The Journal of Clinical Pharmacology最新文献

{"title":"Predicting Oral HIV Pre-Exposure Prophylaxis Efficacy in Cisgender Women Across Pregnancy and Postpartum","authors":"Yifan Yu MS,&nbsp;Kristina M. Brooks PharmD,&nbsp;Gustavo F. Doncel MD,&nbsp;Brookie M. Best PharmD,&nbsp;Mark A. Marzinke PhD,&nbsp;Mark Mirochnick MD,&nbsp;Peter L. Anderson PharmD,&nbsp;Landon Myer MD,&nbsp;Connie Celum MD,&nbsp;Renee Heffron PhD,&nbsp;Jenell Coleman MD,&nbsp;Dvora L. Joseph Davey PhD,&nbsp;Lanxin Zhang PhD,&nbsp;Max von Kleist PhD,&nbsp;Craig W. Hendrix MD,&nbsp;Jeremiah D. Momper PharmD, PhD,&nbsp;Robert Bies PharmD, PhD,&nbsp;Rachel K. Scott MD","doi":"10.1002/jcph.70278","DOIUrl":"10.1002/jcph.70278","url":null,"abstract":"<p>Cisgender women face an increased risk of HIV acquisition during pregnancy and postpartum. Oral pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir disoproxil fumarate (F/TDF) is recommended in pregnancy despite limited published pharmacokinetic (PK) and efficacy data during pregnancy. Altered PK during pregnancy may reduce prophylactic efficacy and necessitate higher adherence. Tenofovir alafenamide (TAF) is a newer tenofovir prodrug with higher tenofovir diphosphate (TFV-DP) exposure in peripheral blood mononuclear cells (PBMCs), but the prophylactic efficacy of F/TAF across different reproductive stages in women is understudied. We adapted a multiscale modeling framework to predict the prophylactic efficacy of F/TDF and F/TAF across varying adherence levels and during the second trimester, third trimester, and 6–12 weeks postpartum. Clinical trial simulations were conducted utilizing PBMC TFV-DP and emtricitabine triphosphate concentrations as surrogate markers for F/TAF and F/TDF efficacy. For both F/TDF and F/TAF, prophylactic efficacy was lowest during the second trimester, increased in the third trimester (but remained below nonpregnant levels), and was highest postpartum. At high adherence levels of five or more pills per week, predicted effectiveness remained high across pregnancy and postpartum and effectiveness exceeded 97% for both regimens, with maximum decreases in the second trimester of only 0.9 percent point for F/TDF and 0.3 percent point for F/TAF. These findings suggest that adherence is the primary determinant of PrEP effectiveness during pregnancy and postpartum, while pregnancy-related PK changes have a limited impact on efficacy.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148882321","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":"Effect of Food on Balcinrenone/Dapagliflozin Pharmacokinetics and the Pharmacokinetics of Balcinrenone When Dosed with a P-gp Inhibitor","authors":"Anna L. Eriksson MD, PhD,&nbsp;Deeyen Karsanji BSc,&nbsp;Amy H. Shi PhD,&nbsp;Joanna Parkinson PhD,&nbsp;Maria Heijer MSc,&nbsp;Edward Austin BSc,&nbsp;Bosse Lindmark MSc,&nbsp;Charlotta Vedin-Nilsson BSc,&nbsp;Judith Hartleib-Geschwindner PhD,&nbsp;Maria Leonsson-Zachrisson MD, PhD,&nbsp;Hans Ericsson PhD","doi":"10.1002/jcph.70282","DOIUrl":"10.1002/jcph.70282","url":null,"abstract":"<p>Balcinrenone (AZD9977) is a novel selective non-steroidal mineralocorticoid receptor antagonist with a distinct mode of action being developed as a fixed-dose combination with the sodium–glucose cotransporter-2 inhibitor dapagliflozin for the treatment of heart failure with impaired kidney function, and chronic kidney disease. In this Phase 1 randomized open-label three-way crossover study we investigated the effect of food on balcinrenone/dapagliflozin pharmacokinetics, and the pharmacokinetics of balcinrenone when dosed with a P-glycoprotein (P-gp) inhibitor. Fourteen healthy participants were administered an oral capsule of balcinrenone/dapagliflozin 40 mg/10 mg in three dosing periods: fasted (reference), fed (high-fat, high-calorie meal) and with a P-gp inhibitor (quinidine 300 mg × 2). Balcinrenone exposure was comparable in the fed and fasted states (geometric mean ratios [GMRs] [90% CI]: maximum plasma concentration [C_max] 1.05 [0.88, 1.25]; area under the plasma concentration–time curve from time 0 to infinity [AUC_inf] 1.12 [1.06, 1.19]). In the fed state, dapagliflozin AUC_inf was comparable to the fasted state (GMR [90% CI] 1.05 [1.01, 1.09]), whereas C_max was decreased (GMR [90% CI] 0.59 [0.51, 0.69]), in line with previous dapagliflozin food interaction studies. Co-administration with quinidine increased balcinrenone exposure: GMRs (90% CI) 1.48 (1.24, 1.76) and 1.24 (1.17, 1.31) for C_max and AUC_inf, respectively, but AUC fold increase was &lt;2, the level used for classification of sensitive P-gp substrates. All interventions were well tolerated. In conclusion, this study supports dosing of balcinrenone/dapagliflozin without regard to food. Balcinrenone is not considered a sensitive P-gp substrate. No P-gp based dosing precautions are warranted based on this study.