The Journal of Clinical Pharmacology最新文献

{"title":"Population Pharmacokinetic Model-Based Dose Selection of Extended-Release Injectable Olanzapine (TV-44749) for Subcutaneous Use in Phase 3 Clinical Trial in Adults with Schizophrenia","authors":"Itay Perlstein PhD,&nbsp;Irina Cherniakov PhD,&nbsp;Anna Elgart PhDMBA,&nbsp;Roberto Gomeni PhD,&nbsp;Dikla Gutman PhD,&nbsp;Avia Merenlender Wagner PhD,&nbsp;Rajendra Singh PhD","doi":"10.1002/jcph.70144","DOIUrl":"10.1002/jcph.70144","url":null,"abstract":"<p>TV-44749 is a long-acting subcutaneous (SC) injectable olanzapine based on a novel copolymer drug delivery technology ensuring controlled olanzapine release over the dosing interval. TV-44749's formulation and SC route of administration aim to eliminate the causes of post-injection delirium/sedation syndrome (PDSS) that may occur with the intramuscular LAI olanzapine formulation. The main objective of this analysis was to utilize a population pharmacokinetic (PPK) modeling and simulation approach to select TV-44749 doses for a Phase 3 clinical trial that are comparable to the oral olanzapine approved doses and achieve dopamine D2 receptor occupancy (D2RO) within the therapeutic range. The PPK model was developed using data from a Phase 1 study in healthy participants and patients with schizophrenia or schizoaffective disorder. The Phase 1 study consisted of an oral olanzapine period followed by a washout and then single or multiple doses of TV-44749. The PK model was characterized by a double Weibull input function representing a two-phase drug release: an initial rapid release of a fraction of the dose, followed by a delayed and sustained release of a second fraction with two-compartment disposition model. The predicted steady-state pharmacokinetic parameters (C_max, C_avg, and C_trough) of once-monthly TV-44749 doses of 318, 425, and 531 mg were comparable to daily oral doses of 10, 15, and 20 mg, respectively. The exposure values resulted in simulated D2RO levels within the recommended range (60%–80%) and were therefore selected for the Phase 3 trial of TV-44749 (SOLARIS; NCT05693935).</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12775547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913388","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 Pharmacokinetics to Support Intravenous and Enteral Methadone Dosing in Children","authors":"Kevin M. Watt MD, PhD,&nbsp;Elizabeth J. Thompson MD,&nbsp;Lisa Lam PharmD,&nbsp;Kanecia Zimmerman MD, PhD, MPH,&nbsp;Christoph P. Hornik MD, PhD, MPH,&nbsp;Andrew M. Atz MD,&nbsp;Allison Fernandez MD,&nbsp;Susan R. Hupp MD,&nbsp;Varsha Bhatt-Mehta PharmD, MS, FCCP,&nbsp;Daniel K. Benjamin Jr MD, PhD, MPH,&nbsp;Ravinder Anand PhD, MS,&nbsp;Michael Cohen-Wolkowiez MD, PhD,&nbsp;Daniel Gonzalez PharmD, PhD,&nbsp;P. Brian Smith MD, MHS, MPH,&nbsp;Edmund V. Capparelli PharmD,&nbsp;the Best Pharmaceuticals for Children Act — Pediatric Trials Network Steering Committee","doi":"10.1002/jcph.70143","DOIUrl":"10.1002/jcph.70143","url":null,"abstract":"<p>Methadone is used in hospitalized children to treat pain and iatrogenic opiate withdrawal. Optimal pediatric dosing for both enteral and intravenous methadone is unknown. We conducted two prospective, multi-center, open-label studies to characterize the pharmacokinetics of methadone in the pediatric population. These studies were conducted at a total of 23 US children's hospitals. Ninety-nine children with a median (range) age of 2.3 (0–19.0) years and weight of 13.0 (0.72–159) kg were prescribed methadone per standard of care for treatment of pain or iatrogenic opiate withdrawal. Ninety-nine children received median (range) methadone doses of 0.11 (0.01–0.39) mg/kg intravenously and 0.10 (0.01–0.61) mg/kg enterally. Ten participants received only intravenous doses; 78 received only enteral doses; and 11 received intravenous and enteral doses. We analyzed 263 pharmacokinetic samples with a median (range) methadone plasma concentration of 42.2 (0.9–729.2) ng/mL. A one-compartment population pharmacokinetic model described the methadone data well. Median (range) empiric Bayesian estimates of clearance, volume of distribution, and half-life were 0.17 (0.009–1.50) L/h/kg, 4.99 (0.97–20.6) L/kg, and 20.5 (3.0–86.2) h, respectively. Dosing simulations showed that doses of 0.1 mg/kg every 8 h (intravenous) and 0.2 mg/kg every 8 h (enteral) achieved exposures associated with pain control and reduction in withdrawal symptoms. Based on observed exposures and model simulations, we recommend a starting dose of 0.1 mg/kg intravenous or 0.2 mg/kg enterally (max 10 mg) every 8 h. Because of wide interindividual variability, this dose should be titrated to effect.