The Journal of Clinical Pharmacology最新文献

{"title":"JCP Annual Reviewer List","authors":"","doi":"10.1002/jcph.70006","DOIUrl":"https://doi.org/10.1002/jcph.70006","url":null,"abstract":"<p>The Editors of <i>The Journal of Clinical Pharmacology</i> would like to acknowledge and thank our peer reviewers for their contribution to the journal. Below is a list of those individuals who reviewed for <i>JCP</i> in 2024.</p><p>Claude Abdallah</p><p>Mariam Ahmed</p><p>Karel Allegaert</p><p>Barbara Ameer</p><p>Elham Amini</p><p>Guohua An</p><p>Marion Anliker-Ort</p><p>Glen Apseloff</p><p>Vikram Arya</p><p>Amal Ayyoub</p><p>April Barbour</p><p>Luke Baxter</p><p>Dallas Bednarczyk</p><p>Charles Berde</p><p>Simon Berger</p><p>Chandrali Bhattacharya</p><p>Robert Bies</p><p>Xavier Boulenc</p><p>Dominic Bräm</p><p>Dion Brocks</p><p>Kristina Brooks</p><p>Gilbert Burckart</p><p>David Burger</p><p>Jan Steven Burgerhart</p><p>James Burris</p><p>Elisa Calvier</p><p>Yanguang Cao</p><p>Bruce Carleton</p><p>Francisco Cezar</p><p>Ayyappa Chaturvedula</p><p>Bing Chen</p><p>Cuiping Chen</p><p>Qiaoxi Chen</p><p>Hee-Jae Choi</p><p>Imti Choonara</p><p>Sheryl Coppola</p><p>Michael Court</p><p>Tim Cressey</p><p>André Dallmann</p><p>Borje Darpo</p><p>Sjoerd de Hoogd</p><p>Natalia de Moraes</p><p>Saskia de Wildt</p><p>Jasper Dingemanse</p><p>Stefanie Drescher</p><p>Andrea Edginton</p><p>Taher Entezari-Maleki</p><p>Thomas Erb</p><p>Kerry Estes</p><p>Ene Ette</p><p>Federica Ferrari</p><p>William Figg</p><p>Michael Fossler</p><p>Yoko Franchetti</p><p>Lan Gao</p><p>Francis Gengo</p><p>Paul Glue</p><p>Klervi Golhen</p><p>Mathangi Gopalakrishnan</p><p>Verena Gotta</p><p>Navin Goyal</p><p>Howard Greenberg</p><p>Yue Guo</p><p>Manish Gupta</p><p>Neeraj Gupta</p><p>Arthur Harralson</p><p>Hazem Hassan</p><p>Eric Helmer</p><p>Guenther Hochhaus</p><p>Christoph Hornik</p><p>Marissa Anne Horrigan</p><p>Chuanpu Hu</p><p>Angela Jeong</p><p>Kunal Jhunjhunwala</p><p>Yu Jiang</p><p>Zheng Jiao</p><p>William Jusko</p><p>Shamir Kalaria</p><p>Tobias Kanacher</p><p>Gary Kaplan</p><p>Michael Kays</p><p>Gregory Kearns</p><p>Tony Kiang</p><p>Myong-Jin Kim</p><p>Mark Kirstein</p><p>Gilbert Koch</p><p>Joan Korth-Bradley</p><p>Elke Krekels</p><p>Rajesh Krishna</p><p>Parag Kumar</p><p>K. E. Kvitne</p><p>Mayur Ladumor</p><p>Brooke Langevin</p><p>Lucy Lee</p><p>David Lehmann</p><p>Xiaonan Li</p><p>Yali Liang</p><p>Yi Ting Lien</p><p>Shufang Liu</p><p>Xiaomei Liu</p><p>Pradeep Lukka</p><p>Donald Mager</p><p>Kelly Mahar</p><p>Paul Malik</p><p>Ron Mathot</p><p>Ilan Matok</p><p>Anna M. Mc Laughlin</p><p>Jaydeep Mehta</p><p>Bernd Meibohm</p><p>Peter Mesenbrink</p><p>Gerd Mikus</p><p>Jeremiah Momper</p><p>Jatinder Mukker</p><p>Anne Nafziger</p><p>James Nguyen</p><p>Toan Duc Nguyen</p><p>Jin Niu</p><p>Maria Noftz</p><p>Ken Ogasawara</p><p>Kayode Ogungbenro</p><p>Charles Oo</p><p>Manjunath Pai</p><p>Keyur Parmar</p><p>Richard Parrish</p><p>Cody Peer</p><p>Scott Penzak</p><p>George Perentesis</p><p>Juan Jose Perez Ruixo</p><p>Sheila Annie Peters</p><p>Elimika Pfuma Fletcher</p><p>Natella Rakhmanina</p><p>Arun Ram</p><p>Michael Reed</p><p>Michael Rieder</p><p>Karen Rowland-Yeo</p><p>Ana Ruiz-Garcia</p><p>Ma","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"533-534"},"PeriodicalIF":0.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of Cannabis Per Se Laws: A Semi-Mechanistic Pharmacometrics Model for Quantitative Characterization of THC and Metabolites in Oral Users","authors":"Peizhi Li PharmD,&nbsp;Guohua An MD, PhD","doi":"10.1002/jcph.6181","DOIUrl":"10.1002/jcph.6181","url":null,"abstract":"<p>Recreational cannabis use has increased notably in the United States in the past decade, with a recent surge in oral consumption. This trend has raised concerns about driving under the influence. Current cannabis-impaired driving laws lack standardization, with some states implementing blood Δ9-tetrahydrocannabinol (THC) <i>per se</i> limits (1, 2, and 5 ng/mL). However, these