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148882276","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":"THC Precision Dosing Requires Exposure Provenance and Psychiatric Phenotyping","authors":"Yu-Yuan Hung MD,&nbsp;Lien-Chung Wei MD, MPH","doi":"10.1002/jcph.70283","DOIUrl":"10.1002/jcph.70283","url":null,"abstract":"&lt;p&gt;Lu and colleagues identified 12 cannabinoid population pharmacokinetic models from 11 studies, including nine models of delta-9-tetrahydrocannabinol (THC).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Absorption was the most variable phase; bioavailability varied from 22% to 91%, while administration route, formulation, and prior use influenced variability.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Their proposed model repository is an important foundation for model-informed dosing. We suggest that its clinical value will depend on two additional domains: exposure provenance and standardized psychiatric phenotyping.&lt;/p&gt;&lt;p&gt;First, a nominal THC dose is not necessarily an analytically comparable exposure. Discordance between labeled and measured cannabinoid content has been demonstrated in commercial edible products.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; A minimum provenance dataset should therefore record regulatory source, product and lot, measured versus labeled THC and cannabidiol content, route and formulation, dose, timing, fed state, previous cannabis exposure and tolerance, alcohol, nicotine and other substances, liver function, and CYP-relevant concomitant medicines. Studies of standardized medicinal products should be distinguished from unverified or illicit exposures; the latter may inform external validity but should not be pooled as though dose certainty were equivalent.&lt;/p&gt;&lt;p&gt;Second, concentration–time data should be linked prospectively to repeated psychiatric outcomes. A core set could include anxiety or panic, perceptual disturbance or paranoia, manic symptoms, cognition, sedation, sleep, functioning, onset and offset, and whether urgent treatment was required. Baseline psychotic and bipolar disorders, suicidality, and substance-use disorders should be prespecified vulnerability variables. A synthesis of 162 studies found substantial design-dependent variation in cannabis-associated psychotic symptoms and identified mental-health vulnerabilities as relevant predictors.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; A six-patient Taiwanese psychiatric-emergency case series further illustrates that cannabis-associated psychosis can present with severe behavioral and safety consequences, although it cannot estimate population risk.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;A useful modeling hierarchy would use analytically standardized trials to establish structural pharmacokinetics, then test transportability in real-world cohorts while explicitly propagating uncertainty in product content and co-exposures. Linking predicted exposure metrics to prespecified psychiatric endpoints could identify when similar plasma profiles have dissimilar clinical consequences.&lt;/p&gt;&lt;p&gt;Precision dosing should therefore mean more than predicting THC concentration. It should connect a verified product and exposure history to a reproducible psychiatric phenotype. Adding these fields to a common repository would make future models more clinically interpretable for both clinical pharmacologists and psychiatrists.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Yu-Yuan Hung&lt;/b","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148882332","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":"Beyond Pharmacokinetics: Gaps for Rational Use of Medicinal Cannabis","authors":"Shuang Lu MCom,&nbsp;Xin Liu MSc,&nbsp;Linda Truong PhD,&nbsp;Zheng Liu PhD,&nbsp;Fei Guo PhD,&nbsp;Jennifer Martin PhD,&nbsp;Xiao Zhu PhD","doi":"10.1002/jcph.70284","DOIUrl":"10.1002/jcph.70284","url":null,"abstract":"<p>A recent letter highlights important gaps in translating population pharmacokinetic (popPK) models of Δ9-tetrahydrocannabinol (THC) into clinically appropriate dosing, raising two considerations: exposure provenance and the unclear exposure–response relationship for psychiatric outcomes.