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70143","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145866178","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":"Response to Comment on “Population Pharmacokinetics of Valemetostat and Exposure–Response Analyses of Efficacy and Safety in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma”","authors":"Hiroyuki Inoue MS,&nbsp;Xiaoning Wang PhD,&nbsp;Ramon Garcia PhD,&nbsp;Brian Reilly PharmD, PhD,&nbsp;Masaya Tachibana PhD,&nbsp;YoungJun Yoo PharmD,&nbsp;Yvonne Lau PhD,&nbsp;Yang Chen PhD","doi":"10.1002/jcph.70132","DOIUrl":"10.1002/jcph.70132","url":null,"abstract":"&lt;p&gt;Dear Dr. Bhise and colleagues,&lt;/p&gt;&lt;p&gt;We sincerely appreciate your thoughtful and valuable comments on our manuscript.&lt;/p&gt;&lt;p&gt;We acknowledge the limitations of this study, and several of the concerns you pointed out have been thoroughly discussed in the manuscript.&lt;/p&gt;&lt;p&gt;In particular, the evaluation of the exposure–efficacy relationship based on a single-dose level restricts the statistical power to detect significant exposure–response (ER) relationships. Therefore, we think it is difficult to draw definitive conclusions about efficacy from this analysis. However, we conducted an evaluation of the ER relationship using a full modeling approach incorporating spike and slab priors, which helps reduce confounding risk by appropriately accounting for covariate effects. We consider that we have made efforts to detect the ER relationship more accurately, even when the exposure range is narrow. Additionally, given the observed overall response rate (ORR) of 44% and the median duration of response of 11.9 months, a 200 mg dose once daily (QD) of valemetostat provides a meaningful therapeutic benefit to patients with peripheral T-cell lymphoma (PTCL) compared with existing treatments.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; We also provide the dosing recommendations for patients with hepatic impairment or those taking a cytochrome P450 3A (CYP3A) and/or P-glycoprotein (P-gp) modulator based on the results from dedicated clinical pharmacology studies.&lt;span&gt;&lt;sup&gt;2-5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Regarding exposure–safety analyses, we used the valemetostat unbound average concentration up to event (Cavgtte) as the primary exposure metric. While this approach allowed us to account for dose modifications during the study period, we acknowledge that it might introduce a bias. To address this concern, we also conducted sensitivity analyses using the unbound average concentration during Cycle 1 (CavgC1), which assumes no dose modifications. This metric is not influenced by dose modifications and is independent of the timing of the event. We confirmed that the conclusions derived from the CavgC1-based models were consistent with those obtained using Cavgtte.&lt;/p&gt;&lt;p&gt;For the handling of covariates, we fully acknowledge the importance of carefully considering the factors you highlighted. In our analyses, we employed a full covariate modeling approach that included both main effects and interaction effects. Notably, in addition to the statistically significant main effects of hepatic function (according to the National Cancer Institute–Organ Dysfunction Working Group [NCI–ODWG]) and baseline level of lactate dehydrogenase (LDH) on Grade ≥3 treatment-emergent adverse events (TEAEs), baseline LDH also demonstrated a statistically significant interaction with thrombocytopenia risk, indicating a steeper ER relationship in patients with elevated LDH levels. While these patients may require careful attention, simulations conducted using resampled data from the analysis population showed that no sub","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70132","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145851319","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":"Elranatamab Exposure–Safety Analysis in Relapsed or Refractory Multiple