limits have been criticized for their inaccuracy and unreliability, highlighting the need for legal refinement. Addressing this issue requires understanding the complex pharmacokinetics (PK) and pharmacodynamics (PD) of THC, cannabis's primary psychoactive component, which can be characterized using a population PK model. However, existing PK models mainly focus on inhalation data and do not account for the growing number of oral cannabis users. To bridge this gap, a semi-mechanistic population PK model was developed using data from 10 published studies following intravenous or oral administration of cannabis to characterize THC and its metabolites in oral users. Simulated THC plasma concentrations for doses from 2.5 mg to 100 mg in frequent and occasional users were used to evaluate the effectiveness of existing <i>per se</i> limits. Results showed that the 1 ng/mL limit was least effective due to a high risk of false positives, while the 2 and 5 ng/mL limits remain inconclusive due to limited PD data linking blood THC levels to impairment. These findings suggest that the existing <i>per se</i> laws may not fully address the complexity of cannabis impairment, underscoring the need for further research and refinement of cannabis-impaired driving laws.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"535-549"},"PeriodicalIF":0.0,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6181","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014461","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":"Characterization of Renal OAT3 and Hepatic CYP3A Activities in Pregnant Women with Acute Pyelonephritis Using the Endogenous Biomarker Cortisol and 6β-Hydroxycortisol","authors":"João Paulo Bianchi Ximenez PhD,&nbsp;Jhohann Richard de Lima Benzi PhD,&nbsp;Julia Cristina Colombari MA,&nbsp;Matheus de Lucca Thomaz MA,&nbsp;Adriana Rocha PhD,&nbsp;Ana Cláudia Rabelo e Silva MA,&nbsp;Patrícia Pereira dos Santos Melli MD,&nbsp;Geraldo Duarte PhD, MD,&nbsp;Vera Lucia Lanchote PhD","doi":"10.1002/jcph.6186","DOIUrl":"10.1002/jcph.6186","url":null,"abstract":"<p>This study evaluates the impact of acute pyelonephritis in pregnant women on the <i>in vivo</i> activity of renal OAT3 using the endogenous biomarker (EB) 6β-hydroxycortisol (6β-OHF) renal clearance (CL_renal 6β-OHF) and AUC_6β-OHF validated by correlating with the secretion clearance (CL_sec) of the probe drug furosemide. Additionally, 6β-OHF formation clearance (CL_formation 6β-OHF) as well as urinary (Ae_6β-OHF/Ae_F) and plasma (AUC_6βOHF/AUC_F) ratios were also evaluated as EB for hepatic CYP3A activity. Pregnant women in their third trimester of gestation, diagnosed with acute pyelonephritis, were recruited before (pre-treatment, n = 8) and after (post-treatment, n = 8) cefuroxime treatment and resolution of acute pyelonephritis. All participants received a single dose of furosemide 40 mg for evaluation of OAT3 <i>in vivo</i> activity on both occasions followed by collection of urine and serial blood samples for 24 h. The CL_renal 6β-OHF (geometric mean and 95% CI) increased from 1.81 L/h (0.86-3.83) to 11.82 L/h (6.58-21.24), whereas the AUC_6β-OHF decreased from 44.85 ng h/mL (30.96-64.98) to 24.20 ng h/mL (16.05-36.48) pre- and post-treatment. Significant statistical correlations were observed between furosemide CL_sec and CL_renal 6β-OHF (R = 0.88, <i>P</i> = .01) and AUC_6β-OHF (R = −0.66, <i>P</i> &gt; .001). Additionally, the CL_formation 6β-OHF was lower in pre-treatment 26.81 L/h (10.18-70.59) than in post-treatment 96.18 L/h (64.21-144.09), whereas AUC_6βOHF/AUC_F ratios were decreased from 0.014 (0.010-0.019) pre-treatment to 0.009 (0.006-0.013) post-treatment. Regarding Ae_6β-OHF/Ae_F ratios, no differences were observed between pre-treatment and post-treatment. In conclusion, CL_renal 6β-OHF evaluates renal OAT3 activity when CYP3A is inhibited, whereas CL_formation 6β-OHF evaluates hepatic CYP3A when OAT3 is inhibited, such as in pregnant women with acute pyelonephritis.