</p><p>The nominal THC dose does not necessarily reflect the actual dose received. This discrepancy can arise from the product itself, given documented discordance between labeled and measured cannabinoid content,<span>¹</span> batch-to-batch inconsistency, and variation in regulatory source. Most of the published THC population PK studies reported only limited information on product-level details.<span>²</span> Also, it can arise from the patient, since adherence to the intended dosing regimen is rarely assessed and is a practical challenge in real-world settings. Both factors can contribute to the known large variability in THC pharmacokinetics, partly reflected in the wide between-subject variability in bioavailability identified across the reviewed models. Standardized recording of product provenance in future clinical trials, through a structured reporting checklist, would help close the first gap. Confirmation of administered dose, such as biochemical verification of intake or electronic dose-monitoring devices, would help address the second.</p><p>Although the current review focused on PK variability of THC, the deep understanding of exposure–response relationship is essential for better interpretation of exposure differences on clinical outcomes. However, such PK–PD studies remain scarce and endpoints are largely limited to acute effects such as “feeling high,” alertness, and heart rate.<span>^3-5</span> These studies also lack heterogeneous or real patient populations, as well as evaluation under long-term or repeated dosing. Extending PK–PD research to better reflect real-world psychiatric outcomes will require this kind of broader, longer-term evidence, grounded in reliable exposure characterization.</p><p>Our PopPK model repository serves as a quantitative starting point for describing THC disposition. Moving beyond pharmacokinetics, however, will require closing several gaps: verifying product provenance and patient adherence to reduce dose uncertainty, and extending PK–PD research toward heterogeneous, real patient populations with longer-term dosing and psychiatric endpoints. Addressing these gaps will be necessary to better guide dosing in medicinal cannabis practice.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148882278","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":"Dose Selection for Ceftibuten Combined with Avibactam Tomilopil, a Potential Oral Alternative to Carbapenems for Patients with Complicated Urinary Tract Infections","authors":"Siddhee A. Sahasrabudhe MS, PhD,&nbsp;Satoshi Shoji PhD,&nbsp;Abhijeet S. Jakate PhD,&nbsp;Bisrat K. Abraham MD, MPH,&nbsp;Sima S. Toussi MD,&nbsp;Benjamin J. Maligalig MPH,&nbsp;Amanda S. Darekar MSc,&nbsp;Sakambari Tripathy MSc, MPhil,&nbsp;Constantino Kantaridis MD, DPM,&nbsp;Josue K. Mfopou MD, PhD, DPM,&nbsp;Oxana Selivanova PhD,&nbsp;Arthur Bergman PhD,&nbsp;Negar Niki Alami MD,&nbsp;Ravi Shankar P. Singh PhD, FCP","doi":"10.1002/jcph.70263","DOIUrl":"https://doi.org/10.1002/jcph.70263","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>There are currently no oral treatment options for infections caused by extended spectrum β‑lactamase-producing Enterobacterales. Avibactam tomilopil, a novel oral prodrug of avibactam, is being developed in combination with the oral cephalosporin, ceftibuten, as a potential treatment for patients with complicated urinary tract infections (cUTIs). The safety, tolerability, and pharmacokinetic profiles of single and multiple doses of avibactam tomilopil (900 to 1350 mg) and ceftibuten (400 to 1600 mg), alone and/or in combination were evaluated in three Phase 1 trials in healthy participants. Avibactam tomilopil was rapidly metabolized to active avibactam and plasma avibactam exposure increased proportionately with dose. Both avibactam and cis-ceftibuten had similar plasma half-lives, and were predominantly renally excreted. While there was negligible food effect on ceftibuten exposures, plasma avibactam exposure in the fed state for a fixed-dose combination ceftibuten-avibactam tomilopil tablet was higher compared with the fasted state. Based on joint probability of target attainment simulations using a simultaneous oral ceftibuten‑avibactam tomilopil population pharmacokinetic model, a tablet formulation ceftibuten 400 mg + avibactam tomilopil 1200 mg dosed every 8 h without regard to food is proposed for Phase 3 evaluation in adult patients with cUTIs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <p>Trial registration: NCT03931876; NCT05554237; NCT06593054.