The Journal of Clinical Pharmacology最新文献

{"title":"AI is Excellent at the Discovery and Identification of Unrecognized Scientific Knowledge but There Is No Evidence That AI Can Create New Scientific Knowledge","authors":"Leslie Z. Benet PhD, FCP","doi":"10.1002/jcph.70223","DOIUrl":"10.1002/jcph.70223","url":null,"abstract":"<p>AI has the ability to identify scientific and clinical relationships previously not recognized, but there are no examples where AI can take this information to create new scientific knowledge. New scientific knowledge is created by assembling identified relationships that lead to hypotheses, using this information to design experiments and learning from the results of these experiments. AI can greatly facilitate the assembling of the identified relationships, and in science perhaps, AI should be the abbreviation for “Artificial Identification.” The above prototype served as the basis for the founding this past Fall (2025) of Periodic Labs (Periodic.com) by a team that “co-created ChatGPT, DeepMind's GNoME, OpenAI's Operator (now Agent), the neural attention mechanism, MatterGen; have scaled autonomous physics laboratories; and have contributed to important materials discoveries of the last decade.” The team writes “We've come together to scale up and reimagine how science is done” and they have received over $300 million in seed funding.</p><p>A September 30, 2025, <i>New York Times</i> article titled “AI Scientific Discovery and Periodic Labs,” states that so-called neural networks, that is, AI systems that facilitate chatbots like ChatGPT, identify patterns in vast amounts of information on the internet to mimic the manner that words are put together and “can even write computer programs and do math problems.” The article then cites two of Periodic's co-founders Liam Fedus (co-creator of ChatGPT and former VP of OpenAI) and Dogus Cubuk (past lead of materials science and chemistry at GoogleDeepMind) as believing that “no matter how many textbooks and academic papers these systems analyze, they cannot master the art of scientific discovery. To reach that, they say, AI technologies must also learn from physical experiments in the real world.” Dr. Cubuk states that a chatbot “can't just reason for days and come up with an incredible discovery. Humans can't do that, either. They run many trial experiments before they find something incredible — if they even do.” Periodic plans to build its own lab “where robots — physical robots — will run scientific experiments on an enormous scale.” Periodic.com asserts, “We're starting in the physical sciences.”</p><p>Will Periodic's paradigm be successful in generating new knowledge in clinical pharmacology and clinical medicine? Can physical robots run scientific experiments that will have relevance in clinical pharmacology and clinical medicine? To do so, one must assume that in vitro–in vivo extrapolation (IVIVE) will work. My position is that Periodic's paradigm will frequently not be successful in creating new knowledge in clinical pharmacology and clinical medicine since in vitro studies, a powerful tool in the physical sciences, may not recognize the inherent differences between chemistry and pharmacokinetics.</p><p>Since mid-2022, we have published a series of papers demonstrating that all drug metab","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70223","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148303705","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":"Flip-Flop Pharmacokinetics in Pregnancy and the Future of Obstetric Pharmacology","authors":"Ahizechukwu C. Eke MD,PhD,MPH","doi":"10.1002/jcph.70229","DOIUrl":"10.1002/jcph.70229","url":null,"abstract":"<p>Pregnancy fundamentally alters the pharmacologic landscape through dynamic changes in gastrointestinal physiology, tissue perfusion, plasma volume, adipose distribution, protein binding, renal clearance, placental transport, and immunologic regulation.<span><sup>1-3</sup></span> Most pregnancy pharmacokinetic discussions have therefore centered on altered clearance and volume of distribution. This emphasis is appropriate for many small molecules, but is incomplete for modern therapeutic platforms whose systemic exposure is governed by slow release from an absorption site.<span><sup>4</sup></span> Long-acting injectables, subcutaneous biologics, implantable systems, depot formulations, and extended-release formulations increasingly place absorption at the center of the concentration–time profile.<span><sup>4</sup></span></p><p><i>Flip-flop pharmacokinetics</i> occurs when the rate of drug absorption becomes slower than the rate of elimination.<span><sup>5, 6</sup></span> Under this condition, the terminal slope of the plasma concentration–time curve reflects continued absorption kinetics rather than elimination kinetics alone.