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"556-563"},"PeriodicalIF":0.0,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980277","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":"Physiologically based Pharmacokinetic/Pharmacodynamic Modeling (PBPK/PD) of Famotidine in Pregnancy","authors":"Xiaomei I. Liu PharmD,&nbsp;Dionna J. Green MD,&nbsp;John van den Anker MD, PhD, FCP, FAAP,&nbsp;Homa K. Ahmadzia MD, MPH,&nbsp;Joaquin Calderon MD,&nbsp;Gilbert J. Burckart PharmD,&nbsp;André Dallmann PhD","doi":"10.1002/jcph.6185","DOIUrl":"10.1002/jcph.6185","url":null,"abstract":"<p>Famotidine, a H₂-receptor antagonist, is commonly used to treat heartburn and gastroesophageal reflux disease during pregnancy. However, information on the pharmacokinetics (PK) of famotidine in pregnant patients is limited since pregnant patients are usually excluded from clinical trials. This study aimed to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for famotidine in non-pregnant and pregnant populations, and to combine it with a pharmacodynamic (PD) model to predict the effect of famotidine on intragastric pH. Clinical data for model evaluation were taken from the literature. The PBPK model successfully predicted famotidine PK in non-pregnant and pregnant populations. The ratio of predicted versus observed PK parameters in non-pregnant populations ranged from 0.66 to 1.33 for the area under the concentration–time curve and from 0.50 to 1.27 for peak concentration (C_max). In the pregnant populations, these ratios were 0.94 and 1.17 for early pregnancy, 0.82 and 1.29 for mid-pregnancy, and 0.72 and 1.06 for late pregnancy, respectively. Compared to the non-pregnant population, famotidine exposure was predicted to be decreased by, on average, 24% in mid-pregnancy and 20% in late pregnancy. The PBPK/PD model adequately captured the increase in intragastric pH observed in non-pregnant adults after famotidine intake and suggested a similar effect in mid- and late pregnancy. High inter-individual variability and minor discrepancies between model predictions and clinical observations indicate a need for further clinical data to reliably inform dosing strategies and therapeutic outcomes for famotidine in pregnant populations.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"564-574"},"PeriodicalIF":0.0,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967119","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":"Street Pharmacology: Toxico-Dermatology of Injection Drug Use","authors":"David F. Lehmann PharmD, MD,&nbsp;Aryana Nazem BS,&nbsp;Jeanna Marraffa PharmD, MPH, DABAT, FAACT,&nbsp;Ramsay Sami Farah MD","doi":"10.1002/jcph.6176","DOIUrl":"10.1002/jcph.6176","url":null,"abstract":"<p>Street medicine is a point-of-care, mobile approach that services the needs of unhoused individuals who are otherwise unable to access medical care in traditional settings. The prevalence of injection drug use combines with the pipeline of illicit substances, to produce a constellation of severe, potentially life-threatening dermatological disorders unique to this population. This review applies principles of clinical pharmacology to clarify the mechanisms underlying the dermatological toxicity of xylazine, desomorphine, and 3,4-methylenedioxymethamphetamine (MDMA).</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"550-555"},"PeriodicalIF":0.