The Journal of Clinical Pharmacology最新文献

Extracorporeal membrane oxygenation (ECMO) support of critically ill pediatric patients is associated with increased risk of thromboembolic events, and unfractionated heparin is used commonly for anticoagulation. Given reports of acquired antithrombin (AT) deficiency in this patient population and associated concern for heparin resistance, AT activity measurement and off-label AT replacement have become common in pediatric ECMO centers despite limited optimal dosing regimens. We conducted a retrospective cohort study of pediatric ECMO patients (0 to <18 years) at a single academic center to characterize the pharmacokinetics (PK) of human plasma-derived AT. We demonstrated that a two-compartment turnover model appropriately described the PK of AT, and the parameter estimates for clearance, central volume, intercompartmental clearance, peripheral volume, and basal AT input under non-ECMO conditions were 0.338 dL/h/70 kg, 38.5 dL/70 kg, 1.16 dL/h/70 kg, 40.0 dL/70 kg, and 30.4 units/h/70 kg, respectively. Also, ECMO could reduce bioavailable AT by 50% resulting in 2-fold increase of clearance and volume of distribution. To prevent AT activity from falling below predetermined thresholds of 50% activity in neonates and 80% activity in older infants and children, we proposed potential replacement regimens for each age group, accompanied by therapeutic drug monitoring.

Obesity is a disease of epidemic proportions in the United States and contributes to morbidity and mortality for a large part of the population. In addition, the financial costs of this disease to society are high. Lifestyle modifications are key to prevention and treatment but adherence and long-term success have been challenging. Bariatric surgery has been available and pharmacologic approaches, first developed in the 1950s, continue to be an option; however, existing formulations have not provided optimal clinical efficacy and have had many concerning adverse effects. Over the last decade, glucagon-like peptide-1 (GLP-1) receptor agonists, a novel group of medications for the treatment of type 2 diabetes, were found to produce significant weight loss. Several formulations, at higher doses, received FDA approval for the treatment of obesity or those overweight with weight-related co-morbidities. More hormone-based therapies were and are being developed, some with dual or triple-receptor agonist activity. Their use, however, is not without questions and concerns as to long-term safety and efficacy, problems with cost and reimbursement, and how their use may intersect with public health efforts to manage the obesity epidemic. This review will focus on the GLP-1 receptor agonists currently used for weight loss and discuss their pharmacology, pertinent research findings establishing their benefits and risks, issues with prescribing these medications, and a perspective from a public health point of view.

On July 1, 2024, we will say goodbye to Dion Brocks, James Burris, Monette Cotreau, Michael Court, Vera Donnenberg, Kerry Estes, Michael Jann, William Jusko, Adel Karara, Jing Li, Melanie Nicol, George Perentesis, Mark Ratain, Catherine Sherwin, Antonio Tugores, and John Wagner as outgoing members of the Editorial Board of the Journal of Clinical Pharmacology (JCP). On behalf of the American College of Clinical Pharmacology (ACCP), I would like to profusely thank all of them for their outstanding service as Editorial Board members and sincerely hope they will continue to serve as peer reviewers for the Journal as well as submit their best original and review work to JCP for many years to come.

At the same time, I am excited to extend a warm welcome to our newly appointed Editorial board members Karel Allegaert, Luke Baxter, David Burger, Carter Cao, Ayyappa Chaturvedula, Andre Dallmann, Elimika Pfuma Fletcher, Verena Gotta, Navin Goyal, Hazem Hassan, Chuanpu Hu, Zheng Jiao, Gilbert Koch, Don Mager, Cody Peer, Ana Ruiz-Garcia, Sinno Simons, Janelle Vaughns, Wei Zhao, and Victoria Ziesenitz.

It is important to emphasize that members of the Editorial Board not only have an extremely important role in enhancing the scientific quality of the Journal but also carry an important responsibility in strategically supporting the growth of the Journal. To succeed in reaching these goals, an efficient, effective, and collegial collaboration between members of the Editorial Board, the Chair and Members of the ACCP's Publications Committee, ACCP staff, the Senior Managing and Associate Managing Editors, the Publisher, the Associate Editors, and Editor-in-Chief is absolutely necessary.

The future of JCP is bright and promising. Several initiatives such as the development of graphical and video abstracts, plain language summaries, and, last but not least, mentoring of new and junior peer reviewers, are either ongoing or under active deliberations. In addition to actively contributing to the success of these exciting initiatives, we count on the Editorial Board members to provide constructive suggestions on how we can collectively improve the quality and global visibility and impact of our Journal. I have unequivocal and unwavering confidence in the strengths of this outstanding Editorial Board and am looking forward to receiving their innovative and creative ideas in the near future.