<span><sup>5</sup></span> This distinction is not merely semantic. A drug may appear to have a long half-life because it is slowly entering the circulation from a depot, subcutaneous space, formulation matrix, tissue reservoir, or biologic transport pathway, even when systemic elimination remains efficient. In pregnancy, this issue becomes clinically relevant because the physiologic determinants of absorption and tissue release change across gestation and reverse postpartum.<span><sup>2</sup></span> Thus, direct pregnancy-specific evidence for true flip-flop kinetics remains limited for many agents.</p><p>However, the convergence of long-acting therapeutics with gestational changes in gastrointestinal transit, regional perfusion, extracellular fluid expansion, adipose remodeling, lymphatic uptake, maternal metabolism, placental transport, and biologic disposition creates a plausible and increasingly important framework for pregnancy pharmacology. The goal is, therefore, not to declare flip-flop kinetics ubiquitous in pregnancy, but to highlight when it should be prospectively considered, measured, modeled, and distinguished from altered elimination.</p><p>Under conventional first-order extravascular pharmacokinetics, absorption occurs more rapidly than elimination.<span><sup>1, 2</sup></span> In a simplified one-compartment oral model, the absorption rate constant is greater than the elimination rate constant. Stated conceptually:</p><p>K<sub>a</sub> > K<sub>e</sub>where K<sub>a</sub> represents the absorption rate constant, and K<sub>e</sub> represents the elimination rate constant. Consequently, the terminal elimination phase of the concentration–time curve primarily reflects systemic elimination processes, and the observed half-life approximates elimination half-life.</p><p>In contrast, flip-flop pharmacokinetics occ","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70229","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148296918","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":"Ketamine Dosing Across Clinical Indications: A Narrative Review Organized by Proposed NMDA-Related Mechanisms","authors":"Paul Glue MD, FRCPsych,&nbsp;Ben Beaglehole PhD FRANZCP","doi":"10.1002/jcph.70225","DOIUrl":"10.1002/jcph.70225","url":null,"abstract":"<p>Ketamine is a non-competitive antagonist at the N-methyl-D-aspartate (NMDA) glutamate receptor. It was approved by the US Food and Drug Administration for anesthesia in 1970. The only other related US regulatory approval since then has been for esketamine nasal spray for depression in 2019. Over this time ketamine has been repurposed by mainly academic researchers, reporting clinical activity in diverse disorders such as status epilepticus, acute asthma, hyperactive delirium, and treatment resistant depression and anxiety. Importantly, dosing and length of treatment varies considerably by indication. Clinical indications responsive to ketamine fall into three categories: those where glutamatergic tone is normal and NMDA antagonism produces a desired effect (e.g., single bolus dosing for anesthesia, procedural sedation, and acute pain treatment); disorders where there is overactivity in glutamatergic tone and NMDA antagonism is therapeutic (e.g., prolonged infusion dosing for status epilepticus or status asthmaticus); and disorders where NMDA antagonism can enhance neuroplasticity (e.g., intermittent bolus treatment for depression/anxiety). Ketamine doses and duration of dosing differ for each of these three categories. This categorization may help generate hypotheses regarding dosing strategies for other potential novel indications such as eclampsia, anorexia nervosa, or functional neurological disorders.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70225","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148296960","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":"Correction to “A Phase 1 Study Evaluating the Pharmacokinetics and Safety of Avacopan in Participants With End-Stage Kidney Disease on Hemodialysis”","authors":"","doi":"10.1002/jcph.70221","DOIUrl":"https://doi.org/10.1002/jcph.70221","url":null,"abstract":"<p>Mohrmann C, Oberoi RK, Flach SD, et al. A phase 1 study evaluating the pharmacokinetics and safety of avacopan in participants with end-stage kidney disease on hemodialysis. J Clin Pharmacol. 2026;66(4):e70195. doi:10.1002/jcph.70195</p><p>In the article cited above, the legend defining the colors within Figure 2 was omitted. The corrected figure is shown below.</p><p>The authors regret this error.