Clinical Pharmacology And Therapeutics[JOURNAL]
Sun
200 papers
Effects of Trimethoprim on Three Previously Proposed Putative Biomarkers for OCT2/MATE-Mediated Renal Drug-Drug Interactions in Healthy Volunteers.
Picurová J, Müller F, Auge D … +3 more , König J, Fromm MF, Gessner A
Clin Pharmacol Ther · 2026 Jul · PMID 42400553 · Publisher ↗
Regulatory agencies request the assessment of the potential of new drugs to cause transporter-mediated drug-drug interactions (DDI). This assessment can be improved by integrating endogenous biomarkers during drug develo...
Regulatory agencies request the assessment of the potential of new drugs to cause transporter-mediated drug-drug interactions (DDI). This assessment can be improved by integrating endogenous biomarkers during drug development. Regarding the renal excretion of drugs such as metformin, the organic cation transporter (OCT) 2 and multidrug and toxin extrusion proteins (MATE) 1 and 2-K are of major importance. However, fully validated, sensitive, and specific biomarkers for these transporters are still lacking. In previous in vivo and in vitro studies, 5-aminovaleric acid betaine (5AVAB), serotonin (5HT), and 1-methylhistamine (1MH) emerged as promising biomarker candidates for OCT2/MATE-mediated DDI. Therefore, we further investigated their suitability for clinical risk assessment by evaluating the effects of the OCT2/MATE inhibitor trimethoprim in healthy volunteers and by determining IC values for the inhibition of OCT2- and/or MATE1-mediated uptake of the potential biomarkers by trimethoprim, cimetidine, pyrimethamine, and dolutegravir in vitro. Trimethoprim reduced the amount excreted into urine of 5AVAB, 5HT, and 1MH in vivo by 95.1 ± 5.67%, 78.9 ± 6.56%, and 51.9 ± 14.3%, respectively (all P < 0.001) as well as the renal clearance of 5AVAB and 5HT by 93.6 ± 5.85% and 73.8 ± 12.8%, respectively (both P < 0.001). When comparing the IC values with unbound inhibitor plasma concentrations, trimethoprim, cimetidine, and pyrimethamine preferentially inhibit the MATE1-mediated transport, whereas dolutegravir inhibits the OCT2-mediated transport of the biomarker candidates. In conclusion, this study further supports the suitability of 5-aminovaleric acid betaine (5AVAB), serotonin (5HT), and 1-methylhistamine (1MH) as promising biomarkers for OCT2/MATE-mediated DDI.
Clinical Characterization of Enzyme and Transporter Precipitants to Evaluate Drug-Drug Interactions for Orforglipron, a Small Molecule Glucagon-Like Peptide-1 Receptor Agonist.
Morse BL, Coutant DE, Ma X … +5 more , Raha S, Aithal K, Nicoll C, Rougée LRA, Bhattachar S
Clin Pharmacol Ther · 2026 Jul · PMID 42399716 · Publisher ↗
Orforglipron is an orally administered, small-molecule glucagon-like peptide-1 receptor agonist in clinical development for the treatment of type 2 diabetes and obesity. Orforglipron is a substrate of CYP3A4, organic ani...
Orforglipron is an orally administered, small-molecule glucagon-like peptide-1 receptor agonist in clinical development for the treatment of type 2 diabetes and obesity. Orforglipron is a substrate of CYP3A4, organic anion transporting polypeptides (OATPs) 1B/1B3, and P-glycoprotein (P-gp); however, precipitants commonly used to define these mechanisms have not been fully characterized. The enzyme- and transporter-mediated DDI profile of orforglipron and that of CYP3A4/OATP1B/P-gp precipitants were characterized in six phase 1 clinical studies in healthy participants. Orforglipron pharmacokinetics were assessed with clarithromycin, carbamazepine, cyclosporine, and quinidine. Precipitant effects on CYP3A and OATP1B activity were measured using midazolam and coproporphyrin-I (CP-I). Orforglipron effects on CYP3A, P-gp, BCRP, and OATP1B were evaluated using midazolam, digoxin, rosuvastatin, simvastatin, atorvastatin, and CP-I. Mechanistic interrogation of the simvastatin interaction was also conducted. Clarithromycin, carbamazepine, and quinidine had minimal effect on CP-I pharmacokinetics, while the cyclosporine effect was substantial. Cyclosporine and quinidine weakly increased midazolam exposure. Orforglipron exposure increased in the presence of clarithromycin and cyclosporine and decreased with carbamazepine, demonstrating orforglipron exposure is affected by precipitants of CYP3A4 and OATP1B. Quinidine did not meaningfully change orforglipron exposure. Orforglipron had no clinically meaningful effect on the exposure of midazolam, digoxin, or atorvastatin. A weak increase in rosuvastatin exposure was consistent with BCRP inhibition, as CP-I data confirmed orforglipron does not affect OATP1B. Increase in simvastatin acid exposure was attributed to the unique disposition of simvastatin rather than enzyme or transporter inhibition. These findings address mechanistic precipitant knowledge gaps and provide a framework for managing potential orforglipron DDIs in clinical practice.