</p>\u0000 </section>\u0000 </div>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70263","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862450","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":"PBPK-Based Prediction of Oliceridine Exposure in Breast Milk and Relative Infant Dose During the First 24 h After Cesarean Delivery","authors":"Yixi Ding BS,&nbsp;Ke Liu BS,&nbsp;Shuaishuai Zhang BS,&nbsp;Yanxu Zhang MS,&nbsp;Xin Tan BS,&nbsp;Weimin Xu MS","doi":"10.1002/jcph.70228","DOIUrl":"https://doi.org/10.1002/jcph.70228","url":null,"abstract":"<p>Oliceridine is an intravenous opioid analgesic for postoperative pain control, but data on transfer into human milk and infant exposure during early breastfeeding remain limited. This study used a postpartum physiologically based pharmacokinetic (PBPK) framework to estimate oliceridine milk exposure and relative infant dose (RID) on postoperative Day 1 (0-24 h) after cesarean delivery under a reconstructed patient-controlled intravenous analgesia regimen. Maternal plasma exposure was simulated in PK-Sim; milk exposure was extrapolated using an externally specified milk-to-plasma ratio (M/P). RID was calculated from mean milk concentration, infant milk intake, and the maternal weight-normalized daily dose. An exposure scaling factor from an independent adult intravenous reference scenario was applied only as a post hoc proportional correction to RID. Morphine benchmarking assessed the physiological plausibility of the M/P extrapolation step, and a 4-24 h temporal sensitivity check examined the influence of the initial accumulation phase. In the base case, maternal plasma AUC over 0-24 h was 120.59 ng·h/mL; mean plasma and milk concentrations were both 5.025 ng/mL. The uncorrected model-predicted RID was 0.375%, and the ESF-corrected RID was 0.307%, both below the empirical 10% reference threshold. In one-way sensitivity analysis, M/P and infant milk intake had greater effects on corrected RID than maternal body weight within the prespecified ranges. The maximum corrected RID was 0.818% in the two-way scan and 1.235% under the prespecified high-exposure scenario. These findings provide a preliminary, assumption-bounded quantitative reference for modeled relative infant exposure under prespecified postoperative Day 1 extrapolation assumptions.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862464","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":"Simulation-Based Evaluation of Busulfan Sampling Strategies in Adults and Adolescents Undergoing Allogeneic Hematopoietic Stem Cell Transplantation","authors":"Zhiyuan Tan PhD,&nbsp;Federica R. Achini-Gutzwiller MD, PhD,&nbsp;Arjan C. Lankester MDPhD,&nbsp;Joost G. K. van der Hem MD,&nbsp;Peter A. von dem Borne MD, PhD,&nbsp;Dirk Jan. A. R. Moes PharmD, PhD,&nbsp;Tim Preijers PharmD, PhD","doi":"10.1002/jcph.70281","DOIUrl":"https://doi.org/10.1002/jcph.70281","url":null,"abstract":"<p>Busulfan, used in hematopoietic stem cell transplantation, exhibits a narrow therapeutic index and high pharmacokinetic (PK) variability. Therapeutic drug monitoring (TDM) is currently employed to achieve target exposure. However, there is no consensus on an optimal limited sampling strategy (LSS) for busulfan on the once-daily (QD) regimen. A virtual cohort of adult patients (n = 1000) receiving OD intravenous busulfan 3.2 mg/kg as a 3-h infusion was generated by Monte Carlo simulation using three published busulfan population PK models. For each one- and two-sample LSS, individual PK parameters were estimated from Day-1 sample(s) by maximum a posteriori Bayesian estimation and used to estimate the 4-day cumulative AUC. A model-informed precision-dosing (MIPD) analysis quantified the target-attainment benefit of TDM per design. The best-performing designs were validated in an external cohort (n = 37) with adults and adolescents. Across all three models, a two-sample early-plus-late schedule was the most informative, and the recommended two-sample design was 3 and 7 h after the start of infusion. TDM guided by a well-chosen LSS approximately doubled cumulative-target attainment, whereas a single early 3-h sample was markedly weaker. In the external cohort, two-sample designs recovered the cumulative 4-day AUC to ∼5%–8% MAPE versus ∼11%–13% for a single 3-h sample. For OD intravenous busulfan in adults and adolescents, a two-sample schedule at 3 and 7 h after the start of infusion supports the correct dosing decision and, through MIPD-guided dose adjustment, approximately doubles target attainment; a single 6-h sample is a simpler but less robust alternative.