</p><p><b>a. Avacopan</b></p><p></p><p><b>b. M1</b></p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70221","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148174564","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":"Street Pharmacology: The Mechanistic Basis of Clinical Pharmacology Underlying the Microdosing Method of Buprenorphine–Naloxone With a Focus on the Unhoused Population","authors":"David F Lehmann PharmD, MD, FCP,&nbsp;Olivia Tanner MS, MPH,&nbsp;Eliesha Pepple AAS,&nbsp;Zarina Rashid Smith PMHNP-BC, FNP-BC, PNP-BC,&nbsp;Mia Ruiz-Salvador BS","doi":"10.1002/jcph.70213","DOIUrl":"10.1002/jcph.70213","url":null,"abstract":"<p>Expanded use of buprenorphine–naloxone use, particularly for marginalized communities, such as the unhoused, is an established priority. Unfortunately, due to fear of the precipitation of opioid withdrawal, this goal remains unmet. In response, microdosing methods during the initial week of treatment do not require opioid abstinence and do not precipitate withdrawal. This review establishes the scientific basis for microdosing that is centered on the pharmacodynamic principle of pseudo-irreversibility for a partial agonist, such as buprenorphine.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148145338","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":"Ontology-Enhanced Deep Learning for Mechanistic Prediction of Drug–Drug Interactions: A Clinically Interpretable Framework","authors":"Adeeb Noor PhD","doi":"10.1002/jcph.70220","DOIUrl":"10.1002/jcph.70220","url":null,"abstract":"<p>Drug–drug interactions (DDIs) have critical impacts on patient safety and healthcare efficiency because of their significant contributions to adverse drug reactions. Accurately predicting DDIs and their biological mechanisms is therefore essential, yet remains challenging. This study aims to enhance prediction accuracy and mechanistic interpretability by leveraging biomedical ontologies. We developed ontology-based embeddings from SIDER, DrugBank, and Gene Ontology data to represent phenotypic, functional, and mechanistic drug characteristics, providing biologically enriched features for neural network-based prediction of DDIs. The proposed framework achieved robust performance, validated externally (receiver operating characteristic area under the curve values up to 0.94), and effectively predicted DDIs across 11 pharmacokinetic and pharmacodynamic mechanisms. These mechanism-specific predictions emphasize the biological and pharmacological relevance of putative DDIs, enhancing interpretability by identifying high-risk DDI mechanisms linked to known adverse reactions. Our approach, integrating ontology-based embeddings with deep learning, therefore not only significantly improves DDI prediction but also supports clinical decisions to mitigate adverse drug reactions risks, albeit indirectly.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148145271","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":"Acetylation Variability in Elderly Tunisians: Implications for Isoniazid Dose Individualization","authors":"Yasmine Khefacha PharmD,&nbsp;Syrine Ben-Hammamia MD,&nbsp;Mouna Ben Sassi MD,&nbsp;Khouloud Ferchichi MD,&nbsp;Mouna Daldoul MD,&nbsp;Hanene El Jebari PhD,&nbsp;Mohamed Zouari PhD,&nbsp;Issam Salouage MD,&nbsp;Rim Charfi MD,&nbsp;Riadh Daghfous MD,&nbsp;Emna Gaies MD,&nbsp;Sameh Trabelsi MD","doi":"10.1002/jcph.70217","DOIUrl":"10.1002/jcph.70217","url":null,"abstract":"<p>The relationship between age and isoniazid acetylation phenotype remains insufficiently characterized, particularly in elderly populations, where pharmacokinetic variability and susceptibility to toxicity may be increased. This study aimed to characterize isoniazid acetylation phenotypes in elderly Tunisian patients using a phenotypic index and to assess its clinical implications. A retrospective study was conducted on 476 Tunisian tuberculosis patients treated with isoniazid between 2019 and 2024. Plasma concentrations at 3 h post-dose (C₃) were used to determine the acetylation index (I₃) and classify patients as rapid acetylators (RAs) or slow acetylators (SAs). Associations between acetylation phenotype, C_3, dose adjustments, adverse events, and clinical variables were assessed using non-parametric and categorical statistical tests. Slow acetylators represented 68.1% of the cohort and were associated with significantly higher isoniazid exposure and a greater proportion of supra-therapeutic concentrations. Overall, 66.0% of patients exhibited supra-therapeutic concentrations. Acetylator status significantly influenced dose adjustment requirements, with 89.2% of SAs requiring modification, mainly dose reductions. Adverse events occurred in 34.9% of patients and were significantly more frequent in SAs compared with RAs (44.1% vs 15.1%, <i>p</i> &lt;.001). No significant association was observed between age and acetylation phenotype or plasma exposure, although age was associated with adverse events. Renal function showed no significant correlation with acetylation status or exposure. The high interindividual variability observed supports the use of phenotypic assessment (I₃) to guide individualized dosing, particularly in settings where NAT2 genotyping is not routinely available. Prospective studies integrating pharmacogenetic and pharmacokinetic approaches are warranted to refine precision therapy in this high-risk population.