The Journal of Clinical Pharmacology最新文献

{"title":"Pharmacokinetics and Pharmacodynamics of Intravenous Magnesium Sulfate in Pediatric Acute Asthma Exacerbations","authors":"Joseph E. Rower PhD, DABCP,&nbsp;Michael D. Johnson MD, MS,&nbsp;Joseph J. Zorc MD, MSCE,&nbsp;Bashar Shihabuddin MS, MD,&nbsp;Mengtao Dai MStat,&nbsp;Bradley J. Barney PhD,&nbsp;Yaron Finkelstein MD, DABCP","doi":"10.1002/jcph.6179","DOIUrl":"10.1002/jcph.6179","url":null,"abstract":"<p>Pediatric asthma exacerbations represent a significant cause of emergency department use and hospitalizations. Despite available treatment options, many children's exacerbations are refractory to standard therapies and require adjunct treatments. The Intravenous Magnesium: Prompt use for Asthma in Children Treated in the Emergency Department study investigated the pharmacology of intravenous magnesium sulfate (IVMg) in treating pediatric asthma exacerbations. Specifically, the objectives of the study included (1) externally validating a previously published population pharmacokinetic model and (2) linking serum magnesium concentrations with outcomes including asthma severity score (efficacy) and hypotension (safety). Data were obtained from 49 children prospectively treated with IVMg (placebo, 50 or 75 mg/kg) after presenting to the pediatric emergency department with an acute asthma exacerbation. Reductions in Pediatric Respiratory Assessment Measure scores were associated with both total and ionized serum magnesium area under the concentration–time curve (AUC_{0–2 h}). Despite frequent study-specific blood pressure monitoring, hypotension was uncommon in IVMg-treated participants (n = 2/31), and no concentration dependence was observed. The findings signal that IVMg may be an efficacious and safe option for treating moderate–severe pediatric acute asthma exacerbations in the ED. Importantly, this study is the first to suggest a serum exposure target (total serum magnesium AUC_{0-2 h} &gt;63.1 mg h/L) reflective of effective IVMg dosing in pediatric acute asthma. While further study in a larger clinical trial is needed to refine and validate this exposure target, these findings support the continued study of IVMg therapy as an adjunct therapeutic option in the setting of pediatric asthma exacerbations.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 6","pages":"665-674"},"PeriodicalIF":0.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6179","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142957188","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 and Simulation to Support a Change in the FDA-Labeled Dosing Frequency of RHB-105 Low-Dose Rifabutin Triple Therapy for Helicobacter pylori Eradication","authors":"Nimish Vakil MD,&nbsp;Colin W. Howden MD,&nbsp;Shailja C. Shah MD,&nbsp;Kuan-Fu Chen PhD,&nbsp;Elliot Offman BSc Pharm, MSc, PhD,&nbsp;June S. Almenoff MD, PhD,&nbsp;Kely L. Sheldon PhD","doi":"10.1002/jcph.6178","DOIUrl":"10.1002/jcph.6178","url":null,"abstract":"<p>Patient adherence is vital for <i>Helicobacter pylori</i> eradication. Simplifying therapy dosing schedules may promote patient adherence, enhance treatment success rates, and help mitigate the development of antibiotic resistance. We aimed to assess plasma and intragastric rifabutin, amoxicillin, and omeprazole concentrations comparing two dosing schedules of RHB-105 (every 8 h and a more flexible three-times daily schedule, at 8 a.m., 12 p.m., and 6 p.m.) using a validated physiologically based pharmacokinetic (PBPK) model. Leveraging <i>in vitro</i> and <i>in vivo</i> information on the pharmacokinetics of the three components of RHB-105, we developed mechanistic absorption PBPK models to predict plasma and intragastric concentration–time profiles for each component. There were only negligible differences in the area under the concentration–time curves (AUC) for plasma and the intragastric compartment, and maximal concentration (C_max) with only up to a 1.1-fold difference for rifabutin, amoxicillin, and omeprazole between dosing schedules. Overlapping 90% confidence intervals for both AUC and C_max support that overall exposures are comparable regardless of dosing every 8 h or three-times daily for all three drugs. Drug exposure was highly similar for rifabutin, amoxicillin, and omeprazole with each dosing schedule. Novel mechanistic absorption PBPK modeling supports the approval and use of the more flexible dosing schedule for RHB-105, simplifying patient experience and potentially increasing adherence.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 6","pages":"779-786"},"PeriodicalIF":0.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6178","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915775","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":"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":"Population Pharmacokinetic Model of Platinum Disposition in Cancer Patients Receiving Cisplatin and Randomized to 5-HT3 Antagonist Antiemetic Drugs","authors":"Lauren E. Thompson PhD,&nbsp;Avisek Ghimire MS,&nbsp;Xia Wen PhD,&nbsp;Christine Kim PharmD,&nbsp;Cathleen L. Doherty PhD,&nbsp;Brian T. Buckley PhD,&nbsp;Daniel W. Bowles MD,&nbsp;Cindy L. O'Bryant PharmD,&nbsp;Edgar A. Jaimes MD,&nbsp;Lauren M. Aleksunes PharmD, PhD,&nbsp;Melanie S. Joy PharmD, PhD","doi":"10.1002/jcph.6177","DOIUrl":"10.1002/jcph.6177","url":null,"abstract":"<p>Cisplatin is a platinum-based chemotherapeutic drug used to treat many types of cancer. The aim of this study was to develop a population pharmacokinetic model that incorporates plasma unbound and bound platinum levels. Cancer patients undergoing their first or second cycle of cisplatin-containing chemotherapy (n = 33) were