Symposium Report: Stakeholders' Perspectives on Phase 1 Trials in Japanese Prior to Multi-Regional Clinical Trials and Future Pathways.
Kobayashi Y, Matsushima N, Takai N … +4 more , Sato D, Hoshino S, Ishiguro A, Iimura Y
Clin Pharmacol Ther · 2026 Jul · PMID 42394402 · Publisher ↗
A new guideline clarifying basic principles for conducting a phase 1 trial in Japanese prior to multi-regional clinical trials was issued in December 2023 to streamline global drug development and accelerate access to no...
A new guideline clarifying basic principles for conducting a phase 1 trial in Japanese prior to multi-regional clinical trials was issued in December 2023 to streamline global drug development and accelerate access to novel drugs. To foster a shared understanding of the guideline and discuss future pathways, the regulatory agency and industry jointly organized a public symposium. This report summarizes the proceedings of the symposium.
Methotrexate and folic acid supplementation in rheumatoid arthritis: A Japanese claims database and 538,985 patients from April 2015 to November 2020.
Takabatake K, Takeda M, Nakamura M … +5 more , Kawabe K, Hanaoka S, Hayashi H, Sahashi Y, Ooba N
Int J Clin Pharmacol Ther · 2026 Jul · PMID 42390075 · Publisher ↗
OBJECTIVES: To assess the use of laboratory monitoring, folic acid supplementation, and folinate calcium therapy in patients with rheumatoid arthritis (RA) receiving first-line methotrexate (MTX) according to the 2019 Ja...
OBJECTIVES: To assess the use of laboratory monitoring, folic acid supplementation, and folinate calcium therapy in patients with rheumatoid arthritis (RA) receiving first-line methotrexate (MTX) according to the 2019 Japan College of Rheumatology safety updates and using a large Japanese claims database (DeSC). MATERIALS AND METHODS: Patient data for the period 2015 - 2020 were retrieved from the database, and patients were identified who had presented with active disease. The number of patients commencing with MTX treatment and receiving concomitant disease-modifying antirheumatic drug and folic acid supplementation were determined together with information on recommended laboratory testing (blood tests, serum creatinine, chest radiography, and KL-6) in the year prior to MTX initiation. The impact of the 2019 Japan College of Rheumatology guidelines was assessed by comparing the extent of folic acid supplementation before and after publication of the guidelines. RESULTS: Of the 1,574 patients identified with active RA, 919 (58.4%) started MTX. Folic acid was co-administered in 85.1% of MTX users, with no significant change in supplementation rates before and after the introduction of the 2019 guidelines (81.8 vs. 82.2%, p = 0.56), indicating that these safety protocols were already well-established. Baseline blood tests were carried out in 99.8% and chest radiography in 69.2% of patients. After commencing MTX treatment, the monitoring of serum creatinine (87.2 vs. 93.7%, p < 0.05) and KL-6 (15.2 vs. 28.4%, p < 0.05) increased significantly. The frequency of chest radiography decreased to 56.0% (p < 0.05), reflecting a shift toward more sensitive diagnostic tools in clinical practice. No patients required folinate calcium rescue therapy. CONCLUSION: MTX prescribing and monitoring in RA is generally carried out in accordance with clinical guidelines. Although folic acid supplementation is recommended and widely implemented, ~ 20% of patients do not receive it. Monitoring is generally carried out rigorously, but safety data indicate that these measures should receive more attention in high-risk elderly populations who were probably under-represented in this study.
Cardiac arrest in an adolescent following an overdose of antidepressants comprising sertraline, quetiapine fumarate, and lamotrigine: Case report.
Zheng L, Zhang L, Wang F … +3 more , Jiang Y, Lv F, Li G
Int J Clin Pharmacol Ther · 2026 Jul · PMID 42390074 · Publisher ↗
Antidepressant overdose is a prevalent method of self-harm in patients with depression including bipolar disorder. According to the published literature, typical adverse effects are seizures, prolonged QT intervals, and...
Antidepressant overdose is a prevalent method of self-harm in patients with depression including bipolar disorder. According to the published literature, typical adverse effects are seizures, prolonged QT intervals, and arrhythmias, with cardiotoxicity primarily observed in adults. This paper reports the first documented case of an 11-year-old adolescent with depression who ingested a massive overdose comprising sertraline (60 tablets at 50 mg, giving a total dose of 3 g), quetiapine fumarate (50 tablets at 100 mg giving a total dose of 5 g) and lamotrigine (120 tablets at 25 mg giving a total dose of 3 g). At ~ 4 hours post ingestion, the patient developed hypoxemia, hypotension, persistent seizures, resulting in cardiac arrest. This case report offers critical insights into the clinical management of such cases involving pediatric populations.
