The Journal of Clinical Pharmacology最新文献

{"title":"An Updated Comprehensive Pharmacovigilance Study of Drug-Induced Thrombocytopenia Based on FDA Adverse Event Reporting System Data","authors":"Li Kunyu Undergraduate,&nbsp;Shi Shuping Undergraduate,&nbsp;Su Chang Undergraduate,&nbsp;Cao Yiyue Undergraduate,&nbsp;Xiong Qinyu Undergraduate,&nbsp;Zhang Ting PhD,&nbsp;Wu Bin MD","doi":"10.1002/jcph.2389","DOIUrl":"10.1002/jcph.2389","url":null,"abstract":"<p>Drug-induced thrombocytopenia (DIT) deserves both clinical and research attention for the serious clinical consequences and high prevalence of the condition. The current study aimed to perform a comprehensive pharmacovigilance analysis of DIT reported in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, with a particular focus on drugs associated with thrombocytopenia events. A disproportionality analysis of DIT was conducted using reports submitted to FARES from January 2004 to December 2022. Both the information component (IC) and reporting odds ratio (ROR) algorithms were applied to identify an association between target drugs and DIT events. A total of 15,940,383 cases were gathered in FAERS, 168,657 of which were related to DIT events. The top 50 drugs ranked by number of cases and ranked by signal strength were documented. The top 5 drugs ranked by number of cases were lenalidomide (10,601 cases), niraparib (3726 cases), ruxolitinib (3624 cases), eltrombopag (3483 cases), and heparin (3478 cases). The top 5 drugs ranked by signal strength were danaparoid (ROR 37.61, 95%CI 30.46-46.45), eptifibatide (ROR 34.75, 95%CI 30.65-39.4), inotersen (ROR 34.00, 95%CI 29.47-39.23), niraparib (ROR 30.53, 95%CI 29.42-31.69), and heparin (ROR 28.84, 95%CI 27.76-29.97). The top 3 involved drug groups were protein kinase inhibitors, antimetabolites, and monoclonal antibodies and antibody-drug conjugates. The current comprehensive pharmacovigilance study identified more drugs associated with thrombocytopenia. Although the mechanisms of DIT have been elucidated for some drugs, others still require further investigation.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138471083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Infliximab Concentrations in Participants with Moderate to Severe COVID-19","authors":"Stephen J. Balevic MD, PhD,&nbsp;Dima Dandachi MD, MPH,&nbsp;Danielle Dixon DO,&nbsp;Richard M.W. Hoetelmans PharmD, PhD,&nbsp;Sam Bozzette MD, PhD,&nbsp;Matthew W. McCarthy MD,&nbsp;the ACTIV-1 Study Team","doi":"10.1002/jcph.2388","DOIUrl":"10.1002/jcph.2388","url":null,"abstract":"<p>Infliximab is a chimeric monoclonal antibody that binds to soluble and membrane-bound tumor necrosis factor-alpha (TNF-α). TNF-<i>α</i> is a proinflammatory cytokine implicated in severe coronavirus disease 2019 (COVID-19), driving acute respiratory distress syndrome.<span>^{1, 2}</span> Accordingly, infliximab was investigated as a potential therapeutic agent for patients with moderate to severe COVID-19 in ACTIV-1, a randomized, double-blind, placebo-controlled trial.<span>³</span> The purpose of this analysis was to descriptively characterize infliximab concentrations in this unique patient population.</p><p>The inclusion and exclusion criteria for ACTIV-1 have already been published.<span>³</span> Infliximab was administered as a single dose of 5 mg/kg intravenous infusion on day 1, in addition to standard-of-care therapy. Samples for infliximab quantitation were collected on day 1, within 24 hours of the first dose, day 8 (±1 day if hospitalized or ±3 days if collected after discharge), day 29 (±3 days), and prior to discharge. Infliximab was quantified using a validated enzyme-linked immunosorbent assay. Samples beneath the quantifiable limit were excluded. Exploratory, descriptive pharmacokinetic (PK) analyses were performed in Phoenix WinNonLin and NLME (version 6.3 or later) (Certara, Durham, NC, USA). The subpopulations analyzed were stratified by clinical variables, including age, sex, weight, baseline C-reactive protein level, and baseline absolute lymphocyte count.