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70217","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148139511","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 High Cost of Inexpensive Medicines","authors":"George Selali Blewusi MD, MPH,&nbsp;Ruohui Zheng PhD,&nbsp;Lobna Gaayeb PhD,&nbsp;Charles Flexner MD","doi":"10.1002/jcph.70216","DOIUrl":"10.1002/jcph.70216","url":null,"abstract":"&lt;p&gt;Some obsolete medications die quietly. Others, like the Hydra from the voyages of Hercules, grow new heads with every attempt to cut them down. Once hailed as a breakthrough antihistamine, terfenadine, despite being withdrawn from the market in the U.S. and most high-income countries, now lurks in the shadows of global pharmacies, dodging regulation. But its persistent availability tells a deeper story: one of fractured oversight, economic desperation, and the dangerous illusion that when it comes to medicine, “the cheapest option wins.”&lt;/p&gt;&lt;p&gt;Terfenadine was withdrawn from the U.S. market in the late 1990s, and later in most of Europe due to its association with torsade de pointes.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; Despite this, terfenadine remains available as a prescription drug in some countries, including China and India. A recent case report highlights the danger of continued access to this potentially lethal drug.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; This commentary probes its continued availability, alongside other medications long withdrawn in high-income countries, and calls for stronger pharmacovigilance to protect patients.&lt;/p&gt;&lt;p&gt;We reviewed the drug registries of 193 countries for the availability of terfenadine, stavudine, and dideoxycytidine, all barred due to serious adverse effects. Of these, 151 registries were accessible online, while the remaining were unavailable.&lt;/p&gt;&lt;p&gt;Terfenadine was present in 11 of the 151 registries, stavudine in 30, and dideoxycytidine in 1 (Indonesia), all summarized in Table 1.&lt;/p&gt;&lt;p&gt;Terfenadine was withdrawn from the U.S. market in 1998 because of fatal arrhythmias that occurred when this drug was used in patients with any condition that reduced its metabolism, including advanced liver disease and certain drug–drug interactions.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Its withdrawal influenced the development of modern pharmacokinetic drug interaction guidelines.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Stavudine was also withdrawn due to serious adverse effects, including lactic acidosis, hepatotoxicity, lipoatrophy, and peripheral neuropathy,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; and dideoxycytidine is no longer in use due to its ability to cause severe polyneuropathy.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Terfenadine is a potent hERG channel blocker that is converted to its active metabolite by the cytochrome P450 (CYP) 3A4 enzyme in the liver and small intestine.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Coadministration of this drug with potent CYP3A4 inhibitors reduces its metabolism, leading to accumulation and increased risk of fatal arrhythmias via hERG blockade.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; The eventual withdrawal of terfenadine, taking into account product removal, disposal, and class-action settlements, came at a cost of about US$6 billion.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The unregulated use of prescription medications is widespread, particularly in low- and middle-income countries (LMICs), where oversight is often weak or fragmented. In this study, stavudine was still marke","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70216","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148139563","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":"Comment on “Understanding Atomoxetine Exposure Variability in Children and Adolescents with ADHD through Population Pharmacokinetics”","authors":"Madhuri Tribhuvan MS,&nbsp;Shashikant N. Phatke BDS","doi":"10.1002/jcph.70211","DOIUrl":"10.1002/jcph.70211","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;We read with great interest the study by Tobin et al examining atomoxetine exposure variability through a population pharmacokinetic framework in pediatric attention-deficit/hyperactivity disorder.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; The effort to integrate genetic determinants into dosing strategies represents an important step toward individualized therapy in this heterogeneous population.&lt;/p&gt;&lt;p&gt;A central concern relates to the assumption that achieving a target plasma concentration of 400 ng/mL is an adequate surrogate for clinical response. While the model successfully reduces pharmacokinetic variability, the linkage between exposure metrics and symptomatic improvement remains insufficiently established. The presence of a substantial proportion of non-responders despite adequate exposure suggests that pharmacodynamic heterogeneity may dominate treatment outcomes.