Recombinant human growth hormone in pediatric patients using the FAERS database: Safety profile and update for the period 2004 - 2024.
Tu L, Jiang H, Liu J … +4 more , Lin Y, Wang S, Tu Y, Hong Q
Int J Clin Pharmacol Ther · 2026 Jul · PMID 42390073 · Publisher ↗
OBJECTIVE: To investigate safety signals associated with recombinant human growth hormone (rhGH) using the FDA Adverse Event Reporting System (FAERS) and make recommendations for its application. BACKGROUND: rhGH is wide...
OBJECTIVE: To investigate safety signals associated with recombinant human growth hormone (rhGH) using the FDA Adverse Event Reporting System (FAERS) and make recommendations for its application. BACKGROUND: rhGH is widely used in the management of pediatric growth disorders, but a comprehensive evaluation of its safety in pediatric populations is limited. MATERIALS AND METHODS: Adverse event (AE) reports involving patients under 18 years of age where rhGH was the primary suspect (PS) drug were retrieved from the FAERS database for the period beginning the first quarter of 2004 to the end of the third quarter of 2024. The reports were standardized and duplicate reports removed. Disproportionality analysis of AE signals was conducted using four complementary methods, namely i) reporting odds ratio (ROR), ii) proportional reporting ratio (PRR), iii) Bayesian confidence propagation neural network (BCPNN), and iv) empirical Bayesian geometric mean (EBGM). RESULTS: A total of 33,888 AE reports were retrieved and analyzed. Disproportionality analysis identified 167 positive signals across 19 System Organ Classes (SOCs), the most frequently of which was "Investigations," and the most common preferred term (PT) was "Arthralgia". In addition to confirmed AEs, several endocrine-related signals were also recognized including a) fluctuations in thyroid-stimulating hormone, b) increase in unbound concentrations of thyroxine, c) type 1 diabetes mellitus, d) low concentrations of high-density lipoprotein, and e) abnormal body odor. CONCLUSION: A comprehensive safety profile was established for rhGH when used in pediatric populations and comprising several newly identified potential AE signals. The findings underscore the importance of surveillance to mitigate risks and ensure the safe clinical use of rhGH.
Resolving CYP2D6 Structural Complexity with Long-Read Sequencing: Implications for Tamoxifen Precision Dosing in Thai Breast Cancer Patients.
Boonyuen U, Talukam S, Jacob BAC … +7 more , Matphong W, Chamchoy K, Reamtong O, Meesiripan N, Yamagishi J, Phanchana M, Rattadilok C
Clin Pharmacol Ther · 2026 Jul · PMID 42387636 · Publisher ↗
Cytochrome P450 2D6 (CYP2D6)-mediated bioactivation of tamoxifen to endoxifen is a key determinant of therapeutic efficacy in estrogen receptor-positive breast cancer. In Asian populations, the high prevalence of structu...
Cytochrome P450 2D6 (CYP2D6)-mediated bioactivation of tamoxifen to endoxifen is a key determinant of therapeutic efficacy in estrogen receptor-positive breast cancer. In Asian populations, the high prevalence of structurally complex CYP2D6 alleles complicates conventional genotyping, limiting accurate genotype-phenotype correlation. To address these gaps, long-read Oxford Nanopore sequencing was applied to resolve CYP2D6 structural complexity and evaluate its impact on endoxifen metabolism. The study cohort included 492 Thai breast cancer patients, with multivariable analysis performed on 361 individuals receiving standard-dose tamoxifen to determine the association between CYP2D6 activity scores and plasma endoxifen concentrations. Long-read sequencing identified 82 distinct diplotypes and successfully resolved complex structural variations, including the prevalent CYP2D6*36 + *10 non-identical duplication. Overall, 46.55% of patients were classified as having decreased enzyme function, primarily intermediate metabolizers (45.53%). CYP2D6 activity score emerged as the strongest determinant of endoxifen exposure (P < 0.001). Decreased-function genotypes were significantly associated with lower endoxifen levels (using an exploratory benchmark of ≤5.97 ng/mL), independent of parent drug concentration. These findings demonstrate that long-read sequencing enables the precise resolution of CYP2D6 structural complexity. By accurately capturing rare and complex CYP2D6 alleles, the results indicate that standard genotyping may misclassify certain patients, potentially placing a large portion of the studied population at an unrecognized risk of low tamoxifen exposure.
Identification of a Functional CYP2C8 Variant Allele that Alters Splicing, Reduces Protein Expression, and Increases Drug Exposure.
