consequence of the antibiotic agents, our findings may help to increase awareness of the possibility of the increased onset of idiosyncratic drug reactions (SJS/TEN and liver injury) in antipyretic analgesic users because of infections.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"60 9","pages":"1177-1184"},"PeriodicalIF":2.4,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38029370","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":"Severity of Topiramate-Related Working Memory Impairment Is Modulated by Plasma Concentration and Working Memory Capacity.","authors":"Samuel P Callisto,&nbsp;Sílvia M Illamola,&nbsp;Angela K Birnbaum,&nbsp;Christopher M Barkley,&nbsp;Sai Praneeth R Bathena,&nbsp;Ilo E Leppik,&nbsp;Susan E Marino","doi":"10.1002/jcph.1611","DOIUrl":"https://doi.org/10.1002/jcph.1611","url":null,"abstract":"<p><p>Drug side effects that impair cognition can lead to diminished quality of life and discontinuation of therapy. Topiramate is an antiepileptic drug that elicits cognitive deficits more frequently than other antiepileptic drugs, impairing multiple cognitive domains including language, attention, and memory. Although up to 40% of individuals taking topiramate may experience cognitive deficits, we are currently unable to predict which individuals will be most severely affected before administration. The objective of this study was to show the contributions of plasma concentration and working memory capacity in determining the severity of an individual's topiramate-related cognitive impairment. Subjects were enrolled in a double-blind, placebo-controlled crossover study during which they received a single dose of either 100, 150, or 200 mg topiramate. Working memory function was assessed using a modified Sternberg working memory task with 3 memory loads administered 4 hours after dosing. After adjustment for differences in working memory capacity, each 1 μg/mL of topiramate plasma concentration was associated with a 3.6% decrease in accuracy for all memory loads. Placebo effects occurred as a function of working memory capacity, with individuals with high working memory capacity experiencing less severe placebo-related impairment compared with those with low working memory capacity. Our results demonstrate that severity of topiramate-related cognitive deficits occurs as a function of both drug exposure and baseline cognitive function. By identifying patient- and exposure-related characteristics that modulate the severity of cognitive side effects, topiramate dosing strategies may be individually tailored in the future to prevent unwanted cognitive impairment.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"60 9","pages":"1166-1176"},"PeriodicalIF":2.9,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1611","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37840459","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":"Atogepant Has No Clinically Relevant Effects on the Pharmacokinetics of an Ethinyl Estradiol/Levonorgestrel Oral Contraceptive in Healthy Female Participants.","authors":"Wendy Ankrom,&nbsp;Jialin Xu,&nbsp;Marie-Helene Vallee,&nbsp;Marissa F Dockendorf,&nbsp;Danielle Armas,&nbsp;Ramesh Boinpally,&nbsp;K Chris Min","doi":"10.1002/jcph.1610","DOIUrl":"https://doi.org/10.1002/jcph.1610","url":null,"abstract":"<p><p>The incidence of migraine is higher among women than men and peaks during the reproductive years, when contraceptive medication use is common. Atogepant, a potent, selective antagonist of the calcitonin gene-related peptide receptor-in development for migraine prevention-is thus likely to be used by women taking oral contraceptives. This phase 1, open-label, single-center, 2-period, fixed-sequence study examined the effect of multiple-dose atogepant 60 mg once daily on the single-dose pharmacokinetics of a combination oral contraceptive, ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg (EE/LNG), in healthy postmenopausal or oophorectomized women. For participants in period 1, a single dose of EE/LNG was followed by a 7-day washout. In period 2, atogepant was given once daily on days 1-17; an oral dose of EE/LNG was coadministered with atogepant on day 14. Plasma pharmacokinetic parameters for EE and LNG were assessed following administration with and without atogepant. Twenty-six participants aged 45-64 years enrolled; 22 completed the study in accordance with the protocol. The area under the concentration-time curve extrapolated to infinity (AUC_0-∞ ) of LNG was increased by 19% when administered with atogepant. Coadministration of atogepant and a single dose of EE/LNG did not substantially alter the pharmacokinetics of EE; the ∼19% increase in plasma AUC_0-∞ of LNG is not anticipated to be clinically significant. Overall, atogepant alone and in combination with EE/LNG was generally well tolerated, with no new safety signals identified.