Myeloma","authors":"Pooneh Soltantabar PhD,&nbsp;Jennifer Hibma PharmD,&nbsp;Diane Wang PhD,&nbsp;Umberto Conte PharmD,&nbsp;Anne Hickman DVM PhD,&nbsp;Mohamed Elmeliegy PhD","doi":"10.1002/jcph.70130","DOIUrl":"10.1002/jcph.70130","url":null,"abstract":"<p>Elranatamab, a bispecific antibody targeting B-cell maturation antigen, is approved for the treatment of relapsed or refractory multiple myeloma (RRMM). An exposure–safety analysis was conducted using the data from patients with RRMM across four clinical studies, MagnetisMM-1, 2, 3, and 9 (NCT03269136, NCT04798586, NCT04649359, and NCT05014412). The selected safety endpoints included grade ≥3 infections, neutropenia, anemia, and thrombocytopenia. Additionally, the relationship between the elranatamab exposure and dose interruptions and discontinuation events was explored. The results showed no statistically significant relationship between elranatamab exposure and the incidence of these safety events. The flat exposure–safety relationship with the evaluated safety endpoints suggested a similar probability of experiencing these events with the 76-mg once-weekly (QW) regimen compared with lower doses within the efficacious dose range (215–1000 µg/kg, equivalent to 16–76 mg). These data support the use of a full dose of 76 mg QW and do not indicate that selecting a lower dose would significantly mitigate the risk for adverse events. Additionally, these findings support managing elranatamab adverse drug reactions through temporary dose interruption rather than dose reduction.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12710126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769539","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 Pharmacokinetics of Bictegravir During Pregnancy and Postpartum: Role of Adherence in Maintaining Therapeutic Exposure","authors":"Steven Sun PharmD,&nbsp;Mina Nikanjam MD, PhD,&nbsp;Mark Mirochnick MD,&nbsp;Kathleen M. Powis MD,&nbsp;Ahizechukwu C. Eke MD, PhD, MPH,&nbsp;Alice Stek MD,&nbsp;Priyanka Arora PhD,&nbsp;Tim R. Cressey PhD,&nbsp;Kristina M. Brooks PharmD,&nbsp;Brookie M. Best PharmD, MAS,&nbsp;Edmund V. Capparelli PharmD,&nbsp;Jeremiah D. Momper PharmD, PhD","doi":"10.1002/jcph.70134","DOIUrl":"10.1002/jcph.70134","url":null,"abstract":"<p>Bictegravir is an integrase strand transfer inhibitor available in fixed-dose combination with emtricitabine and tenofovir alafenamide for HIV treatment. The objectives of this study were to develop a population pharmacokinetic model for bictegravir during pregnancy and postpartum, identify main drivers of between-subject variability, and evaluate the role of adherence patterns in maintaining therapeutic exposure. Intensive bictegravir concentration–time data were used from IMPAACT 2026, a pharmacokinetic study of selected antiretroviral drugs during pregnancy and postpartum. Five hundred and eight bictegravir plasma concentrations from 27 participants during the second and third trimesters of pregnancy and postpartum were utilized for model development. A one-compartment structural model best described bictegravir PK. Pregnancy increased bictegravir apparent clearance (CL/F) by 61% compared to postpartum, while Black/African American race was associated with a 32% increase in apparent volume of distribution (Vd/F). Plasma albumin concentrations were associated with a 43% decrease in CL/F and body weight was associated with a 120% increase in Vd/F over the range of observed values. Monte Carlo simulations predicted median (90% prediction interval) pre-dose bictegravir concentrations of 920 ng/mL (265–2081) during the third trimester and 3399 ng/mL (1423–6391) postpartum, exceeding the protein-adjusted 95% effective concentration (162 ng/mL). Adherence simulations predicted a single missed dose at steady-state during the third trimester results in 43.7% of virtual subjects with concentrations below pharmacodynamic target, while two consecutive missed doses result in 90.4% with concentrations below target. These results show that while standard bictegravir dosing is effective during pregnancy, consistent adherence is critical to maintain effective therapeutic exposures.