Mykkänen AJH, Hirvensalo P, Klein K … +12 more , Kaminska D, Grube M, Tapaninen T, Kiiski JI, Neuvonen M, Männistö VT, Pihlajamäki J, Tzvetkov M, Schwab M, Tornio A, Backman JT, Niemi M
Clin Pharmacol Ther · 2026 Jul · PMID 42387303 · Publisher ↗
This study investigated genetic determinants of the pharmacokinetics of the CYP2C8 index drugs repaglinide and gemfibrozil, and their interaction in healthy participants. Sequencing data from a study with montelukast rev...
This study investigated genetic determinants of the pharmacokinetics of the CYP2C8 index drugs repaglinide and gemfibrozil, and their interaction in healthy participants. Sequencing data from a study with montelukast revealed a novel functional CYP2C8 allele (rs2071426, CYP2C8*19), predicted to create an intronic splice donor site. In human liver samples, CYP2C8*19 associated with transcript-specific changes in CYP2C8 mRNA expression, reduced CYP2C8 protein expression, and decreased enzyme activity. Consistently, participants with the CYP2C8*19/*19 genotype had 45% greater area under the plasma repaglinide concentration-time curve from time zero to infinity (AUC) than participants with CYP2C8*1/*1 (P = 1.6 × 10). Participants with CYP2C8*1/*3 had 26% smaller AUC (P = 0.0033) and those with CYP2C8*1/*4 had 51% greater AUC (P = 8.2 × 10). The fold increase in repaglinide AUC caused by gemfibrozil was 36% (P = 1.3 × 10) smaller in CYP2C8*19/*19 participants than in CYP2C8*1/*1 participants. In a genome-wide association study (GWAS), SLCO1B1 c.521 T>C (rs4149056) associated with increased repaglinide AUC (P = 4.5 × 10; n = 172) and SLCO1A2 variants associated with decreased AUC (P < 10). In a GWAS of repaglinide after gemfibrozil pretreatment, SLCO1C1 variants associated with decreased AUC (P < 1.6 × 10; n = 66). Participants with the poor function SLCO1B1 genotype showed a 32% smaller fold increase in repaglinide AUC following gemfibrozil than participants with the normal function SLCO1B1 genotype (P = 0.0045). This study characterizes CYP2C8*19 as a novel decreased function allele and shows that CYP2C8 and SLCO1B1 genotypes affect the gemfibrozil-repaglinide interaction.
The triple neuromodulatory-immunomodulatory axis.
Woodcock-Kloberdanz BG
Int J Clin Pharmacol Ther · 2026 Jun · PMID 42376906 · Publisher ↗
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Risk of Hyperkalemia in Patients with Heart Failure Treated with Spironolactone in Combination with Sacubitril/Valsartan vs. Renin-Angiotensin System Inhibitors.
Crum KL, Vaduganathan M, Desai RJ
Clin Pharmacol Ther · 2026 Jun · PMID 42374912 · Publisher ↗
We aimed to compare the risk of hyperkalemia in patients with heart failure initiating spironolactone while receiving sacubitril/valsartan vs. those initiating while on a RASi in a real-world clinical setting among a het...
We aimed to compare the risk of hyperkalemia in patients with heart failure initiating spironolactone while receiving sacubitril/valsartan vs. those initiating while on a RASi in a real-world clinical setting among a heterogeneous population. We conducted a new-user, active comparator cohort study of patients with heart failure initiating spironolactone from April 1, 2016, to July 31, 2024, using a large national commercial insurance database. Patients were classified as RASi users (continuous ACEi/ARB use ≥30 days prior to and including spironolactone initiation) or ARNI users (continuous sacubitril/valsartan use over the same period). Propensity score based fine-stratification weighting was used for confounding control. Outcomes included hyperkalemia (serum potassium >5.5 mmol/L) and severe hyperkalemia (>6 mmol/L), assessed over a maximum follow-up of 180 days. About 57,926 patients initiated spironolactone: 8,589 while on ARNI (mean age: 70.6 years, 39.5% female) and 49,337 while on RASi (mean age: 72.8 years, 48.6% female). Incidence rates (95% confidence intervals) for hyperkalemia were lower among ARNI users (9.44 (8.46, 10.51) vs. 12.55 (12.07, 13.04) per 100 person-years), corresponding to a weighted rate difference of -1.20 (-1.74, -0.60) events per 100 person-years. Adjusted hazard ratios (95% CI) were 0.89 (0.79-1.01) for hyperkalemia and 0.74 (0.57-0.95) for severe hyperkalemia. Findings were consistent across subgroups. Initiation of spironolactone among patients with heart failure receiving sacubitril/valsartan was associated with a lower risk of severe hyperkalemia, compared with RASi use. This study expands upon previous findings suggesting the risk of hyperkalemia when using MRAs may be mitigated through the substitution of sacubitril/valsartan for RASi.