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142957189","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":"Severe Impact of Omeprazole Timing on pH-Sensitive Dasatinib Absorption: Unveiling Substantial Drug–Drug Interaction","authors":"Per Andersson PhD,&nbsp;Magnus Brisander PhD,&nbsp;Charlotta Liljebris PhD,&nbsp;Gérald Jesson MSc,&nbsp;Hans Lennernäs PhD","doi":"10.1002/jcph.6173","DOIUrl":"10.1002/jcph.6173","url":null,"abstract":"<p>The absorption and bioavailability of most tyrosine kinase inhibitors are affected by gastrointestinal pH as they are weak basic lipophilic drugs. Hence, concomitant use of acid reducing agents (ARAs) is frequently restricted. Particularly comedication of crystalline dasatinib (Sprycel) and proton-pump inhibitors (PPIs) should be avoided. Drug–drug interaction (DDI) studies with PPIs report approximately 40%-80% bioavailability reduction of dasatinib. Limitations in the design of these studies do not allow for assessing the near maximum DDI as timing of PPI dosing was either not reported or 22 h prior to dasatinib intake. We conducted a DDI study of crystalline dasatinib and omeprazole in healthy, fasted participants, investigating the impact of PPI comedication on dasatinib plasma exposure at a time point when the near maximum DDI effect is expected. Participants were administered omeprazole (day 2-5) to reach steady state. On day 6, a single dose of crystalline dasatinib was given. Crystalline dasatinib dosing alone on day 1 served as control (single dose). The dosing interval between omeprazole administration and crystalline dasatinib was 10 h (median [range: 9-10 h]). Dasatinib C_max and AUC_0-24 were reduced by 96% and 89% by omeprazole comedication. C_max was 224.6 ± 104.7 ng/mL (mean ± SD) and 8.0 ± 4.5 ng/mL (<i>P</i> &lt; .0001) and AUC_0-24 was 797.6 ± 274.5 and 90.6 ± 38.1 h·ng/mL (<i>P</i> &lt; .0001) without and with omeprazole. T_1/2 was 5.7 ± 1.5 h (mean ± SD) with crystalline dasatinib dosing alone and could not be reliably calculated with comedication. To ensure optimal patient outcome, it is vital to investigate bioavailability of pH-sensitive drugs at the maximal DDI effect of ARAs to understand the worst-case influence for efficient clinical management.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"588-597"},"PeriodicalIF":0.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6173","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899608","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":"Drug–Drug Interaction Potential of Mavacamten with Midazolam: Combined Results from Clinical and Model-Based Studies","authors":"Samira Merali PharmD, MS,&nbsp;Caroline Sychterz MS,&nbsp;Vidya Perera PhD,&nbsp;Lu Gaohua PhD,&nbsp;Victoria Florea MD,&nbsp;Bindu Murthy PharmD","doi":"10.1002/jcph.6175","DOIUrl":"10.1002/jcph.6175","url":null,"abstract":"<p>Mavacamten is a potential inducer of cytochrome P450 (CYP) 3A4 and could reduce the effectiveness of concomitant drugs that are metabolized by CYP3A4, such as midazolam. This study aimed to determine if repeat doses of mavacamten achieving clinically relevant exposures affected midazolam exposure. This was a single-center, open-label study in healthy participants. Participants received: on day 1, midazolam 5 mg; on days 2-3, mavacamten 25 mg; on days 4-16, mavacamten 15 mg; and on day 17, mavacamten 15 mg and midazolam 5 mg. Plasma concentrations of mavacamten, midazolam, and the midazolam metabolite 1′-hydroxymidazolam were measured. A physiologically based pharmacokinetic (PBPK) model was used to simulate the effect of mavacamten-mediated CYP3A4 induction on midazolam exposure by CYP2C19 phenotype. Thirteen adult participants were enrolled (46.2% were female; mean [SD] age: 34.0 [9.0] years). Compared with midazolam alone, midazolam coadministered with mavacamten decreased the maximum observed plasma concentration (C_max), area under the drug concentration-time curve (AUC) from time zero to infinity (AUC_0-inf), and AUC from time zero to last measurable concentration (AUC_0-last) for midazolam by 7%, 13%, and 24%, respectively; for 1′-hydroxymidazolam, AUC_0-inf and AUC_0Ȁlast increased by 20% and 11%, respectively. Ten participants experienced adverse events and the majority were mild in severity. The PBPK model predicted the clinical trial data well. The PBPK simulation assessed that the overall impact of mavacamten on midazolam C_max and AUC was predicted to be weak regardless of CYP2C19 phenotype. At clinically relevant exposures, mavacamten had a negligible effect on midazolam exposure.