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769558","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":"Tolerability, Safety, and Pharmacokinetics of Ivermectin After Nasal Application in Healthy Adult Subjects","authors":"Stefan Wissel PhD,&nbsp;Philipp Wissel PhD,&nbsp;Matthias Rischer PhD,&nbsp;Felix Häberlein PhD,&nbsp;Hilde Riethmüller-Winzen PhD,&nbsp;Hanns Häberlein PhD","doi":"10.1002/jcph.70137","DOIUrl":"10.1002/jcph.70137","url":null,"abstract":"<p>Nasal epithelium is the site of infection for SARS-CoV2 viruses, with interactions of the viral spike protein with the ACE2 receptor of the host cell. Molecular docking studies have shown that ivermectin shields the spike protein and thereby prevents binding to ACE2. Nasal application of high doses of ivermectin could be the right therapeutic approach in the treatment and prevention of COVID-19. Tolerability, safety, and pharmacokinetics of ivermectin, administered nasally as 5% microsuspension (F004), were investigated in a randomized, double-blind, parallel-groups, placebo-controlled phase 1 study in 28 healthy adults. Bioavailability of a single dose of 14 mg ivermectin was determined with AUC_0–t^T of 1701.1 ng/mL h (AUC_0–∞ of 2382.7 ng/mL h, calculated), C_max of 96.2 ng/mL, T_max of 4.4 h, and T_1/2 of 59.9 h. Following 42 mg/day multiple dose (3 × 14 mg every 6 h) administered nasally over 5 days, AUC_0-∞ of 2194.4 ng/mL h was analyzed, and 96% of ivermectin concentrations were still measurable 12 h after the last dose. F004 was safe in this study and well-tolerated. Nine (F004 group) and three (placebo group) of 28 subjects reported 14 symptoms, including a few systemic but mainly local nasal adverse events (AE). The number of subjects reporting AE decreased continuously after both F004 and placebo treatment. All subjects recovered fully with no AE recorded at the end of the study. Nasal examination showed stable patterns of nasal mucosal grading, mucosal bleeding, and crusting of the mucosa. Nasally administered ivermectin is well tolerated in high concentrations and could provide systemic therapeutic benefits in addition to local effects.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12710153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769574","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 Importance of the Peer Review Process to Safeguard Scientific Integrity","authors":"Kenneth T. Moore DBE, MS, FAHA, FCP","doi":"10.1002/jcph.70146","DOIUrl":"10.1002/jcph.70146","url":null,"abstract":"&lt;p&gt;In an era defined by information overload, limited time, and competing professional demands, the role of the peer reviewer often comes at the expense of personal or free time. Yet, despite these challenges, performing this role remains an essential contribution to maintaining trustworthy science. I realize as I write this, I am also proclaiming “Do as I say, not as I do,” as I have fallen victim to continually declining requests to act as a peer reviewer because of an ever-increasing workload from my employer, or important commitments I have made to my family and friends. However, today, where misinformation about science and medicine spreads rapidly across social media platforms, where political agendas often distort evidence-based discourse, and where questionable “science” circulates without scrutiny, the peer review process, more than ever, serves as a critical safeguard for ensuring the credibility and rigor of science. Thus, if one identifies as a proponent of the scientific method and values a logical, data driven, and evidence-based foundation for scientific and medical dialogue, then active participation as a peer reviewer is less of an option and more of an ethical and professional responsibility. We cannot passively stand by and watch the ongoing deterioration of public trust in the professions we devoted our lives to. Rather, we must collectively reaffirm our commitment to credible research and the mechanisms by which knowledge remains verifiable, reproducible, and transparent.&lt;/p&gt;&lt;p&gt;At its core, peer review is a process that brings scientific and medical manuscripts to evaluation by independent experts within the same field of study. This process helps to ensure that the research being published meets the standards of validity, originality, and methodological soundness, while also safeguarding ethical integrity.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; By filtering out research that does not meet these standards, the peer review process serves as a quality assurance mechanism that helps not only protect the academic record on the subject, but ultimately the public welfare.