Composite Endpoints in Contemporary Cardiovascular Trials: Trends in Phase 3 Trials and Key Issues in Regulatory Review.
Sugano H, Narukawa M
Clin Pharmacol Ther · 2026 Jun · PMID 42374601 · Publisher ↗
Interpreting composite endpoints in cardiovascular drug development is a key challenge, particularly when events of different clinical relevance are combined into a single primary outcome. Previous reviews noted that con...
Interpreting composite endpoints in cardiovascular drug development is a key challenge, particularly when events of different clinical relevance are combined into a single primary outcome. Previous reviews noted that conventional composite endpoints may mask clinically meaningful differences at the individual component level and be mainly driven by less clinically important "soft" events, raising concerns about how overall treatment effects should be understood. Despite these concerns, information remains limited on how composite endpoints are used in current cardiovascular drug development programs and how their interpretation influences regulatory decision-making. Thus, we conducted a descriptive review of cardiovascular phase III trial publications and ClinicalTrials.gov registries (2015-2024) that specified a composite primary endpoint and identified 173 trials. Hard endpoints such as death remain common; however, the range of events included in composite endpoints has increased in recent years. The examination of regulatory evaluations of composite endpoints in new drug applications for cardiovascular diseases-including chronic heart failure, transthyretin amyloid cardiomyopathy, and cardiovascular conditions requiring antithrombotic therapy-in Japan, the United States, and the European Union revealed that regulatory agencies consistently raised concerns across regions regarding differences in clinical importance among components and the interpretability of composite results. These findings highlight the need to consider differences in clinical importance among components and carefully interpret the composite endpoint results in the context of individual component outcomes, both in trial design and evaluation.
Patient-Specific Determinants of Response to BCMA- and GPRC5D-Targeted CAR T-Cell Therapy in Multiple Myeloma: A QSP Analysis of Clinical Trial and Real-World Data.
Kostiou V, Chelliah V, van der Graaf PH … +4 more , Kierzek AM, Farzana T, Mailankody S, Jurgens EM
Clin Pharmacol Ther · 2026 Jun · PMID 42364971 · Publisher ↗
Despite promising outcomes in CAR T-cell therapy for relapsed/refractory multiple myeloma (RRMM), nearly all patients eventually relapse. Resistance and relapse may be driven by CAR T-cell and tumor-intrinsic factors. He...
Despite promising outcomes in CAR T-cell therapy for relapsed/refractory multiple myeloma (RRMM), nearly all patients eventually relapse. Resistance and relapse may be driven by CAR T-cell and tumor-intrinsic factors. Here, we developed a mechanistic quantitative systems pharmacology (QSP) model of multiple myeloma growth and CAR T-cell therapy using measurable biomarkers to predict and identify factors associated with response and relapse. The model incorporates key components to explore disease dynamics and CAR T-cell expansion. Our model reproduced published pharmacokinetics and biomarker response data from anti-BCMA and anti-GPRC5D CAR T-cell therapies. We then validated the model using clinical biomarker data from a total of 29 real-world RRMM patients treated with commercial anti-BCMA CAR T. Virtual trial simulations, exploring the impact of variable baseline disease and CAR T characteristics on response, predicted that factors associated with worse outcomes are intrinsic to tumor cells (disease burden, low-antigen expression) and CAR T cells (low CAR T-induced killing rate). Interestingly, simulations suggested that a lower baseline percentage of normal plasma cells is associated with higher overall response. The developed model was also used to predict the outcome of BCMA-targeted and GPRC5D-targeted combination CAR T-cell treatment. Sequential combination therapy simulations predicted a better response in scenarios starting with anti-GPRC5D CAR T infusion, followed by anti-BCMA CAR T infusion. Our model can serve as a framework to investigate response mechanisms as well as multi-antigen targeting, and to optimize clinical trial design and dosing regimens.
Reply to: "The Future of Clinical Pharmacology: The Right Medicine at the Right Dose for Each Patient".
Rizk ML, Visser SAG
Clin Pharmacol Ther · 2026 Jun · PMID 42363635 · Publisher ↗
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Ruxolitinib Pharmacokinetics and Exposure-Toxicity Relationship in Hematologic Malignancies and Immune-Mediated Diseases: A Prospective Observational Study.
Tachet J, Meyer SC, Grandoni F … +9 more , Haefliger E, Nagy-Hulliger M, Halter JP, Passweg JR, Haefliger D, Bardinet C, Decosterd LA, Guidi M, Girardin FR
Clin Pharmacol Ther · 2026 Jun · PMID 42338396 · Publisher ↗
Ruxolitinib pharmacokinetics (PK) has been characterized in clinical trials but remains poorly documented in real-world practice. This project aimed to investigate ruxolitinib PK in routine clinical practice, identify fa...