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"598-606"},"PeriodicalIF":0.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6175","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847960","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":"Preclinical and Clinical Pharmacokinetics of JNJ-75220795, an siRNA Therapeutic Targeting PNPLA3, for Metabolic Dysfunction-Associated Steatohepatitis","authors":"Jae Yoon Jeon PharmD, PhD,&nbsp;Vivaswath S. Ayyar PhD,&nbsp;Shohei Ouchi MPharm,&nbsp;Elisa Fabbrini MD, PhD,&nbsp;Anastasiya Koshkina PharmD,&nbsp;Jeffery J. Prusakiewicz PhD,&nbsp;Jed Dallas BS,&nbsp;Txheng Yang BA,&nbsp;Wenying Jian PhD,&nbsp;Lijuan Kang PhD,&nbsp;Korin Cofsky BS,&nbsp;Brian Rady PhD,&nbsp;Ryo Tamamura MS,&nbsp;Yuki Saito MEng,&nbsp;Aimi Yamashita MPH,&nbsp;Tamisha Vaughan PhD,&nbsp;Susan Wendel PhD,&nbsp;Hideo Makimura MD, PhD,&nbsp;Dénes Csonka PharmD, PhD,&nbsp;Navin Goyal PhD, FCP","doi":"10.1002/jcph.6174","DOIUrl":"10.1002/jcph.6174","url":null,"abstract":"<p>JNJ-75220795 or ARO-PNPLA3 is an investigational small interfering ribonucleic acid agent conjugated with N-acetyl-<span>d</span>-galactosamine that targets the <i>PNPLA3</i> gene, currently being developed for metabolic dysfunction-associated steatohepatitis (MASH). This study evaluated the pharmacokinetics (PK) profile of single subcutaneous doses of JNJ-75220795 in preclinical species as well as in human subjects with homozygous or heterozygous <i>PNPLA3</i> I148M mutation in two phase 1 studies—a first-in-human study in the United States and a first-in-Japanese study in Japan. Preclinical PK in rats and non-human primates (NHP) showed a rapid systemic absorption and elimination following single subcutaneous doses. JNJ-75220795 was predominantly distributed to the liver with peak liver concentrations reached at 4 h and still detectable at 672 and 336 h in rats and NHPs, respectively, with an apparent liver-to-plasma area under the curve (AUC) ratio of 2800 in rats. Consistent with the preclinical findings, clinical PK showed rapid systemic absorption and clearance in humans with median peak concentrations at 3.0-9.0 h and mean short half-life of 3.4-6.2 h. Plasma PK exposure parameters including C_max and AUC increased approximately dose proportionally. Kidney had the second highest tissue exposure following the liver in rats. Renal excretion was a significant but minor elimination pathway as approximately 15%-25% of the administered dose was recovered in urine. Based on the overall data, JNJ-75220795 was primarily localized to the liver and exhibited sustained hepatic exposures, which confer prolonged pharmacodynamic effects in the target organ. The favorable PK profiles of single subcutaneous doses observed in the phase 1 studies support continued clinical development of JNJ-75220795 for the treatment of MASH.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"644-653"},"PeriodicalIF":0.0,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142802834","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":"The Impact of Survival Benefit and Study Design on FDA Approval for Anticancer Drugs Over the Past Decades","authors":"Koji Ishizuka MSc, MBA,&nbsp;Shunsuke Ono PhD","doi":"10.1002/jcph.6172","DOIUrl":"10.1002/jcph.6172","url":null,"abstract":"<p>Despite the tremendous effort in the oncology community, the success rate of anticancer development remained low at 30% to 40% from the Phase 3 study to the regulatory approval. The factors associated with the regulatory approval for market authorization have gained interest in the community to improve the success rate of drug development. Using the data from 208 Phase 3 studies for anticancer drugs, we explored the possible factors associated with the US Food and Drug Administration's (FDA's) approval by multivariate logistic regression