&lt;/p&gt;&lt;p&gt;Moreover, the peer review process plays an important role in advancing knowledge and fostering innovation. It can facilitate intellectual exchange by encouraging researchers to refine their methods, clarify findings or interpretations, question assumptions, and even explore potential new directions not previously considered.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; In this way, peer review is more than just a gatekeeping function, it acts as a source of collaboration, accountability, and innovation that sustains the continuous evolution of science.&lt;/p&gt;&lt;p&gt;The integrity of this process depends fundamentally on the ethical conduct and professional responsibility of reviewers. Reviewers must approach their task with impartiality, confidentiality, and respect for the intellectual property of others. Declaring conflicts of interest, whether financial, personal, or professional, is not merely a","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70146","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769614","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 Rational Approach to Pharmacotherapy in Pregnancy","authors":"Gregory W. Kirschen MD, PhD,&nbsp;Kevin Watt MD, PhD,&nbsp;Ahizechukwu C. Eke MD, PhD, MPH","doi":"10.1002/jcph.70145","DOIUrl":"10.1002/jcph.70145","url":null,"abstract":"<p>Most pregnant individuals are exposed to at least one medication, whether prescription or over the counter, during pregnancy. Despite the ubiquity of medication use in pregnancy, there remains no standardized framework to guide clinicians in selecting the most appropriate pharmacotherapy that balances maternal needs with fetal safety. This gap contributes to variability in prescribing practices and uncertainty in clinical decision making. In this article, we propose a structured schema for evaluating and selecting drug therapy during pregnancy. Our approach emphasizes careful consideration of maternal and fetal factors, integration of the unique physiologic changes of pregnancy, and systematic appraisal of the best available evidence. Recognizing the frequent absence of robust pharmacokinetic and safety data, we also provide pragmatic principles and rules of thumb to guide clinicians in estimating the likelihood of placental transfer and potential fetal exposure. This framework is designed to support clinicians in making more informed, transparent, and evidence-based decisions while also identifying areas for future research.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12710685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769560","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":"Antibody Transfer From Mother to Fetus/Infant: An Opportunity for Model-Informed Precision Medicine","authors":"Miramar Sami Kardouh PharmD,&nbsp;Tyler Dunlap PharmD,&nbsp;Rui Zhong PhD,&nbsp;Jacqueline B. Tiley PhD,&nbsp;Yanguang Cao PhD","doi":"10.1002/jcph.70136","DOIUrl":"10.1002/jcph.70136","url":null,"abstract":"&lt;p&gt;Therapeutic antibodies have become increasingly important for the treatment of autoimmune disorders, such as inflammatory bowel disease (IBD), in pregnant patients and mothers.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; For example, a retrospective study assessing the pattern of biologics use from pre-pregnancy to postpartum has reported 71.6% have continued biologics use at least once during pregnancy. Compared to patients with rheumatoid arthritis, patients with Crohn's disease and ulcerative colitis were more likely to continue the biologic during pregnancy, while patients with psoriasis or psoriatic arthritis were less likely to continue biologic use. The percentage of pregnant subjects with live birth that continued biologics declined from 68.6% in trimester 1 to 58.8% in trimester 2 to 48.6% in trimester 3.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; While transplacental transfer of endogenous antibodies supports passive immunity against infectious diseases to the fetus and newborn, the long-term safety of therapeutic antibodies that cross the placenta remains poorly understood. The impact of transplacental transfer of therapeutic antibodies and their impact on fetal health represents a substantial knowledge gap in maternal pharmacotherapy with consequences for clinical decision-making.