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70281","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862463","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":"Long-Acting Injectable Antiretroviral Therapies for HIV Treatment and Prevention: Clinical Pharmacology, Recent Advances and Future Opportunities","authors":"Alexandra Dunbar MS,&nbsp;Natella Rakhmanina MD, PhD, FAAP, FCP, AAHIVS,&nbsp;Justin Unternaher MPH,&nbsp;Peter L. Anderson PharmD,&nbsp;Kristina M. Brooks PharmD, FCP","doi":"10.1002/jcph.70249","DOIUrl":"10.1002/jcph.70249","url":null,"abstract":"<p>Long-acting (LA) antiretroviral (ARV) medications represent a significant advancement in the HIV treatment and prevention field. LA ARVs help reduce daily pill burden and thus optimize adherence, which has translated into sustained virologic suppression in persons with HIV, prevention of HIV transmission among those at risk, and improved patient satisfaction. This review examines the clinical pharmacology considerations, clinical trials, and real-world use of small molecule LA injectable ARVs, specifically cabotegravir, rilpivirine, and lenacapavir, in adults with or at risk of acquiring HIV, with a particular focus on the pharmacokinetic data and considerations with these agents as implementation expands. Special attention is also paid to understudied populations such as pediatrics and pregnant and breastfeeding women. Discussion of the underlying pharmacokinetics is provided to highlight considerations regarding time to onset of protection, handling residual concentrations and the potential for the development of resistance with treatment discontinuation, factors contributing to variability in drug exposure and relationships between exposure and efficacy. Despite the promise that these LA injectable ARVs hold, there are still opportunities for further investigation to optimize patient care, and these considerations are also covered.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13505248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148814658","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":"Advancing Neonatal Drug Development Through Industry–Academic Collaboration","authors":"Rangasamy Ramanathan MD,&nbsp;Jacob V. Aranda MD,&nbsp;Daniele De Luca MD,&nbsp;Victoria Niklas MD","doi":"10.1002/jcph.70273","DOIUrl":"10.1002/jcph.70273","url":null,"abstract":"&lt;p&gt;A recent review on the future of neonatology published by &lt;i&gt;The Lancet Child &amp; Adolescent Health Commission&lt;/i&gt; focused on addressing the challenges in advancing health outcomes for infants in their first month of life, which the authors rightly consider a public health problem.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; To address the inherent challenges in neonatal drug development, the Commission made several key recommendations. This included fostering cross-disciplinary collaborations and engaging key opinion leaders in neonatal clinical pharmacology to leverage preclinical and translational data derived from studies of diseases with comparable biological and pathophysiological characteristics. To strengthen funding support for preclinical and translational research aimed at elucidating the mechanisms underlying neonatal diseases, and thereby improving the evidence base for research and development decision-making. It further recommended that neonatal disorders be recognized as orphan areas to encourage investment and innovation. The prioritization of clinical studies involving repurposed drugs through active collaboration and dialogue with experts in the field was also strongly endorsed.&lt;/p&gt;&lt;p&gt;Importantly, the Commission recognized that a potentially critical factor in realizing these recommendations is industry–academic partnerships to overcome insufficient funding in neonatology drug development and research. More specifically, the Commission proposed that the pharmaceutical industry should revise internal compliance directives in close collaboration with neonatologists to ensure alignment with the unique ethical and clinical considerations of neonatal research and care. It further suggested that strategic priorities be established through structured engagement and dialogue with key opinion leaders in the field of neonatology.