There are also worrisome issues that deserve our immediate and undivided attention. Let us start with the most gruesome one of those: fake science. One of the sources of propagating and promoting fake science is the worrisome emergence of entities colloquially referred to as “paper mills.” One of the modus operandi of such businesses or individuals is to list a scientist as an author of a wholly or partially fabricated paper. The “mill” will then submit the work, generally avoiding the most prestigious journals in favor of journals whose peer review process

This study intended to evaluate the interactions between zamicastat and epoprostenol in healthy human subjects. This was a single-center, open-label, two-period study. In period 1, epoprostenol 8 ng/kg/min was administered alone. In period 2, epoprostenol 8 ng/kg/min was administered following an 8-day treatment with zamicastat. Since the initial dose of epoprostenol showed to be insufficiently tolerated, it was decreased to 6 ng/kg/min. Blood samples were collected to determine the metabolites of epoprostenol and concentrations of zamicastat and its metabolites. A total of 54 subjects were enrolled and data from 28 subjects were available for pharmacokinetic analysis. The epoprostenol plus zamicastat-to-epoprostenol geometric means ratio (GMR) and corresponding 90% confidence interval (CI) for C_av,ss and area under the plasma concentration–time curve from time 0 up to 16 h at steady state (AUC_0-16,ss) of the metabolites of epoprostenol were within the acceptance bioequivalence range (80.00%-125.00%). The intrasubject coefficient of variation (ISCV) was below 10% for both parameters, on both metabolites. For zamicastat AUC_0-τ,ss, the zamicastat plus epoprostenol-to-zamicastat GMR and corresponding 90% CI were within the bioequivalence acceptance range, while for zamicastat C_max,ss, the lower limit of the 90% CI was slightly below the acceptance range. For zamicastat metabolites, C_max,ss and AUC_0-τ,ss and the zamicastat plus epoprostenol-to-zamicastat GMR were below the acceptance bioequivalence range. ISCV was between 30% and 41% for C_max,ss and between 21% and 41% for AUC_0-τ,ss, for zamicastat and both metabolites. This study showed that the administration of zamicastat did not significantly modify the cardiovascular effects of epoprostenol and that the interactions between zamicastat and epoprostenol are not expected to be clinically relevant.

Subarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are common complications following SAH that contribute significantly to the poor outcomes observed in these patients. Intrathecal (IT) nicardipine delivered via an existing external ventricular drain is an off-label intervention that has been shown to be correlated with reduced DCI and improved patient outcomes. The current study aims to characterize the population pharmacokinetic (popPK) properties of intermittent IT nicardipine. Following informed consent, serial cerebrospinal fluid (CSF) samples were obtained from 16 SAH patients (50.4 ± 9.3 years old; 13 females) treated with IT nicardipine every 6 h (q6h, n = 8) or every 8 h (q8h, n = 8) for an average of 72 ± 21 doses. High-performance liquid chromatography was used to quantify CSF concentration from each sample. Our popPK analysis showed that the CSF pharmacokinetics of IT nicardipine in the cohort was adequately described by a two-compartment model with a lag time. Model parameter estimates were reliable (relative standard error <50%). Intracranial pressure influenced both the total clearance and the central volume of nicardipine (i.e., negative correlation, P <−.001). Calculated PK parameters were similar between q6h and q8h dosing regimens. Despite a small cohort of SAH patients, we successfully developed a popPK model to describe the nicardipine disposition kinetics in the CSF following IT administration. These findings may help inform future clinical trials designed to examine the optimal dosing of IT nicardipine.

Uridine 5′-diphospho-glucuronosyltransferases (UGTs) demonstrate variable expression in the pediatric population. Thus, understanding of age-dependent maturation of UGTs is critical for accurate pediatric pharmacokinetics (PK) prediction of drugs that are susceptible for glucuronidation. Ontogeny functions of major UGTs have been previously developed and reported. However, those ontogeny functions are based on in vitro data (i.e., enzyme abundance, in vitro substrate activity, and so on) and therefore, may not translate to in vivo maturation of UGTs in the clinical setting. This report describes meta-analysis of the literature to develop and compare ontogeny functions for 8 primary UGTs (UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B10, UGT2B15, and UGT2B17) based on published in vitro and in vivo studies. Once integrated with physiologically based pharmacokinetics modeling models, in vivo activity-based ontogeny functions demonstrated somewhat greater prediction accuracy (mean squared error, MSE: 0.05) compared to in vitro activity (MSE: 0.104) and in vitro abundance-based ontogeny functions (MSE: 0.129).