prospectively randomized to receive a 5-hydroxytryptamine (5-HT₃) antagonist (5-HT₃A) antiemetic (ondansetron, granisetron, or palonosetron) followed by blood collection over 10 days. Total and unbound platinum levels were quantified using inductively coupled plasma mass spectrometry. Plasma concentrations of bound and unbound platinum were used to develop a nonlinear mixed-effect pharmacokinetic model in Phoenix NLME (v8.3, Certara Inc.). A stepwise search was used to screen covariates that influenced pharmacokinetic parameters. A compartment for bound platinum was added to a two-compartment unbound platinum model to create a combined platinum model. The volume of the central compartment for unbound platinum (V1_u) was significantly impacted by previous cisplatin exposure and the intercompartmental clearance of unbound platinum (CL2_u) was significantly influenced by concomitant lorazepam use. The models also suggested ondansetron- and granisetron-treated subjects had a 331% and 114% increase, respectively, in circulating exposures to unbound platinum than palonosetron-treated subjects. The results suggest platinum pharmacokinetics are altered by concomitant 5-HT₃A antiemetic use, concomitant lorazepam use, and previous exposure to cisplatin. Ondansetron and granisetron co-treatment increased unbound platinum exposure compared to palonosetron co-treatment, suggesting that palonosetron may be a preferred 5-HT₃A to reduce the risk of cisplatin-induced kidney injury.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 6","pages":"763-778"},"PeriodicalIF":0.0,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142878619","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":"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}

{"title":"A Meta-Analysis of the Safety and Immunogenicity of Pharmacokinetic Similarity Studies and Comparative Clinical Studies","authors":"Ping Ji PhD,&nbsp;Sarah J. Schrieber Pharm D,&nbsp;Rachel Glaser MD,&nbsp;Jianmeng Chen MD, PhD,&nbsp;Chinmay Shukla PhD,&nbsp;Suresh Doddapaneni PhD,&nbsp;Sahajwalla Chandrahas PhD","doi":"10.1002/jcph.6165","DOIUrl":"10.1002/jcph.6165","url":null,"abstract":"<p>A biosimilar clinical development program generally includes a pharmacokinetic similarity study and a comparative clinical study. Since both types of studies assess safety and immunogenicity, it is important to evaluate the role of each in determining whether there are any meaningful differences between the proposed biosimilar products and the reference products. We conducted a systematic review and meta-analysis of the safety and immunogenicity data from pharmacokinetic similarity studies and comparative clinical studies, using a database of approved monoclonal antibody and fusion protein biosimilars. Our analysis showed that pharmacokinetic similarity studies provided valuable information for comparing the immunogenicity and safety of the monoclonal antibody and fusion protein biosimilars with their respective reference products. This work underscores the evolving understanding of these biologics and offers insights into the clinical development of biosimilars.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 4","pages":"499-507"},"PeriodicalIF":0.0,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142741069","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":"Ritonavir May Prolong Sedation but is Unlikely to Increase the Risk of Respiratory Arrest in Patients Requiring Intravenous Midazolam for Procedural Sedation","authors":"Jason Arsanious BMedSci,&nbsp;Angela Rowland MD,&nbsp;Michael J. Sorich PhD,&nbsp;Ashley M. Hopkins PhD,&nbsp;Sam Alfred MD,&nbsp;Andrew Rowland PhD","doi":"10.1002/jcph.6171","DOIUrl":"10.1002/jcph.6171","url":null,"abstract":"<p>Intravenous midazolam is frequently used for procedural sedation. Use of ritonavir containing antivirals in patients requiring procedural sedation with intravenous midazolam is postulated to increase the risk or prolong the consequences of exposure related adverse events. The primary objective of this study was to characterize interaction of ritonavir with IV midazolam. The secondary objective was to define the time course over with the interaction of ritonavir with IV midazolam resolves following cessation of ritonavir. Physiologically based pharmacokinetic modeling was used to conduct clinical trials with a parallel group design defining exposure to a single 5 mg IV dose of midazolam in the presence and absence of nirmatrelvir/ritonavir dosed twice daily for 5 days. Simulations comprised 50 virtual healthy subjects aged 20 to 50 years (50% female). Based on FDA criteria, a moderate/strong interaction between nirmatrelvir/ritonavir and intravenous midazolam (area under the curve [AUC] ratio &gt;2) was observed when intravenous midazolam was administered up to 72 h following cessation of nirmatrelvir/ritonavir. The geometric mean (90% CI) midazolam AUC ratio was 9.21 (5.44 to 16.43) when coadministered on the final day of nirmatrelvir/ritonavir dosing. Importantly, there was no change in peak exposure; the geometric mean (90% CI) midazolam maximum concentration ratio was 0.99 (0.99 to 1.00). Use of ritonavir containing antivirals is unlikely to increase a patient's risk of experiencing an exposure related adverse event following administration of intravenous midazolam but may prolong complications in patients who experience an event. A meaningful interaction persists for 72 h following cessation of nirmatrelvir/ritonavir.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 5","pages":"637-643"},"PeriodicalIF":0.0,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142741072","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}