</p><p>A total of 517 patients received infliximab in ACTIV-1. Of these, 408 patients had PK samples drawn, resulting in 897 venous PK samples, of which 821 samples in 392 patients were quantifiable and were recorded as being given after the first dose (Figure S1). Of 408 patients, 151 (37%) were female, and the most common races were White (58.6%) and Black/African American (14.7%); 46.6% were Hispanic or Latino. The median age was 54 years (range 19-95 years), the median weight was 87.6 kg (range 45.5-231.8 kg), and 52.9% of patients were obese, with a median body mass index of 30.5 kg/m² (range 16.2-72.2 kg/m²) (n = 399). Altogether, 53.2% of patients had hypertension and 12% required extracorporeal membrane oxygenation or mechanical ventilation at baseline. Patients received infliximab at a median dosage of 440 mg (range 230-1160 mg). In addition, 1.7% received concomitant tocilizumab, 1.2% received concomitant baricitinib, and approximately 85.3% received concomitant dexamethasone.</p><p>There was an increase in infliximab concentrations as a function of weight, as expected with weight-based dosing. However, there was a prominent decline in dose-adjusted concentrations at baseline (within 24 hours of the first dose) with weight, suggesting an effect of weight on infliximab PK that is not fully corrected by weight-based dosing (Figures 1 and S2). There was also a slight decline in baseline infliximab concentrations ","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2388","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138463844","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 Vision for Expanding the Visibility of the Journal of Clinical Pharmacology: Meet the New Editor-in-Chief and the 3 New Associate Editors!","authors":"John N. van den Anker MD, PhD, FCP,&nbsp;Vikram Arya PhD, FCP,&nbsp;Catherijne A. J. Knibbe PharmD, PhD, FCP,&nbsp;Honghui Zhou PhD, FCP","doi":"10.1002/jcph.2387","DOIUrl":"10.1002/jcph.2387","url":null,"abstract":"<p>Seven remarkable Editors-in-Chief (EICs) have been at the helm of <i>The Journal of Clinical Pharmacology</i> during the last 63 years: Drs McKeen Cattell, Donald K. Adler, John C. Somberg, Deborah L. Keefe, Lisa L. von Moltke, Daniel S. Sitar, and Joseph S. Bertino Jr. These EICs have worked diligently to make the journal into the high-quality, well-respected publication it is today. We especially want to thank the outgoing editorial team (Drs Bertino, Sullivan, Korth-Bradley, and Reed) for their dedication and contributions to the success of the journal.</p><p>As we aim to build on the past successes and further expand the visibility of the journal, we recognize the need for intradisciplinary collaboration among the Publications Committee of the American College of Clinical Pharmacology (ACCP), chaired by Dr Navin Goyal, the Members of the Editorial Board, Krista Levy and ACCP staff, the Managing Editor Elizabeth Marshall, and ACCP's publishing partner Wiley.</p><p>In our view, there is a need to reach out to the parts of the world that are already active or are becoming increasingly active in the field of clinical pharmacology and build a strong relationship that will advance the frontiers of our discipline across the globe, with the journal well positioned to facilitate this outreach and collaboration. For this reason, the new Associate Editors will pay special attention to working with colleagues from India (Dr Vikram Arya), China (Dr Honghui Zhou), and Europe (Dr Catherijne Knibbe).</p><p>We also foresee an increased number of state-of-the-art reviews and editorials published in the journal to provide comprehensive summaries of existing knowledge as well as perspectives and commentaries from subject matter experts. We look forward to active contributions from the current and future Members of the Editorial Board.</p><p>Finally, we acknowledge the benefit of seasoned professionals serving at the helm, but also are committed to the goal of training and supporting the growth of Early Stage Professionals, encouraging them to share their vision, learn advanced peer review skills, and join the Editorial Board as they become the future leaders of our discipline.</p><p>Last but not least, allow us to introduce the new Editor-in-Chief and Associate Editors with a series of short biographies.