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; The management of chronic disease during pregnancy and lactation has undergone a paradigm shift in recent years with increasing focus on maintaining maternal disease control while ensuring healthy outcomes for the fetus or infant. More robust data is needed to support dosing strategies that optimize the health of both expecting mothers and their children.&lt;/p&gt;&lt;p&gt;Currently, most evidence supporting antibody dosing strategies in pregnant patients is based on observational studies, attributable to the ethical challenges of conducting clinical trials during pregnancy. Reliance on observational, or clinically convenient data, has led to inconsistent clinical recommendations for the use and dosing of antibody drugs during pregnancy. Our compilation of selected societal guidelines highlights the variability in recommendations for antibody drug use in selected autoimmune disorders, particularly with respect to dosing schedules (Table S1). Post-approval pregnancy studies, when conducted, tend to prioritize severe congenital malformations as safety endpoints, often challenged with the detection of milder outcomes due to limitations of sample size and/or follow-up time, which could still affect infant health. Meanwhile, hormonal, immunological, and microbial fluctuations during pregnancy can alter the course of autoimmune diseases, influencing risk of relapse, attack severity, and postpartum recovery.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Drug labeling typically adopts a cautious stance, prioritizing fetal safety over maternal well-being, despite risk signals that are often ambiguous. Data gaps persist, particularly with respect to the mechanisms that govern dynamics of antibody pha","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70136","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769611","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":"Leveraging Model Integrated Bioequivalence (MIBE) to Address Regulatory Concerns and Waive Repeat Bioequivalence Studies—A Case Study with Clopidogrel","authors":"Mathangi Gopalakrishnan PhD,&nbsp;Adithya Karthik Bhattiprolu MPharm,&nbsp;Joga Gobburu PhD,&nbsp;Rajkumar Boddu PhD,&nbsp;Veena Kambam MPharm,&nbsp;Sohel Mohammed Khan MPharm,&nbsp;Anuj Kumar Saini PhD,&nbsp;Sivacharan Kollipara PhD","doi":"10.1002/jcph.70142","DOIUrl":"10.1002/jcph.70142","url":null,"abstract":"<p>In recent years, model-informed strategies such as the model integrated bioequivalence (MIBE) approach have gained significance due to their ability to enable decision making, streamline drug product development, and to waive bioequivalence studies, as applicable. In this work, we demonstrate the successful application of the MIBE approach that led to the waiver of a repeat fasting and fed bioequivalence studies for clopidogrel bisulfate 300 mg tablets. In the pivotal bioequivalence study, pharmacokinetic sampling in fasting and fed conditions was performed until 12 h, shorter than the recommended sampling up to at least three half-lives of the drug. The mean half-life of reference listed drug clopidogrel was 6 h. During dossier review, a query was received from the regulatory agency to assess the impact of early termination of the study on AUC_0–inf and bioequivalence assessment, although the pivotal study demonstrated average bioequivalence. To address this, a population pharmacokinetic model was developed under fasting and fed conditions based on the pilot study data that included data until 24 h. Further, the pivotal study pharmacokinetic parameters were predicted based on a model developed with pilot data and complete profiles until 10 half-lives were simulated. The model-derived parameters were utilized to assess preserving Type-1 error rate at 5% and bioequivalence was simulated. The simulations demonstrated average bioequivalence under fasting and fed conditions, and the 90% confidence intervals within 80%–125%. Overall, the MIBE approach demonstrated that truncated sampling till 12 h did not compromise the interpretability of pivotal study, thereby alleviating the need for a repeat bioequivalence study.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769595","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}