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Without integrating exposure–response relationships or validated clinical endpoints into the model, dose optimization based solely on pharmacokinetics risks achieving numerical targets without meaningful therapeutic benefit. Incorporation of symptom scales or functional outcomes into model-informed frameworks would strengthen clinical applicability and guide decision thresholds.&lt;/p&gt;&lt;p&gt;The treatment of each subject–occasion as an independent entity within a two-stage framework raises questions regarding the interpretability of variability components. Although this approach improves convergence, it conflates between-subject and between-occasion variability, thereby limiting mechanistic insight into intra-individual fluctuations. The supplementary data demonstrate marked within-subject variability in absorption patterns across visits, which may reflect modifiable factors such as adherence, gastrointestinal physiology, or circadian influences. By not explicitly modeling these sources, the framework may overestimate intrinsic variability and reduce the precision of individualized predictions. A hierarchical approach that preserves within-subject structure could better distinguish stable pharmacogenetic effects from transient physiological variability.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The modeling strategy prioritizes relative bioavailability adjustments over clearance effects to explain genotype-associated differences. While this improves statistical fit, it introduces potential ambiguity in physiological interpretation. The observed magnitude of bioavailability differences across CYP2D6 phenotypes exceeds prior reports and may partly compensate for unmodeled absorption complexities rather than reflect true presystemic metabolism alone. This has implications for clinical translation, as dosing recommendations based on inflated bioavailability estimates could lead to underexposure in certain subgroups, particularly when extrapolated beyond the study population.&lt;/p&gt;&lt;p&gt;Another consideration is the limited representation of key metabolic phenotypes. The small","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70211","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148057746","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 Phase 1 Study to Evaluate the Potential Drug–Drug Interaction Between Islatravir and Lenacapavir","authors":"Haeyoung Zhang PharmD, PhD,&nbsp;Steve West MSPH,&nbsp;Nerissa Kwok PharmD,&nbsp;Christine Mkaya MS,&nbsp;John Ling PhD,&nbsp;Ramesh Palaparthy PhD,&nbsp;Diane Longo PhD,&nbsp;Gillian Gillespie MB BChir,&nbsp;Cyril Llamoso MD,&nbsp;Martin Rhee MD,&nbsp;Dhananjay D. Marathe PhD","doi":"10.1002/jcph.70218","DOIUrl":"10.1002/jcph.70218","url":null,"abstract":"<p>People with HIV-1 may find adhering to life-long daily oral antiretroviral therapy difficult, which can lead to treatment failure or drug resistance. Longer-acting treatments may improve adherence, treatment outcomes, and quality of life. Islatravir (ISL), a nucleoside reverse transcriptase translocation inhibitor, plus lenacapavir (LEN), the first-in-class HIV-1 capsid inhibitor, are being evaluated as a weekly oral regimen for HIV-1. We investigated drug–drug interactions (DDI) between ISL and LEN by evaluating the pharmacokinetics and safety of a single-dose oral co-administration of 20 mg of ISL and 600 mg of LEN relative to single-agent administration in 55 adults without HIV. Co-administration showed similar pharmacokinetic profiles compared with single-agent administration; no clinically meaningful pharmacokinetic DDI was identified. The percent geometric least-squares mean (%GLSM) ratios for ISL exposure parameters were 88%–105%, and corresponding 90% confidence intervals (CIs) were within prespecified bounds (60%–167%). While there were no clinically significant differences in LEN exposure between ISL+LEN and LEN administration, the %GLSM ratios for LEN exposures were 80%–90%, with 90% CIs within 60%–167% except for maximum LEN concentration. High percentage coefficient of variation was observed for LEN pharmacokinetic parameters, resulting in relatively wide 90% CIs. ISL and LEN were generally well tolerated, with no serious or Grade 3 or 4 adverse events, deaths, or discontinuations of the study due to an adverse event. These results and positive initial findings from an ongoing Phase 2 study (NCT05052996) support further clinical development of ISL and LEN as a weekly combination oral treatment for HIV-1.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148057777","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}