</p><p>The new Editor-in-Chief is:</p><p><b>Dr John van den Anker MD, PhD</b>, who received his MD and PhD degree from the Erasmus University in Rotterdam, The Netherlands, and completed additional training in Pediatrics, Neonatal Medicine, and Clinical Pharmacology.</p><p>He is a Professor of Pediatrics, Pharmacology, Physiology, Genomics, and Precision Medicine at the George Washington University School of Medicine and Health Sciences, Washington, DC, and holds the Evan and Cindy Jones Endowed Chair in Pediatric Clinical Pharmacology. He also is the Eckenstein-Geigy Distinguished Professor of Pediatric Pharmacology at the University Children's Hospital of Ba","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2387","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138452877","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":"Physiologically Based Pharmacokinetic Modeling for Maribavir to Inform Dosing in Drug-Drug Interaction Scenarios with CYP3A4 Inducers and Inhibitors","authors":"Grace Chen PhD,&nbsp;Kefeng Sun PhD,&nbsp;Ingrid Michon PhD,&nbsp;Zoe Barter PhD,&nbsp;Sibylle Neuhoff PhD,&nbsp;Lipika Ghosh PhD,&nbsp;Katarina Ilic MD, PhD, MPH,&nbsp;Ivy H. Song PhD","doi":"10.1002/jcph.2385","DOIUrl":"10.1002/jcph.2385","url":null,"abstract":"<p>Maribavir, an orally available antiviral agent, has been approved in multiple countries for the treatment of patients with refractory post-transplant cytomegalovirus (CMV) infection and/or disease. Maribavir is primarily metabolized by CYP3A4; coadministration with CYP3A4 inducers and inhibitors may significantly alter maribavir exposure, thereby affecting its efficacy and safety. The effect of CYP3A4 inducers and inhibitors on maribavir exposure was evaluated based on a drug-drug interaction (DDI) study and physiologically-based pharmacokinetic (PBPK) modeling. The effect of rifampin (a strong inducer of CYP3A4 and moderate inducer of CYP1A2), administered at a 600 mg dose once daily, on maribavir pharmacokinetics was assessed in a clinical phase 1 DDI study in healthy participants. A full PBPK model for maribavir was developed and verified using in vitro and clinical pharmacokinetic data from phase 1 studies. The verified PBPK model was then used to simulate maribavir DDI interactions with various CYP3A4 inducers and inhibitors. The DDI study results showed that coadministration with rifampin decreased the maribavir maximum plasma concentration (C_max), area under the plasma concentration-time curve (AUC), and trough concentration (C_trough) by 39%, 60%, and 82%, respectively. Based on the results from the clinical DDI study, the coadministration of maribavir with rifampin is not recommended. The PBPK model did not predict a clinically significant effect of CYP3A4 inhibitors on maribavir exposure; however, it predicted that strong or moderate CYP3A4 inducers, including carbamazepine, efavirenz, phenobarbital, and phenytoin, may reduce maribavir exposure to a clinically significant extent, and may prompt the consideration of a maribavir dosing increase, in accordance with local approved labels and/or regulations.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2385","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138441473","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 and Pharmacodynamic Analysis of Acetaminophen and Ibuprofen Dual Therapy for Patent Ductus Arteriosus Closure in Preterm Neonates at Less Than 29 Weeks of Gestation","authors":"Mohammed Almoslem PharmD, PhD,&nbsp;Sanket D. Shah MD,&nbsp;Valvanera Vozmediano PhD,&nbsp;Serge Guzy PhD,&nbsp;Sarah Kim PhD,&nbsp;Mark L. Hudak MD,&nbsp;Stephan Schmidt PhD","doi":"10.1002/jcph.2386","DOIUrl":"10.1002/jcph.2386","url":null,"abstract":"<p>Patent ductus arteriosus (PDA) is a blood vessel that critically supports fetal circulation. The ductus naturally closes within a few days after birth. However, it can stay open in premature neonates for an extended period of time, which is associated with increased mortality and various co-morbidities. Ibuprofen and indomethacin are currently the only 2 drugs approved for inducing PDA closure, but both have been associated with adverse renal and bleeding events. Clinical evidence suggests that combining acetaminophen (APAP) and ibuprofen treatments can decrease the need for surgical ligation. The