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; We strongly endorse these recommendations and advocate that the industry has played a vital, irreplaceable role in drug development in neonatology. Herein, we showcase industry–academic partnerships that have driven major innovations in neonatology and describe how they can be a template for further success to deliver on the Commission's recommendations.&lt;/p&gt;&lt;p&gt;Despite less industry-sponsored drug development in neonatology than in many other fields, such investment has enabled important breakthroughs, including the development and global adoption of surfactant&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; and caffeine.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; Surfactant was the first drug specifically developed for the treatment of neonates and reduced neonatal mortality and pulmonary air leaks by about 50%.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; In the United States alone, the introduction of surfactant was associated with a 6% reduction in infant mortality.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Caffeine can also be considered one of the most cost-beneficial and effective therapies in the newborn. It has been demonstrated that premature infants who receive caf","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13505236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148814630","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/Pharmacodynamic Translation and Model-Informed Drug Development for Oligonucleotide Therapeutics","authors":"Paridhi Gupta PhD,&nbsp;Mindy Magee PharmD,&nbsp;Vivaswath S. Ayyar PhD","doi":"10.1002/jcph.70267","DOIUrl":"10.1002/jcph.70267","url":null,"abstract":"<p>Small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) have emerged as clinically validated therapeutic modalities, with approvals and late-stage development programs spanning rare genetic, neurologic, cardiovascular, metabolic, and infectious diseases. Despite these advances, oligonucleotide development presents unique challenges compared with small molecules and biologics, including rapid plasma distributive clearance, nuclease-mediated degradation, limited extrahepatic distribution, and prolonged pharmacodynamic effects driven by tissue retention and intracellular mechanisms such as RNA-induced silencing complex loading or RNase H-mediated activity. Consequently, tissue disposition and intracellular pharmacology most often govern therapeutic response more directly than plasma exposures alone, complicating conventional approaches to dose selection, efficacy prediction, and safety assessment. Model-informed drug development (MIDD) offers a quantitative framework to address these challenges through integration of preclinical, translational, and clinical data into empirical, mechanistic, and systems-level models. This review summarizes current and emerging MIDD applications in oligonucleotide therapeutics, with primary emphasis on siRNAs and complementary insights from ASOs. Approaches discussed include empirical and semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) models, physiologically based pharmacokinetic (PBPK) frameworks describing tissue-selective biodistribution and intracellular disposition, and quantitative systems pharmacology (QSP) models linking molecular target modulation with downstream biologic and clinical responses. Collectively, these approaches have supported cross-species translation; human dose selection; clinical trial optimization; and mechanistic understanding of oligonucleotide absorption, distribution, metabolism, excretion, and pharmacology. Finally, we discuss future opportunities and remaining challenges for MIDD in oligonucleotide therapeutics, including enabling extrahepatic delivery, characterizing interindividual variability, and integrating systems-level and data-driven approaches to improve translational predictability and accelerate development of next-generation oligonucleotide medicines.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148809203","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}