Ruxolitinib pharmacokinetics (PK) has been characterized in clinical trials but remains poorly documented in real-world practice. This project aimed to investigate ruxolitinib PK in routine clinical practice, identify factors driving its variability, and explore exposure-response relationships to assess the potential role of therapeutic drug monitoring. In total, 221 steady-state ruxolitinib concentrations from 77 adult patients enrolled across several centers in Switzerland were analyzed. Demographic and clinical data were recorded at each visit. Population pharmacokinetic (popPK) analysis was performed with MonolixSuite® 2024R1 (Lixoft, France). Model-based simulations were used to predict trough concentration (C) and the area under the concentration-time curve over 24 h (AUC) for the recommended dosage regimens, as a function of covariates. An exploratory pharmacokinetic/pharmacodynamic analysis was conducted in the overall cohort. Ruxolitinib PK was characterized by a marked between-subject variability in clearance (45%). Strong cytochrome (CYP) 3A4 or dual CYP2C9/CYP3A4 inhibitors reduced clearance by 39%. At 10 mg twice daily, model-based simulations showed CYP inhibitors increased median C and AUC by 2.9- and 1.7-fold, respectively. Still, no significant exposure-efficacy relationship was identified. However, higher ruxolitinib exposure tended to be associated with increased toxicity in the overall population (C and AUC, P≈0.02-0.03). In clinical practice, ruxolitinib exposure shows substantial variability and is strongly affected by strong CYP inhibitors that are frequently co-administered. Whilst no clear exposure-efficacy relationship was observed, higher exposure was linked to increased toxicity risk, arguing for careful dose adjustment.
Repurposing Registries: Completeness of Real-World Data for Regulatory and HTA Purposes in Three Cancer-Focused Registries.
Wilpshaar MC, Hilarius D, Prada L … +2 more , Weltermann A, Leopold C
Clin Pharmacol Ther · 2026 Jun · PMID 42337928 · Publisher ↗
Despite developments in supporting the identification and selection of fit-for-purpose registries, a translational gap remains between the original purposes of clinically focused registries and their current and future e...
Despite developments in supporting the identification and selection of fit-for-purpose registries, a translational gap remains between the original purposes of clinically focused registries and their current and future expected use in policymaking. This study aimed to assess the extent to which cancer-focused registries collect essential data elements for regulatory and Health Technology Assessment (HTA) processes. Using literature and expert input, a reference dataset of essential data elements was developed. Completeness of data elements in this reference dataset was evaluated on the example of three European, cancer-focused registries, varying in type, coverage, and health system: the Cancer Centre Upper Austria (CCUA) registry, the Dutch Medication Audit (DMA), and the Portuguese Oncology Institute of Porto (RIC IPO Porto) registry. The evaluated registries exhibit clear differences in inclusion criteria driven by their specific aims. Data elements related to comorbidities, concomitant therapies, patient-reported outcome measures (PROMs), resource use, and safety outcomes were lacking partly or completely in all evaluated registries, highlighting the importance of developing disease-specific core datasets to which registry holders can benchmark their data collection. This study also highlights that the initial aims and design of registries impact their strengths and weaknesses in supporting regulatory and HTA decision-making. Optimally repurposing registry data requires capacity building for registry holders and regulatory/HTA stakeholders focusing on mutual understanding of aims, needs, and limitations. Additional research should address data interoperability, standardization, and data quality across registries.
Quantitative Systems Toxicology Model Predicts Obeticholic Acid-Associated Liver Injury in Metabolic Dysfunction-Associated Steatotic Liver Disease.
Mayo AK, Beaudoin JJ, Woodhead JL … +2 more , Watkins PB, Brouwer KLR
Clin Pharmacol Ther · 2026 Jun · PMID 42332345 · Publisher ↗
Obeticholic acid (OCA), a synthetic analog of chenodeoxycholic acid, was approved in 2016 for the treatment of primary biliary cholangitis. Early clinical trials revealed elevated liver biomarkers in healthy subjects rec...
Obeticholic acid (OCA), a synthetic analog of chenodeoxycholic acid, was approved in 2016 for the treatment of primary biliary cholangitis. Early clinical trials revealed elevated liver biomarkers in healthy subjects receiving supratherapeutic OCA doses (100-250 mg). OCA was also evaluated as a treatment for metabolic dysfunction-associated steatotic liver disease (MASLD) but was not approved by the FDA due to liver safety concerns. In this in silico study, we investigated mechanisms of OCA-associated liver injury in virtual healthy and MASLD populations receiving supratherapeutic and therapeutic (10-25 mg) doses, respectively. OCA and metabolite exposures in plasma, sinusoidal blood, liver, and gut compartments were simulated using a physiologically based pharmacokinetic model. In the virtual MASLD population, exposures were increased 2-, 5-, and 10-fold in plasma, sinusoidal, and/or liver compartments relative to baseline. Mechanistic parameters relevant to OCA-mediated liver injury, including bile acid transporter inhibition and mitochondrial dysfunction, were incorporated into the DILIsym model. Predicted liver injury was reported as evaluation of drug-induced serious hepatotoxicity (eDISH) plots, and elevations in alanine aminotransferase, aspartate aminotransferase, and total hepatic bile acids. DILIsym simulations recapitulated liver biomarker elevations observed at supratherapeutic OCA doses in healthy subjects and predicted biomarker increases in the MASLD population under conditions of 5- and 10-fold increased exposures relevant to this population. Bile acid transporter inhibition alone reproduced simulated biomarker elevations, whereas mitochondrial uncoupling alone predicted increased biomarkers only at the highest exposures. Results suggest that DILIsym modeling would have predicted the liver safety concerns that led to withdrawal of OCA from the US market.