objective of this study was to establish a disease–drug–trial model to characterize and predict PDA closure following single and combination drug therapy with ibuprofen and/or APAP in children at less than 29 weeks of gestation. The model was informed by a comprehensive literature review. The results of our analysis suggest that ibuprofen and APAP achieve therapeutic synergy. They further suggest that the younger the preterm neonates, the higher the treatment benefit. A 5-day oral dosing regimen consisting of ibuprofen (20 mg/kg Q24h on day 1, followed by 10 mg/kg Q24h on days 2-5) plus APAP (15 mg/kg Q6h) was deemed appropriate to achieve at least 90% PDA in all preterm neonates evaluated within 1 month of life. The model can now be used to design prospective pediatric trials to evaluate optimal drug combinations for PDA closure in preterm neonates and to refine optimal dosing regimens in cohorts of differing gestational age.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138446711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of a Precision-Dosing Model to a Real-World Cohort of Patients on Infliximab Maintenance Therapy: Drug Usage and Cost Analysis","authors":"Anke L. Nguyen MBBS, FRACP,&nbsp;Peter R. Gibson MBBS, FRACP, PhD,&nbsp;Richard N. Upton PhD,&nbsp;Diane R. Mould PhD,&nbsp;Miles P. Sparrow MBBS, FRACP, DMedSc","doi":"10.1002/jcph.2384","DOIUrl":"10.1002/jcph.2384","url":null,"abstract":"<p>Precision-dosing models forecast infliximab doses to achieve targeted trough concentrations in patients with inflammatory bowel disease (IBD). These models have shown to reduce nonresponse and improve patient outcomes. We compared infliximab doses determined by iDOSE precision dosing with standard dosing, and the associated drug costs, in patients with IBD. In this retrospective study, patients with IBD treated with infliximab every 8 weeks at 5 mg/kg were included. An infliximab dose was named dose X if 3 previous infliximab doses, laboratory values including trough infliximab concentrations, and the patient's weight were recorded. The actual dose X was compared to an iDOSE-predicted dose X. Net drug use and costs were evaluated. A total of 174 patients—56% men; median age, 36 (interquartile range, 29-47) years; 135 with Crohn disease; and 31 with ulcerative colitis—were included, with 417 dose X recordings. Median prior infliximab therapy was 2 (0-4) years. Comparing actual dose X with predicted dose X, 52% and 32% of doses were subtherapeutic when aiming for trough concentrations of 5-10 and 3-7 μg/mL, respectively. Treatment costs increased by 102% and 29% for the 2 trough ranges, respectively. On multivariate regression analysis, subtherapeutic infliximab concentrations were associated with ulcerative colitis compared with Crohn disease (odds ratio, 9.81; 95% confidence interval, 1.28-75.40; <i>P</i> = .028) and predose X infliximab trough concentration [odds ratio, 0.07; 95% confidence interval, 0.03-0.15; <i>P</i> &lt; .001]. Over half of maintenance infliximab drug doses were too low to achieve infliximab blood concentrations of 5 μg/mL or greater. While applying precision dosing may improve patient outcomes, drug costs could be considerably greater.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2384","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"107592578","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":"Griseofulvin-Induced Red and Hot Ears","authors":"Anand Mannu MD,&nbsp;Abhinav Kumar Verma MD,&nbsp;Biju Vasudevan MD,&nbsp;Pankaj Das MD,&nbsp;Lekshmipriya Krishnan MD","doi":"10.1002/jcph.2383","DOIUrl":"10.1002/jcph.2383","url":null,"abstract":"<p>Dear Editor,</p><p>Griseofulvin is a natural product, first isolated in 1939 from <i>Penicillium griseofulvum</i> and was first commercially introduced in 1959. It is a polyketide that is derived from acetyl and malonyl coenzyme A precursor molecules to form dehydrogriseofulvin.<span>¹</span> It inhibits microtubule assembly, affects the formation of the mitotic spindle, and finally inhibits mitosis in dermatophytes.<span>²</span> Griseofulvin is mainly used for dermatophytes; however, other uses include anti-inflammatory, cardiovascular, antitumor, and antiviral activity.