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"60 9","pages":"1157-1165"},"PeriodicalIF":2.9,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1610","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37840458","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 Comprehensive Review of Tocilizumab in COVID-19 Acute Respiratory Distress Syndrome.","authors":"Sajad Khiali, Elnaz Khani, Taher Entezari-Maleki","doi":"10.1002/jcph.1693","DOIUrl":"10.1002/jcph.1693","url":null,"abstract":"<p><p>Currently, the world is facing the pandemic of a novel strain of beta-coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Acute respiratory distress syndrome (ARDS) is the most devastating complication of SARS-CoV-2. It was indicated that cytokine-release syndrome and dominantly interleukin (IL)-6 play a central role in the pathophysiology of ARDS related to the novel 2019 coronavirus disease (COVID-19). Despite the global emergency of the disease, at this time, there are no proven therapies for the management of the disease. Tocilizumab is a potential recombinant monoclonal antibody against IL-6 and currently is under investigation for the management of ARDS in patients with COVID-19. Given these points, we reviewed the current evidence regarding the potential therapeutic role of tocilizumab and its important clinical issues in the treatment of ARDS related to COVID-19.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"60 9","pages":"1131-1146"},"PeriodicalIF":2.4,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323169/pdf/JCPH-60-1131.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38060797","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":"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":"Efficacy, Safety, and Tolerability of ONO-4474, an Orally Available Pan-Tropomyosin Receptor Kinase Inhibitor, in Japanese Patients With Moderate to Severe Osteoarthritis of the Knee: A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group Comparative Study.","authors":"Naoki Ishiguro,&nbsp;Shusuke Oyama,&nbsp;Ryunosuke Higashi,&nbsp;Kunio Yanagida","doi":"10.1002/jcph.1470","DOIUrl":"https://doi.org/10.1002/jcph.1470","url":null,"abstract":"<p><p>We examined the efficacy, safety, and tolerability of ONO-4474 in Japanese patients with osteoarthritis (OA) of the knee. In this multicenter, placebo-controlled, randomized, double-blind, parallel-group comparative study, patients with moderate to severe OA who were refractory to nonsteroidal anti-inflammatory drugs were orally administered 100 mg of ONO-4474 twice daily for 28 days. The primary end point was knee pain during walking, assessed by visual analog scale over 24 hours (VAS₂₄ ). Treatment-emergent adverse events (TEAEs) and adverse drug reactions were reported for safety. In total, 110 patients were randomized (1:1) to receive placebo or ONO-4474. The mean (standard deviation) change in VAS₂₄ scores at week 4 was -26.9 (25.0) mm in the ONO-4474 group and -19.5 (19.6) mm in the placebo group. The difference (ONO-4474 group - placebo group) in posterior mean change in VAS₂₄ at week 4 was -5.8 (posterior standard deviation, 4.4; 95% confidence interval, -14.3 to 2.8) mm. TEAEs were reported in 41.8% of patients in the ONO-4474 group and 18.2% of patients in the placebo group. The most common TEAEs in the ONO-4474 group related to the musculoskeletal system and the peripheral and central nervous systems were myalgia (7.3%), arthralgia (5.5%), dizziness (3.6%), and hypoesthesia (3.6%). Four patients from the ONO-4474 group and 1 patient from the placebo group discontinued treatment because of AEs; however, none were judged to be serious, and all patients recovered or were recovering after discontinuation. ONO-4474 is a novel tropomyosin receptor kinase inhibitor that has an analgesic effect in patients with OA.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"60 1","pages":"28-36"},"PeriodicalIF":2.9,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1470","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37125458","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}