Genetic Determinants of Treatment-Related Bone Toxicity in Pediatric Acute Lymphoblastic Leukemia.
Abaji R, Gagné V, Espagne É … +12 more , Alos N, Del Vecchio V, Ait Said L, Shalmiev A, Fuchs C, Laverdière C, Leclerc JM, Sallan SE, Silverman LB, Sinnett D, Tran TH, Krajinovic M
Clin Pharmacol Ther · 2026 Jun · PMID 42325004 · Publisher ↗
Osteonecrosis and fractures are serious corticosteroid-induced bone toxicities in children treated for acute lymphoblastic leukemia, yet their genetic determinants remain incompletely defined. In this study, we aimed to...
Osteonecrosis and fractures are serious corticosteroid-induced bone toxicities in children treated for acute lymphoblastic leukemia, yet their genetic determinants remain incompletely defined. In this study, we aimed to identify novel genetic contributors to bone toxicity and to evaluate the robustness of both newly identified and previously established risk genotypes in more recent Dana-Farber Cancer Institute treatment protocols. Whole-exome sequencing was first performed in a discovery cohort to identify genetic variants associated with osteonecrosis. A novel association with a variant in the PGAP2 gene was identified and subsequently confirmed in an independent replication cohort, with effects of patient- and disease-related characteristics observed in both cohorts. Next, previously reported candidate gene-derived associations, together with this newly identified variant, were assessed in a more recent cohort to examine their relevance in contemporary treatment protocols. Variants in BCL2L11 and the ACP1-SH3YL1 locus were associated with bone fractures, with a strong synergistic effect and significant modulation by protocol-specific factors, particularly corticosteroid exposure and asparaginase formulation. The PGAP2 variant was associated with the combined osteonecrosis-fracture phenotype. Transcriptomic analyses revealed isoform-specific expression shifts in PGAP2 in patients with osteotoxicity, supporting a potential functional role for altered splicing or gene regulation. Together, our results provide insight into the pharmacogenomic architecture of osteotoxicity in ALL, demonstrating that PGAP2, BCL2L11, and ACP1-SH3YL1 variants remain clinically relevant predictors of bone toxicity across evolving treatment protocols. However, their clinical manifestations appear to be context-dependent, underscoring the importance of integrating genetic susceptibility with pharmacologic exposures and supporting further investigation of the underlying molecular mechanisms.
Application of Virtual Twin PBPK Models in Individuals with Obesity via CYP3A4 Phenotyping Using Endogenous Biomarker Data.
Izat N, Kangne H, Jansson-Löfmark R … +4 more , Hertel JK, Rostami-Hodjegan A, Robertsen I, Galetin A
Clin Pharmacol Ther · 2026 Jun · PMID 42317011 · Publisher ↗
Plasma 4β-hydroxycholesterol (4β-OHC) normalized for the levels of its parent cholesterol (4β-OHC/C) is an endogenous biomarker for hepatic CYP3A4. This study evaluated CYP3A4 activity longitudinally in individuals while...
Plasma 4β-hydroxycholesterol (4β-OHC) normalized for the levels of its parent cholesterol (4β-OHC/C) is an endogenous biomarker for hepatic CYP3A4. This study evaluated CYP3A4 activity longitudinally in individuals while their obesity status was changing. 4β-OHC/C was measured pre-surgery (n = 54) and 2 years after Roux-en-Y gastric bypass (n = 30) and used as an input for creating virtual twins of each patient within physiologically-based pharmacokinetic (VT-PBPK) models, alongside other available data (e.g., demographics). Additionally, individual CYP3A4 abundance quantified from liver biopsies during surgery was available. Predicted CYP3A4 abundance using 4β-OHC/C was within twofold of the measured abundance in 85% of the individuals (n = 54). Pre-surgery VT-PBPK models informed by biomarker data predicted area under curve after intravenous midazolam (AUC) within twofold of observed values in 85% of individuals (geometric mean fold error (GMFE) = 1.58). VT-PBPK models using CYP3A4 protein measurements showed similar performance (83% within twofold, GMFE = 1.66), verifying the biomarker approach. The post-surgery VT-PBPK models were revised to reflect surgery-related alterations and changes in obesity status. Hepatic CYP3A4 activity at 2 years was predicted from 4β-OHC/C measured in the same individuals. Biomarker-informed models predicted midazolam AUC within twofold for 87% of individuals (GMFE = 1.48; n = 30). ~60% of observed oral midazolam PK parameters were predicted within twofold, improving to 70% when the surgery model assumed full intestinal CYP3A4/5 recovery. This study highlights the utility of 4β-OHC/C for continuous monitoring of CYP3A4 activity and possibility to use biomarker-informed VT-PBPK models for individual dose requirements of intravenously administered CYP3A substrates in individuals with obesity over the course of weight loss treatment.