<span>³</span> It has mainly gastrointestinal side effects, but other adverse effects can also be noticed, such as photosensitivity, urticaria, and petechia.<span>⁴</span></p><p>A 45-year-old woman with no known comorbidities presented with complaints of multiple itchy, erythematous annular plaques with central clearing over the lower back and gluteal region for the past month, which was diagnosed as tinea corporis, as a potassium hydroxide mount of skin scraping showed fungal hyphae. She was started on oral griseofulvin 500 mg once daily along with topical clotrimazole cream. After 3 days of treatment, she developed swelling and redness in both ears associated with mild pain and itching. There was no history of trauma, fever, sore throat, ear piercing, otorrhea, swimming, topical application, or any other drug intake except griseofulvin and no history of similar episodes or consumption of griseofulvin in the past. On examination, there was diffuse swelling and erythema of the bilateral pinna also involving the lobules (Figure 1). Warmth and tenderness were present. There was no localized abscess formation and no sign of any trauma, wounds, or lymphadenopathy noted. The otoscopy examination was within normal limits.</p><p>Differential diagnosis of erysipelas, cellulitis, otitis externa, relapsing polychondritis, perichondritis, flushing, photosensitivity, seborrheic dermatitis, and red ear syndrome was made as no fever, swollen lymph nodes or trauma, and involvement of bilateral ears at the first episode with normal blood investigations ruled out above differentials. Griseofulvin was suspected as the culprit drug, which was stopped, and she was prescribed a short course of oral prednisolone 40 mg once daily for 5 days along with emollients. After 5 days of treatment, her symptoms subsided with near complete resolution of erythema and swelling (Figure 2). The itching and pain also subsided. For further confirmation of this adverse effect of the drug, griseofulvin was readministered as a single dose, and the patient developed a similar reaction within 24 hours. Laboratory tests for concentration in blood or other fluids were not done as the facility was not available. There were no alternative causes found for such a reaction. Her Naranjo Scale score was 8, which falls under the “probable” category of adverse drug reaction probability","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2383","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89720152","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":"Clinical Consequences of Altered Drug Disposition in Obesity: Call for Change","authors":"Christopher D. Bruno BA,&nbsp;David J. Greenblatt MD,&nbsp;Jerold S. Harmatz AB,&nbsp;Christina R. Chow PhD","doi":"10.1002/jcph.2308","DOIUrl":"10.1002/jcph.2308","url":null,"abstract":"<p>Obesity is a serious condition with many known comorbid conditions and other health risks. Despite the rising global rates of obesity, drug disposition in this population is typically understudied, which results in limited information guiding the use of drugs in patients with obesity. Presently, dosing adjustments for patients with obesity typically focus on addressing altered drug clearance with body size and are therefore limited to chronic dosing recommendations. These instructions are variable and rarely based on dedicated studies in people with obesity. This review briefly discusses the current clinical use of body measurements to guide chronic dosing instructions and highlights the need for obesity-specific dosing instructions when the half-life of a drug is prolonged (typically through increased volume of distribution) in people with obesity. Examples of drugs with apparent opportunities for either ramp-up, loading, or washout instructions for patients based on body mass index are identified, specifically for vortioxetine, posaconazole, and brexpiprazole. We call for inclusion of people with obesity in clinical studies as a special subpopulation during drug development and propose the use of body mass index to guide dosing decisions among these patients.