analysis. The model incorporated 21 factors from therapeutic context, study design, and outcomes. The hazard ratio (HR) for overall survival (OS) showed a significant association with FDA approval (coefficient: −29.907, <i>P</i> &lt; .001), and the age of control drugs in the market followed (coefficient: −2.581, <i>P</i> = .008). In the model, if the HR for OS changes from 0.75 to 0.85, the probability of FDA approval remarkably decreases from 79.6% to 16.4%. A 50% likelihood of FDA approval is predicted at HR 0.795 for OS. Furthermore, the <i>P</i>-value for the OS test and the width of the confidence interval on HR for OS showed a significant association with the probability of FDA approval. These findings consistently underscore the rigorous standard required for new anticancer drugs to obtain regulatory approval from the FDA.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"607-620"},"PeriodicalIF":0.0,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6172","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142802837","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":"Utilizing an Opportunistic Clinical Study and Population-Based Pharmacokinetic Models to Identify Rational Empiric Dosing Regimens for Piperacillin–Tazobactam in Critically Ill Patients","authors":"Joshua A. Reeder BA,&nbsp;C. Buddy Creech MD,&nbsp;Roger L. Nation PhD,&nbsp;Kenan Gu PhD,&nbsp;Demet Nalbant PhD,&nbsp;Nan Wu PhD,&nbsp;Natalia Jimenez-Truque MD,&nbsp;William Fissell MD,&nbsp;Stephanie L. Rolsma MD, PhD,&nbsp;Nicholas Fishbane MS,&nbsp;Carl M. J. Kirkpatrick PhD,&nbsp;Pratish C. Patel PharmD,&nbsp;Amy Watanabe MS,&nbsp;Cornelia B. Landersdorfer PhD,&nbsp;Patricia Winokur MD,&nbsp;Guohua An MD, PhD","doi":"10.1002/jcph.6161","DOIUrl":"10.1002/jcph.6161","url":null,"abstract":"<p>Determining an effective dosing regimen for piperacillin–tazobactam in critically ill patients is challenging due to substantial pharmacokinetic variability caused by complex pathophysiological changes. To address this need, a prospective clinical study was conducted, which enrolled 112 critically ill patients and employed an opportunistic sampling strategy. Population modeling and simulation were performed to characterize the pharmacokinetics (PK) and probability of target attainment (PTA) of piperacillin–tazobactam under various dosing regimens. Both piperacillin and tazobactam final models were one-compartment models with zero-order input and first-order elimination. Significant covariates included lean body weight for piperacillin and creatinine clearance along with continuous renal replacement therapy (CRRT) for both drugs. Monte Carlo simulations demonstrated that continuous infusion can achieve higher PTA than intermittent and extended infusions. When considering the minimum inhibitory concentration (MIC) of 16 mg/L for <i>Pseudomonas aeruginosa</i> (a frequently encountered bacterial pathogen among critically ill patients) and a PK/PD target of 100% fT &gt;MIC, continuous infusion of 6 g/day is recommended for critically ill patients with a CLcr &lt;60 mL/min, 9 g/day for patients with CLcr in the range of 60 to 129 mL/min, and 12 g/day for patients with a CLcr ≥130 mL/min. In addition, extended infusion represents a good alternative, especially the 3 g q6h or 4 g q6h regimens which can achieve the designated European Committee on Antimicrobial Susceptibility Testing (EUCAST) non-species-related PK/PD breakpoint of 8 mg/L. Our study provided valuable insight into PTA outcomes, which, together with individual renal function of future patients and institution-specific piperacillin susceptibility patterns, may assist physicians when making dosing decisions.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 4","pages":"452-465"},"PeriodicalIF":0.0,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6161","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142773877","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}