Does Next Generation Sequencing (NGS)-Based CYP2D6 Sequencing Improve Genotype-Phenotype Concordance in Tamoxifen-Treated Patients?
Petit J, Plenecassagnes J, Brice A … +5 more , Dalenc F, Mallet L, Chatelut E, Al Saati A, Thomas F
Clin Pharmacol Ther · 2026 Jun · PMID 42312965 · Publisher ↗
CYP2D6 metabolizes about 20% of commonly used drugs, including tamoxifen, a major hormone therapy for breast cancer. Although the relationship between tamoxifen pharmacokinetics and CYP2D6 genotype has been demonstrated,...
CYP2D6 metabolizes about 20% of commonly used drugs, including tamoxifen, a major hormone therapy for breast cancer. Although the relationship between tamoxifen pharmacokinetics and CYP2D6 genotype has been demonstrated, residual variability in drug exposure remains unexplained. Given the high genetic polymorphism of CYP2D6, including copy number variations and hybrid genes, targeted genotyping may fail to capture rare or complex alleles. To explore this limitation, 68 individuals from a cohort of tamoxifen-treated patients were selected based on discordance between CYP2D6 genotype determined by a targeted approach and phenotype assessed from pharmacokinetic data, and were analyzed using full-gene next-generation sequencing with in-house panel and bioinformatics pipeline. Full CYP2D6 gene sequencing refined genotypes in 41% of patients, and changed metabolizer status in 19%, mainly by detecting common alleles missed by the initial targeted assay. After removing these sources of discrepancy, sequencing improved diplotype assignment in 23.5% and metabolizer status classification in 7.4% of patients, largely driven by the detection of structural variants, with an additional contribution from the rare nonfunctional CYP2D6*62 allele, identified in one patient. In addition, several rare variants or variants of uncertain significance (including CYP2D6*22, *23, *28, p.Ala165Gly. and p.Pro264Thr) were identified and further evaluated using adapted in silico prediction strategies, compared with patients' phenotypes and published in vitro data. Comprehensive CYP2D6 sequencing improved gene profiling accuracy in our preselected cohort, while highlighting the remaining challenges of rare variant interpretation in pharmacogenetics-guided therapeutic drug monitoring.
Benchmark of Open-Access Star-Allele Callers to Accurately Assess Haplotypes and Phenotypes in Pharmacogenetic Studies.
Gros-La-Faige MB, Génin E, Herzig AF
Clin Pharmacol Ther · 2026 Jun · PMID 42312650 · Publisher ↗
Genetic polymorphisms are common in pharmacogenes, with sometimes important implications for drug metabolism. Assessing the correct enzyme phenotype from genetic data is thus a crucial step into the development of person...
Genetic polymorphisms are common in pharmacogenes, with sometimes important implications for drug metabolism. Assessing the correct enzyme phenotype from genetic data is thus a crucial step into the development of personalized medicine. Many bioinformatics star-allele callers have been developed for this purpose of identifying the correct star alleles and the associated phenotype, each of them having their specific method and limitations. Despite the important benchmarks that have been made so far, their performances have not yet been fully explored depending on various parameters, such as the type of genetic data provided as input or the individuals' ancestry. Hence, we provide a multi-gene, multi data-type comparison of the accuracy of four commonly used and open-access star-allele callers: PyPGx, ursaPGx, PharmCAT, and Aldy. We found that PyPGx and Aldy are overall more performant than the others, except for CYP2D6 where ursaPGx was the most accurate with its CYP2D6 dedicated caller that relies on the Cyrius software. Comparing to the commercial solution DRAGEN, PyPGx, and Aldy showed better results, except for CYP2D6 where DRAGEN performed best. When only SNP-chip or low-pass sequencing data is available, the use of imputation greatly improves the performance of star-allele callers, allowing performance comparable to that achieved with sequencing data. We also analyzed how concordance between star-allele callers varies depending on population ancestry. Our findings offer guidance on the choice of star-allele caller, depending on the pharmacogene being studied and the resolution of available genetic data.
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