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2308","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71523058","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":"Dosing Strategy of Immunoglobulin (IgG) Replacement Therapies in Obese and Overweight Patients with Primary Immunodeficiency Diseases (PIDDs): A Meta-Analysis of Clinical Trials","authors":"Tingting Zhou PhD,&nbsp;Million A. Tegenge PhD,&nbsp;Basil Golding MD,&nbsp;John Scott PhD","doi":"10.1002/jcph.2368","DOIUrl":"10.1002/jcph.2368","url":null,"abstract":"<p>The current dosing strategy of immune globulin products for the treatment of primary immunodeficiency diseases (PIDDs) in the USA is based on total body weight (BW). The aim of our study was to assess the relationship between dose and trough level, and to determine whether an alternative dosing strategy should be considered for patients who are overweight or obese. We analyzed data in a total of 533 patients from 11 studies. We modeled the relationship between trough level and dose per week using a linear mixed model. We used an over-dispersed Poisson model to model the relationship between infection and trough level. In these analyses, we then combined the study-specific treatment effects using a random-effect or fixed-effect model. The mean administered dose per week was 9.77, 14.00, or 18.17 g in patients who were normal weight, overweight, or obese, respectively. Compared with a patient of normal weight, a 1 g increase in dose per week in a patient who was overweight was associated with a smaller increase in the trough level, 0.08 g/L less (95%CI –0.14 to –0.03 g/L), and a 1 g increase in dose per week in a patient who was obese was associated with a much smaller increase in trough level, 0.01 g/L less (95% CI –0.07 to 0.06 g/L). Last, for a 1 unit (g/L) increase in trough level, the expected number of infections remained the same, with a multiplicative factor of 1.01 (95%CI 0.98-1.04). Overall, we found no compelling evidence to justify a reconsideration of the current dosing strategy based on total BW for patients with PIDDs who are overweight or obese.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2368","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71523059","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":"Obesity Considerations in Pediatric Drug Development, 2016–2021","authors":"Sherbet Samuels PhD,&nbsp;Varsha Bhatt-Mehta PharmD,&nbsp;Kyunghun Park PharmD,&nbsp;Gilbert J. Burckart PharmD, FCP","doi":"10.1002/jcph.2305","DOIUrl":"10.1002/jcph.2305","url":null,"abstract":"<p>Pediatric obesity is a global public health concern. Obesity-related physiological changes may affect the pharmacokinetics of drugs and lead to therapeutic failure or toxicities. An earlier review of pediatric drug development programs from 2007 to 2016 found that, of 89 programs listing obesity-related terms, only 4 (4%) products described pharmacokinetic changes associated with obesity. This review examined obesity considerations for 185 drug products for which pediatric drug development programs were submitted to the US Food and Drug Administration (FDA) between 2016 and 2021. The FDA-authored review documents and drug product labeling were queried for obesity-related terms and the review found 97/185 (52%) drug products had obesity-related terms in these sources. Of the 97 drug products, 55/97 (57%) had obesity-related terms in the FDA-authored reviews only, 13/97 (13%) had obesity-related terms in the drug product labeling only, and 29/97 (30%) had obesity-related terms in both FDA-authored reviews and drug product labeling. Most of the obesity-related information in the drug product labeling originated from data collected from adults. Only 13/185 (7%) drug product labeling contained obesity-related terms in reference to drug pharmacokinetics. Specific dosage recommendations for the use of the drug products in pediatric patients who are obese remain lacking. The dearth of available information to guide drug dosages in the obese pediatric population suggests that further research, innovative approaches, and evidence-based guidelines are needed to inform the optimal therapeutic use of drugs in this population.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2305","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71523065","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}