This study aims to systematically review the efficacy and safety of oral semaglutide in the treatment of type 2 diabetes mellitus (T2DM) and provide a basis for the rational use of the drug in clinical practice. From the database's inception until February 2023, a systematic search was conducted in PubMed, Embase, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang Database, and China Science and Technology Journal Database to identify randomized controlled trials (RCTs) comparing the efficacy of oral semaglutide at dosages of 3, 7, and 14 mg (trial group) against placebo or other positive control drugs (control group) for the treatment of T2DM. Following literature screening and data extraction, the bias risk assessment tool in the Cochrane reviewer handbook 5.1.0 was used to evaluate the literature quality. Meta-analysis was carried out with RevMan 5.4 software. A total of 10 RCTs with 9541 patients were included. The meta-analysis results revealed that compared with placebo or positive control drugs (empagliflozin, sitagliptin, liraglutide, and dulaglutide), oral semaglutide significantly reduced the hemoglobin A1c (HbA1c) in patients (compared to placebo, 3 mg [MD = −0.61%, 95% CI (−0.89, −0.34)], 7 mg [MD = −1.12%, 95% CI (−1.45, −0.79)], 14 mg [MD = −1.08%, 95% CI (−1.32, −0.85)]; compared to positive control drugs (7 mg [MD = −0.26%, 95% CI (−0.38, −0.15)], 14 mg [MD = −0.37%, 95% CI (−0.52, −0.23)]). Oral semaglutide also showed certain advantages over placebo or positive control drugs in terms of weight loss, HbA1c reduction achievement rate, fasting plasma glucose level, and body mass index with overall dose-dependent efficacy. The incidence of nausea, diarrhea, and vomiting caused by oral semaglutide was higher than that of the placebo or positive control drugs, and the incidence of appetite decrease or constipation was higher than that of the placebo. Severe or symptomatic hypoglycemic episodes were reduced compared to positive control drugs. Oral semaglutide has definite clinical benefits of reducing blood glucose, body weight, reducing the risk of hypoglycemia, and with good safety.

Omaveloxolone (SKYCLARYS^®) is approved for the treatment of Friedreich ataxia (FA) in patients aged ≥16 years in the United States and European Union (EU). The recommended dosage is 150 mg administered orally once daily as three 50-mg capsules. However, some patients with FA may have oropharyngeal dysphagia or difficulty swallowing whole capsules; therefore, alternate method(s) of administration are needed. A Phase 1 clinical study in 32 healthy volunteers evaluated the relative bioavailability, safety, and tolerability of a single dose of omaveloxolone when capsule contents were sprinkled on and mixed in applesauce compared to when taken as intact capsules. Palatability when sprinkled on and mixed in applesauce was assessed with a questionnaire. After a single 150-mg dose, the peak and overall exposures of omaveloxolone were similar irrespective of administration method, with the 90% CIs of the geometric least squares mean ratio (%) for maximum plasma concentration (C_max), AUC_0-t, and AUC_0-∞ within the 80% to 125% reference intervals. Omaveloxolone was absorbed more slowly as intact capsules (median t_max, 10 h) compared with sprinkled capsule contents over applesauce (median t_max, 6 h). With chronic daily administration of omaveloxolone to treat FA, the 4-h difference in t_max is not considered clinically relevant. Sprinkled omaveloxolone capsule contents on applesauce were well tolerated, with acceptable palatability and no serious adverse events. Given the similar systemic exposure when capsules were swallowed whole, sprinkling omaveloxolone capsule contents on and mixing in applesauce is a feasible alternative method of administering omaveloxolone and has been included in both the United States and EU prescribing information.

Dear Editor,

The discourse surrounding the article titled “Performance of ChatGPT on Factual Knowledge Questions Regarding Clinical Pharmacy” warrants further examination and critique. The study undertook an evaluation of ChatGPT's efficacy in responding to factual knowledge questions concerning clinical pharmacy. Through a series of 264 questions, ChatGPT's responses were analyzed for accuracy, consistency, quality of the substantiation, and reproducibility, yielding notable results. ChatGPT demonstrated a 79% correctness rate, surpassing the 66% accuracy rate of pharmacists.

Acknowledging the limitations outlined in the discussion section, it is important to note that this study solely focused on factual knowledge questions. The primary objective was to determine ChatGPT's performance in responding to factual knowledge questions rather than its proficiency in clinical reasoning. Consequently, the study refrained from drawing conclusions regarding ChatGPT's impact on clinical decision-making, as this aspect falls under the scope of separate research endeavors.¹

Addressing the limitations, we argue that the scale of 264 questions, and a lack of variety are limitations of this study. The number of questions aligns with similar studies such as the USMLE Step 1, comprising 280 questions,² and the Taiwanese pharmacist licensing examination, consisting of 431 questions.³ Additionally, the span of topics covered in our questions is deemed representative of a pharmacist's factual knowledge base within clinical pharmacy.

The authors acknowledge the need for further investigation into ChatGPT's clinical applicability, for example, with longitudinal studies. Furthermore, exploring ChatGPT's capacity to provide justifications and explanations for its responses could augment its efficacy in aiding pharmacist decision-making processes. Continuous refinement and augmentation of ChatGPT are essential to strengthen its functionality as a tool for pharmacists in the clinic. Still, the indispensable expertise and interpretive skills of clinical pharmacists is pivotal to applying this information in the clinic. The factual information produced by ChatGPT holds potential as a valuable resource, however, it is imperative that the responses undergo rigorous assessment for accuracy and clinical applicability under the scrutiny of clinical pharmacists.

Sincerely,

Merel van Nuland